Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. Most patients receiving ICIs, however, do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs. PATIENTS AND METHODS: The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched peripheral blood mononuclear cell (PBMC) plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis. RESULTS: In both discovery and validation cohorts, low ARG levels at baseline (<42 µM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased programmed death-ligand 1 expression in several immune cell subsets from the myeloid lineage. CONCLUSIONS: We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.

Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance.

BACKGROUND: Immune checkpoint blockers (ICBs) are now widely used in oncology. Most patients, however, do not derive benefit from these agents. Therefore, there is a crucial need to identify novel and reliable biomarkers of resistance to such treatments in order to prescribe potentially toxic and costly treatments only to patients with expected therapeutic benefits. In the wake of genomics, the study of proteins is now emerging as the new frontier for understanding real-time human biology. PATIENTS AND METHODS: We analyzed the proteome of plasma samples, collected before treatment onset, from two independent prospective cohorts of cancer patients treated with ICB (discovery cohort n = 95, validation cohort n = 292). We then investigated the correlation between protein plasma levels, clinical benefit rate, progression-free survival and overall survival by Cox proportional hazards models. RESULTS: By using an unbiased proteomics approach, we show that, in both discovery and validation cohorts, elevated baseline serum level of leukemia inhibitory factor (LIF) is associated with a poor clinical outcome in cancer patients treated with ICB, independently of other prognostic factors. We also demonstrated that the circulating level of LIF is inversely correlated with the presence of tertiary lymphoid structures in the tumor microenvironment. CONCLUSION: This novel clinical dataset brings strong evidence for the role of LIF as a potential suppressor of antitumor immunity and suggests that targeting LIF or its pathway may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICB.

Long-term outcomes and safety after reirradiation in locally recurrent nasopharyngeal carcinoma in a non-endemic area.

PURPOSE: To determine outcomes and toxicities after reirradiation for locally recurrent nasopharyngeal carcinoma (rNPC) and to apply a prognostic index in a non-endemic region. METHODS: We retrospectively reported progression-free survival (PFS), overall survival (OS), and treatment-related toxicities in patients treated with curative intent for locally rNPC. We applied the prognostic model for OS and grade 5 radiotherapy (RT)-related toxicities published by Li et al. and evaluated its prognostic accuracy by receiver operating characteristic (ROC) curve analysis. RESULTS: Between 2005 and 2018, 33 patients were treated for rNPC in our institution. Median follow-up was 60 months. The mean time to local recurrence was 75 months. Six (18%) patients had a persistent grade 3 toxicity from a previous RT course. The median re-RT dose was 66 Gy. After re-RT, 13 patients had local failure and 3 patients had metastatic recurrence. Median PFS was 18 months with a 5-year PFS rate of 29%. Median OS was 35 months with a 5-year OS rate of 37%. Grade 3 or higher toxicities rate was 74%. There were 21% grade 5 toxicities. The median time to a grade 5 toxicity was less than 6 months following re-RT. The prognostic nomogram was not predictive for OS or grade 5 toxicities. CONCLUSION: Reirradiation of rNPC is an effective treatment but is associated with a high rate of life-threatening toxicity. Stratification of patients based on their risk of developing severe toxicity is needed to select patients who will most likely benefit from re-RT.

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma.

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). PATIENTS AND METHODS: We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2. RESULTS: From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). CONCLUSIONS: Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Systemic therapies for salivary gland carcinoma (excluding adenoid cystic carcinoma): REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the therapeutic indications for systemic medical treatment in the management of salivary gland carcinoma (excluding adenoid cystic carcinoma) according to the clinical situation. MATERIALS AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group who drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: Salivary gland carcinoma is rare and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, initial management can be based on a phase of monitoring for indolent disease. Some histological subtypes (salivary duct carcinoma and adenocarcinoma) are more aggressive and require systemic treatment from the outset. To guide systemic treatment, it is recommended to perform immunohistochemistry and molecular biology analyses (overexpression of HER2 and androgen receptors, NTRK fusion, next-generation sequencing). CONCLUSION: Salivary gland carcinoma is a rare tumor for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.

Radiotherapy for salivary gland cancer: REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the indications for radiotherapy in salivary gland cancer and to specify the modalities and target radiation volumes. MATERIAL AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: Postoperatively, radiotherapy to the primary tumor site±to the lymph nodes is indicated if one or more of the following adverse histoprognostic factors are present (risk>10% of locoregional recurrence): T3-T4 category, lymph node invasion, extraglandular invasion, close or positive surgical margins, high tumor grade, perineural invasion, vascular emboli, and/or bone invasion. Intensity-modulated radiation therapy (IMRT) is the gold standard. For unresectable cancers or inoperable patients, carbon ion hadrontherapy may be considered. CONCLUSION: Radiotherapy in salivary gland cancer is indicated in postoperative situations in case of adverse histoprognostic factors and for inoperable tumors.

Systemic therapies for salivary gland cancer: Adenoid cystic carcinoma. REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the therapeutic indications for systemic medical treatment in the management of adenoid cystic carcinoma (ACC) according to the clinical situation. MATERIALS AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group, which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: ACCs are rare tumors and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, progression is often slow. In case of oligometastatic ACC, local treatment should be discussed. The most often indolent nature of polymetastatic ACC can allow management by active surveillance. Molecular screening is recommended, for abnormalities potentially accessible to targeted therapy. CONCLUSION: ACCs are rare tumors for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.

Treatment response in major depression: effects of personality dysfunction and prior depression.

BACKGROUND: The impact of personality dysfunction on the outcome of treatment for depression remains debated. AIMS: To examine the relationship between the number of prior depressive episodes, personality dysfunction and treatment response for depression. METHOD: In a large sample (n = 8229) of adult out-patients with a major depressive episode (DSM-IV), personality dysfunction was assessed using the Standardised Assessment of Personality - Abbreviated Scale (SAPAS). Potential predictors of treatment response at 6 weeks were examined via structural equation modelling. RESULTS: The amount of personality dysfunction and number of prior episodes of depression were both associated with poor response to treatment. Once personality dysfunction was controlled for, the number of prior episodes of depression was not associated with treatment response. CONCLUSIONS: Personality dysfunction is associated with impaired short-term response to antidepressant treatment in major depression. The apparent detrimental effect of prior depression on treatment response may be accounted for by pre-existing personality dysfunction.

[Antepartum depression: prevalence, diagnosis and treatment]. / La dépression de l'antepartum: prévalence, diagnostic, traitement.

INTRODUCTION: The occurrence of depression during pregnancy is a frequent situation that must be distinguished from postpartum depression. It raises many questions regarding its complications and therapeutic options. OBJECTIVES: To provide a systematic review of available data on prevalence, risk factors, and adverse outcomes of antepartum depression, as well as on screening tools and treatments currently available. METHODS: Studies, reviews, and meta-analyses were searched through the Pubmed and Embase databases. Articles related to postpartum depression or specifically focusing on bipolar disorder were excluded. EPIDEMIOLOGY: Prevalence is estimated between 5 and 15%. Risk factors, in addition to those of any depression, are an ambivalent attitude towards pregnancy, previous miscarriages, and medically-assisted or complicated pregnancies. Diagnosis and screening: No specific tool has yet been designed to diagnose or screen antepartum depression, but some scales (EPDS, PRIME-MD PHQ) have been validated. Adverse outcomes: For the mother, adverse outcomes are those of any depression, in addition to an increased risk of delivery complications and of postpartum depression. For the child, there is an increased risk for preterm birth, low birth-weight, and possibly sudden death. TREATMENTS: - Tricyclic antidepressants are widely described as safe during pregnancy. SSRIs show much reassuring data, even though recent studies have raised concerns about cardiac malformations and persistent pulmonary hypertension of the newborn. Electroconvulsive therapy is only indicated in the most severe cases but appears secure under specific safety measures. Most psychotherapies have not been specifically assessed during pregnancy. Other treatments (bright light therapy, rTMS…) have shown some promising but not robust results. CONCLUSION: Antepartum depression is frequent, and potentially severe if not treated. Validation of specific screening tools is warranted. Pharmacological treatment should not be postponed in cases of severe depression. Regarding moderate depressions, it appears reasonable to turn to non-pharmacological treatments, primarily psychotherapies, which therefore should be more thoroughly studied.

[Adjuvant irradiation in breast cancer patients with ATM gene heterozygous mutations: special focus on clinical efficacy/toxicity]. / Toxicité et efficacité de la radiothérapie adjuvante chez les patientes traitées pour un cancer du sein et porteuses d'une mutation hétérozygote du gène de l'ataxie-télangiectasie.

Dysfunction of the ataxia telangiectasia mutated (ATM) gene has been related to defective cell cycle control and genomic instability due to the impaired repair of DNA double strand breaks. Although increased radiosensitivity in ATM heterozygous patients has been suggested in preclinical data, clinical implication of ATM variant remains debated. Despite frequent in vitro hypersensitivity in patients with severe radiation-induced delayed toxicity, heterozygoty for ATM gene does not represent the major cause of unexpected complications after radiation therapy. This might be partially due to potential coexistence of alterations in additional genes that would play a role in development of late radiation-induced adverse response. Although several data suggest that some ATM polymorphisms would increase grade 3 subcutaneous fibrosis at lower doses compared with patients who did not possess these genetic alterations, the relationship between the presence of ATM mutations or sequence variants and radiation-induced toxicity remains controversial in part because of their biological and functional significance. Considering the lack of prospective data, patients with ATM mutation should be considered as candidates for both dose volume and dose reduction clinical trials.

[New developments in the management of nasopharyngeal carcinoma]. / Nouveautés dans la prise en charge des carcinomes nasopharyngés.

Nasopharyngeal carcinoma is a rare condition, with less than 300 cases occurring per year in France. Its treatment can be difficult due to the importance of side effects, but tumor control is usually excellent following a well conducted chemoradiotherapy. This article summarizes the recent advances in nasopharyngeal cancer diagnosis, classification, treatment, surveillance and management of recurrences. Chemotherapy timing is discussed, along with arguments in favor of induction chemotherapy in locally advanced cases. As a survival advantage has been suggested for when patients are treated in high volume center it seems reasonable to refer these young patients for treatment to tertiary expert centers, especially given the low incidence of the disease.

[Validity of vascular depression as a specific diagnostic: a review]. / Validité du concept de dépression vasculaire: une revue de la littérature.

INTRODUCTION: A number of authors have suggested that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. These "vascular depressions" may result from damage of striato-pallido-thalamo-cortical pathways which frequently occurs in cerebrovascular disease. METHOD: We have searched the English and French literature published between 1996 (when the "vascular depression" hypothesis was first stated) and December 2004 through the Medline computer database and examined the validity of the concept of "vascular depression" thanks to four levels of validity: face validity, descriptive validity, construct validity and predictive validity. The face validity is the extent to which experts agree about the existence of a nosological entity. RESULTS: The reviews published in this field broadly support the concept of "vascular depression" as a specific disorder. However many authors highlighted the fact that depression has been shown to precede vascular diseases and that depression and vascular diseases may both share some pathogenic or genetic determinants. These interactive and co-morbid relationships between depression and cerebrovascular diseases are difficult to disentangle. The descriptive validity refers to the degree of the clinical specificity of a disorder. It appears only moderate regarding the clinical studies carried out on this issue. However, a late-onset, the absence of a family history of mental illness, the lack of insight, lassitude, psychomotor retardation, a greater disability and particular neuropsychological dysfunctions may be associated with vascular depression. The construct validity, which refers to the degree to which the physiopathological processes involved in an illness are understood, appears difficult to establish because of the complex interactive relationships between cerebrovascular disease and depression. However, cerebrovascular diseases may contribute to the occurrence of depressive symptoms independently of its psychosocial burden. The predictive validity refers to the degree to which a syndrome is characterized by a specific response to treatment or a specific natural history. As regards response to treatment, vascular depression appears rather specific in the sense of a worse response to antidepressants and electroconvulsive therapy. The studies on the natural history of vascular depression lead to inconsistent results. According to some authors, this relative resistance to treatment may be explained by structural rather than functional, and thus potentially irreversible disruption in neural networks. CONCLUSION: In conclusion, the systematic review of the validity of vascular depression broadly supports this concept. However, further studies are needed to decipher the relationships between depression and cerebrovascular disease. Finally, we suggest that it could be more relevant for future researches in this field if the diagnostic criteria for vascular depression were narrowed and required the presence of both neuro-imaging changes and cerebrovascular disease.

[Frontotemporal dementia: a review]. / La démence frontotemporale: revue de la littérature.

CLINICAL CHARACTERISTICS: Frontotemporal dementia (FTD) is a neurological disorder characterised by the progressive degeneration of the frontal and anterior temporal cortex. FTD, as well as nonfluent progressive aphasia and semantic dementia, belongs to the more generic entity of frontotemporal lobe degeneration. Considering the involvement of the frontal lobe, the initial clinical presentation of FTD may be psychiatric, such as changes in personality or behavioural disorders. Psychiatrists, therefore, have to establish the differential diagnosis with late-onset schizophrenia or affective disorders. An accurate history of the onset of symptoms, thanks to the patient and especially to his/her family, is essential to recognize this dementia. In addition to behavioural changes, memory impairment, and speech disturbances are often present from the beginning. Consensus criteria have been proposed in 1998 that help to bring this diagnosis to mind in clinical practice. The progressive occurrence of personality changes or inappropriate social conducts in the fifth or sixth decade must prompt cognitive evaluation. NEUROCOGNITIVE AND BRAIN IMAGING DATA: A brief cognitive evaluation, such as the frontal assessment battery (FAB) may help to identify a dysexecutive syndrome and to prompt a thorough neuropsychological evaluation. The pattern of neuropsychological impairment reflects the involvement of the frontal lobe and appears different from that of other degenerative diseases, such as Alzheimer's dementia, which involves hippocampal damage. Additional investigations should however be made to detect a potentially curable dementia. Cerebral imaging is essential to the differential diagnosis and also shows evidence for the positive diagnosis of FTD. Structural MRI may initially not show the bilateral atrophy of the frontal lobe, but functional imaging may be helpful in the early stages of the illness by showing evidence of abnormalities in the anterior cerebral hemisphere. PATHOPHYSIOLOGICAL FINDINGS: In recent years, significant advances in the understanding of the pathological characteristics of FTD were made with genetic contribution, especially the discovery of the tau protein involvement. In fact, neuropathological examination with immunohistochemical analysis defines Pick's disease with Pick bodies that belong to tauopathies. Ubiquitinated intraneuronal inclusions may also be found, and some types of FTD have no distinctive pathological feature. However, although a definite diagnosis would only be established after postmortem pathological examination, the clinical, neuropsychological and imaging data enable the early identification of patients with FTD and, subsequently, the appropriate management. THERAPEUTICS: Although the prevalence of FTD reaches 1 Alzheimer's disease (AD) to 1.6 FTD in the general population between 45- and 64-year old, only few studies have focused on the treatment of FTD. Some evidence supports the positive effect of serotonergic agents, especially with regard to behavioural symptoms. Selective serotonin reuptake inhibitors or trazodone should therefore be prescribed in preference to acetylcholinesterase medications as in AD. However, no drug yet has the ability to stop or slow down the degenerative process. The management of daily life also bears specificities related to the younger age of these patients and to their behavioural disorders. Caregivers should receive some education about the characteristics of this dementia and should be helped in social management. As concerns aggressive behaviour, neuroleptics should generally be avoided because of poor tolerance. Finally, the outcome is characterized by a rapid loss of autonomy and sometimes by a premature institutionalisation.

Long-term response in patient with recurrent oropharyngeal carcinoma treated with cetuximab, docetaxel and cisplatin (TPEx) as first-line treatment followed by cetuximab maintenance.

BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody in combination with platinum and 5FU is the standard of care in first-line treatment of patients with recurrent head and neck squamous cell carcinoma (HNSCC), with an expected median outcome of 10months. For this population, development of efficacious and safer therapies is still needed. CASE REPORT: A 62-year-old male with a first recurrence of human papillomavirus positive stage IVA (T3N2bM0) adenocarcinoma of the glossotonsillar sulcus not amenable to locoregional curative treatment was offered chemotherapy as part of the TPEx clinical trial. He was treated by cetuximab (loading dose 400mg/m2 on day 1 cycle 1, then 250mg/m2 weekly), and chemotherapy (cisplatin 75mg/m2 and docetaxel 75mg/m2, on day 1). Cycles were repeated every 21days for 4 cycles (TPEx regimen) with systematic granulocyte colony-stimulating factor support at each cycle. Bi-monthly maintenance cetuximab 500mg/m2 was then administered. The patient showed a clinical complete response according to RECIST 1.1 criteria after 5months maintenance, with progression-free survival of 25months. Relapses that followed were treated with stereotactic irradiation, radiofrequency ablation, cetuximab and paclitaxel. The patient is alive eleven years after cancer diagnosis and remains controlled for his disease, with a cumulative period of 59months of cetuximab administration (equivalence of 121 injections). CONCLUSION: This case report demonstrated that TPEx regimen, by synergistic interaction between taxanes and cetuximab, followed by bimonthly cetuximab maintenance may lead to patient complete remission within the first year of treatment. Furthermore, prolonged intermittent treatment with cetuximab seems to participate in the improved survival associated with preserved quality of life. Key favorable prognostic factors may be moderate tumor differentiation, oropharyngeal location, HPV p16 positive tumor status.