Occupational asbestos exposure and survival among lung cancer patients.

OBJECTIVE: This study investigated the association between occupational asbestos exposure (OAE) and survival in patients with histologically confirmed lung cancer (LC). METHODS: This monocentric study was conducted in the Comprehensive Cancer Centre Léon Bérard, Lyon, France. A systematic screening has been in place since 2014 for occupational exposure to carcinogens using a self-assessment questionnaire sent to all patients newly diagnosed with histologically confirmed LC identified through the multidisciplinary LC board from 2014 to 2019. When the physician suspected a work-related exposure from the questionnaire including job history, an occupational cancer consultation was carried out to detail carcinogen exposures and assess if the LC was work-related. Demographics, clinical characteristics and survival data were extracted from medical records. The association between asbestos exposure and overall survival (hazard ratio and 95% confidence intervals) was estimated by Cox proportional hazards regression. RESULTS: Overall, 702 patients were eligible to the present study, including 180 patients with OAE. In the crude analysis, LCs assessed as moderately or highly attributable to OAE were associated with decreased overall survival (HR = 1.32, 95 %CI 1.04-1.67) compared to LC without OAE or with a low degree of imputability to OAE (median follow-up 28.8 months). After adjustment for confounding (age at diagnosis, smoking status, stage, brain metastasis at diagnosis, and histology), the association of OAE with overall survival was no longer statistically significant (HR = 1.21, 95 %CI 0.94-1.56). CONCLUSION: Overall survival in occupationally asbestos exposed LC patients may be decreased in comparison with non-exposed LC patients, warranting further investigations in larger studies.

Real World Data of Diagnosis, Survival, and Treatment Outcomes in Patients With Metastatic Non Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Metastatic non clear cell renal cell carcinoma (nccRCC) is an heterogenous group, usually excluded from phase 3 trials. We report real life data of prognosis and systemic management of those patients. METHODS: We retrospectively included 102 metastatic nccRCC patients (unspecified papillary, n = 10; type 1 and 2 papillary n = 10 and n = 32; translocation RCC, n = 9; chromophobe, n = 14; collecting duct, n = 14) treated between 2006 and 2020. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Among patients who underwent pathological review, 40.8% presented a complete histological discordance. First line treatments were mainly tyrosine kinase inhibitor (60.8%), combination including immunotherapy (7.8%) or combination of chemotherapy (13.7%). Median ORR ranged from 0% in unspecified papillary RCC to 42.9% in type 1 papillary RCC. Median PFS ranged from 2.9 months in collecting duct carcinoma to 10.9 months in type 1 papillary RCC. Median OS ranged from 6.8 months in collecting duct carcinoma to 29.1 months in MiT family translocation RCC. Thirty (29.4%) patients were included in a treatment trial during their treatment course. CONCLUSION: Metastatic nccRCC patients have variable prognosis due to heterogeneity of histological subtypes. Their diagnosis and access to therapeutic innovation remain suboptimal. Dedicated prospective trials are needed.

An open label, non-randomised, phase IIIb study of trametinib in combination with dabrafenib in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: A subgroup analysis of patients with brain metastases.

BACKGROUND: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T). PATIENTS AND METHODS: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05. RESULTS: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors. CONCLUSION: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

Cemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group.

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.

BACKGROUND: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. METHODS: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. RESULTS: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively. CONCLUSIONS: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

PURPOSE: Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group). METHODS: It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death. RESULTS: 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]). CONCLUSIONS: Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.

Clinical and histological characteristics, and management of melanoma in French Guiana, 2007-2018.

There are few studies available on melanoma in Afro-Caribbean and Amerindian populations of South America. French Guiana deserves a study due to its specific health system and diversity of phototypes. The objectives of this study were to evaluate the incidence, histological and clinical characteristics of melanoma in French Guiana. A retrospective study was conducted from October 2007 to January 2018 on all primary melanomas observed at the Cayenne Hospital Centre. Thirty-nine patients were included. The incidence rate (1.61/106 inhabitants/year) was low compared with mainland France. Median age was 58, and gender ratio 1 : 16. Clear phototype (I/II) patients were the most frequent (38.5%), but a significant amount of melanoma also occurred in darker skin. Median Breslow was higher in dark phototypes than in fair-skinned patients. Superficial spreading melanoma (SSM) was the most common histological type (33.3%), particularly in patients with clear phototype (61.5%). Acral lentiginous melanoma was found only in darker-skinned patients (29.1%). The trunk was involved in 66.6% in the clearest group whereas foot was the most common location in the darkest group (60% in V/VI phototypes). Surgery was the most frequently used treatment (79.5%). At the end of the study period, 53.8% had been lost to follow-up. In conclusion, the incidence of melanoma in French Guiana is lower than in mainland France but remains a public health concern, as dark-skinned populations often present with advanced diseases. Awareness and prevention in these communities must be improved.

Induction chemotherapy in head and neck cancers: Results and controversies.

Standard treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) consists mainly of concurrent chemoradiation (CCR) but induction chemotherapy (IC) by docetaxel-cisplatin-fluorouracil (TPF), followed by CCR, is a strong option. Comparative trials suggest that IC and CCR are equivalent, and some trials suggest superiority of IC, whereas none shows inferiority. IC might have less interest in oropharyngeal cancer (more often linked to HPV infection). When functional laryngeal preservation is the patient's priority, essays strongly suggest that IC is the best treatment. There is little data about a less toxic regimen of IC, but several schemes are promising and need to be developed. An early selection of responders to IC by metabolic imaging must be considered. Intensification attempts with cetuximab were too toxic and unsafe, but trials with immunotherapy are ongoing to enhance TPF efficacy. After IC, CCR either with cetuximab or cisplatin seems to be equally effective.

Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Question of Belief.

Induction chemotherapy (IC) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) has been used for decades. However, its role is yet to be clearly defined outside of larynx preservation. Patients with high risk of distant failure might potentially benefit from sequential treatment. It is now widely accepted that TPF (docetaxel, cisplatin, and fluorouracil) is the standard IC regimen. Essays that have compared this approach with the standard of care, concurrent chemoradiotherapy (CCRT), are mostly inconclusive. Radiotherapy (RT) can be used in the post-IC setting and be sensitized by chemotherapy or cetuximab. Again, no consensus exists but there seems to be trend in favor of potentiation by cisplatin. Less toxic schemes of IC are tested as toxicity is a major issue with TPF. IC might have an interesting role in human papilloma virus (HPV)-related LA HNSCC and lead to CCRT de-escalation.

Carboplatin in combination with weekly Paclitaxel as first-line therapy in patients with recurrent/metastatic head and neck squamous cell carcinoma unfit to EXTREME schedule.

The standard first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma combines Cisplatin, 5 Fluorouracil and Cetuximab, but many patients aren't eligible. We retrospectively evaluated the efficacy and the tolerability of Carboplatin and Paclitaxel in this indication, mostly in patients unfit to Cisplatin. Paclitaxel (80mg/m2) was administered at day 1, 8 and 15 and Carboplatin area under the curve 5 at day 1, repeated every 28 days, for 6 cycles. Carboplatin could be administered at area under the curve 2 at day 1, 8 and 15. 117 patients received this association at our institution, 94 of those were ineligible to cisplatin due to severe comorbidities, age >70years or Performance status >1. The overall response rate was 40%. The median progression free survival for patients ineligible to Cisplatin was 4.4 months [95% CI; 3.4; 5.0] and the median overall survival was 8 months [95% CI; 5.4-10.7]. The most frequent toxicities were hematologic, with 94 grade ≥ 3, mostly in patients who received monthly Carboplatin. Our study shows Carboplatin and Paclitaxel in first-line in recurrent/metastatic head and neck squamous cell carcinoma appear efficient for patients ineligible to Cisplatin and safe when both drugs are weekly administered.

L'immunothérapie dans les cancers ORL.

IMMUNOTHERAPY IN HEAD AND NECK CANCERS: Immunotherapy wave has also touched head and neck cancer. In recurrent or metastatic disease, checkpoint inhibitors (anti PD-1/PD-L1) are approved in 2nd line with a clear benefit on overall survival and quality of life. Multiple clinical studies are in progress in both palliative and curative intent, combined or not with other checkpoint inhibitor (anti-CTLA4) or other standard therapies (radiotherapy, chemotherapy). It is essential to define which patients will benefit from immunotherapy, according to robust biomarkers, in order to increase risk benefit balance by decreasing side effects and selecting those who respond the most. Here we present an overview of immunotherapy in 2018 in head and neck squamous cell cancer.

Cabazitaxel in recurrent/metastatic squamous cell carcinoma of the head and neck: phase II UNICANCER trial ORL03.

Treatments are limited after platinum Cetuximab or anti-PD1 failure for patients with recurrent/metastatic head and neck squamous cell carcinoma. Cabazitaxel has increased overall survival in hormone-refractory metastatic prostate cancer after failure of Docetaxel. Our aim was to detect a signal of activity with Cabazitaxel in patients with head and neck cancer who had failed platinum-, Cetuximab- and taxanes-based chemotherapy. This multicenter phase II trial included progressive patients with an ECOG ≤2. Cabazitaxel was given at 25 mg/m2/3 weeks (maximum of 10 cycles), with growth factors support. Efficacy was centralized and assessed every 6 weeks. The primary endpoint was control rate at six-weeks. A Simon's two-stage optimal design (P0=0.10; P1=0.30) required 29 evaluable patients. At the end of trial, at least 6 non-progressions were required to consider the drug worthy of further study. Out of the 31 enrolled patients, 29 were eligible; 42% had received at least three previous lines of chemotherapy. For the primary end point, 8 patients (27.6%; 95%CI 12.7%-47.2%) had a stable disease at six weeks. Median progression-free survival was 1.05 months (95%CI 0.69-2.07). All patients were analyzed for toxicity: 6 patients had febrile neutropenia. During the 81 cycles administered, 49 grade 3-5 events were observed concerning 81% of the patients, including 35 severe adverse events of which 15 were related to Cabazitaxel. Although Cabazitaxel met its primary endpoint to deserve further investigations, its toxicity makes it difficult to use in frail patients and new schemes are needed (20 mg/m2 for example) if further investigations are launched.

Chemotherapy for recurrent/metastatic head and neck cancers.

Chemotherapy is the only option of treatment for most patients presenting with a recurrent and/or metastatic head and neck squamous cell carcinoma. The triple association of cisplatin, 5-fluorouracile, and cetuximab is still the current standard for fit patients. Other schemes are currently being compared with this protocol in ongoing trials and the association of cisplatin, docetaxel, and cetuximab appears to be the most efficient. The human papilloma virus is very likely a favorable prognostic factor. Immunotherapy with nivolumab or pembrolizumab is now a new standard of treatment in second line after yielding an improvement in overall survival, but predictive markers of efficacy are needed to refine the selection of patients. The combination of paclitaxel and buparlisib appears to be promising.

Chemotherapy for localized head and neck squamous cell cancers.

Concomitant chemotherapy with cisplatin (100 mg/m every 3 weeks) improves outcome for high-risk patients in the postoperative setting and for inoperable disease. Toxicity is increased. Other schemes of potentiation are sometimes used to reduce toxicity, but efficiency is diminished. Cetuximab also improves outcome, but there has been no direct comparison with cisplatin. Immunotherapy is currently being evaluated in association with radiation therapy. Trials are ongoing to evaluate the impact of de-escalation for human papillomavirus-positive patients. The association of docetaxel, cisplatin, and 5-fluorouracil is the standard of induction; it is also the standard treatment for laryngeal preservation. Many trials have attempted to compare the concomitant approach with the sequential treatment; none have managed to show a difference between the two. After induction chemotherapy, there is still no standard of potentiation of radiotherapy.

Neoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: a study of 48 patients.

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.

Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma.

PURPOSE: gamma9delta2 T lymphocytes have been shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes T gammadelta can be selectively expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2). A phase I Study was conducted in patients with metastatic renal cell carcinoma (mRCC) to determine the maximum-tolerated dose and safety of Innacell gammadelta, an autologous cell-therapy product based on gamma9delta2 T lymphocytes, in patients with mRCC. EXPERIMENTAL DESIGN: A 1-h intravenous infusion of gamma9delta2 T lymphocytes was administered alone during treatment cycle 1 and combined with a low dose of subcutaneous interleukin-2 (IL-2, 2 MIU/m2 from Day 1 to Day 7) in the two subsequent cycles (at 3-week intervals). The dose of gamma9delta2 T lymphocytes was escalated from 1 up to 8 x 10(9) cells. RESULTS: Ten patients underwent a total of 27 treatment cycles. Immunomonitoring data demonstrate that gamma9delta2 T lymphocytes are initially cleared from the blood to reappear at the end of IL-2 administration. Dose-limiting toxicity occurred in one patient at the dose of 8 x 10(9) cells (disseminated intravascular coagulation). Other treatment-related adverse events (AEs) included mainly gastrointestinal disorders and flu-like symptoms (fatigue, pyrexia, rigors). Hypotension and tachycardia also occurred, especially with co-administered IL-2. Six patients showed stabilized disease. Time to progression was 25.7 weeks. CONCLUSION: The data collected in ten patients with mRCC indicate that repeated infusions of Innacell gammadelta at different dose levels (up to 8 x 10(9) total cells), either alone or with IL-2 is well tolerated. These results are in favor of the therapeutic value of cell therapy with Innacell gammadelta for the treatment of cancers.