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BACKGROUND AND AIMS: The combination of atezolizumab plus bevacizumab (Atz/Bev) has radically changed the treatment strategy for advanced hepatocellular carcinoma (HCC) but raises questions. Our objectives were to determine survival outcomes and safety in a real-life multicenter French cohort, to investigate the on-treatment prognostic value of the bioinflammatory RECA score, and to perform a matched comparison with patients who previously received tyrosine kinase inhibitors (TKIs). METHODOLOGY: A retrospective analysis of 109 consecutive patients enrolled from September 2020 to January 2023 and a post matched comparison with a TKI cohort (nâ =â 79) by the propensity score matching method. RESULTS: The Atz/Bev population was mainly nonviral disease patients (69%) with Child-Pugh grade A (90%), performance status 0/1 (90%), and Barcelona Clinic Liver Cancer stage B (38%) or stage C (62%) classification. After a median follow-up of 6.5â months (3.6-11.7), overall survival (OS) was 13.0 (5.1-28.7)â months. OS was independently associated with metastasis, increased alkaline phosphatase, and serum bilirubin levels. Treatment-related adverse events were reported in 78% of patients, mostly grade 1 or 2. The RECA score clearly revealed two different prognosis groups after three cycles. No difference in OS was observed after matching between sequential treatment with TKIs and Atz/Bev. CONCLUSION: This real-life study highlights the importance of liver function when using Atz/Bev combination and the necessity of identifying predictive markers of response to HCC therapies. Our findings suggest a change in practices, with a marked proportion of intermediate stages, and support the on-treatment prognostic value of an inflammatory score.
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BACKGROUND: Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile. AIMS: The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab. METHODS: This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5. DISCUSSION: PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Combinação de Medicamentos , Junção Esofagogástrica , Fluoruracila , Leucovorina , Nivolumabe , Pirrolidinas , Neoplasias Gástricas , Timina , Trifluridina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Estudos Prospectivos , Trifluridina/administração & dosagem , Trifluridina/uso terapêutico , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Pirrolidinas/administração & dosagem , Pirrolidinas/uso terapêutico , Feminino , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Receptor ErbB-2/metabolismo , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Adulto , Idoso , Estudos Multicêntricos como AssuntoRESUMO
Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized squamous cell carcinoma of the anal canal (SCCAC), this treatment has been considered as an acceptable alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in chemoradiation therapy (CRT) with simultaneous integrated boost (SIB) radiation therapy (SIB-IMRT) for local SCCAC are not well documented. Patients included in this prospective monocentric cohort study were treated with SIB-RapidArc (a unique RT method treatment for all patients: identical technique, volume and constraints for at-risk organs), mitomycin C and 5-FU each day of RT for 7 weeks (group 1) or capecitabine each day of RT (group 2). Patients treated between July 2009 and August 2017 (group 1) and between November 2012 and April 2018 (group 2) for local SCCAC T2-4 classified as N, M0 or T, N1-3, M0 were included. Primary endpoints were progression-free survival (PFS) and acute toxicities. Results: One hundred forty-seven patients were included, 91 in group 1 and 56 in group 2. The two groups were statistically comparable in terms of sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and TNM. With a median duration of follow-up of 53.5 months, the PFS rate at 3 years was 80% for group 1 and 75% for group 2 (p = 0.32). The 3-year colostomy-free survival rate was 92% for group 1 and 85% for group 2 (p = 0.11). The rate of patients with at least one grade 3 or higher acute toxicity was 35.5% in group 1 and 21.4% in group 2 (p = 0.10), with a trend of fewer acute toxicities with capecitabine. Conclusion: Capecitabine/mitomycin in combination with SIB RapidArc radiation therapy for anal cancer seems as effective as 5-FU-based chemotherapy and is well tolerated with minimal toxicity.
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Neoplasias do Ânus , Radioterapia de Intensidade Modulada , Humanos , Mitomicina/uso terapêutico , Capecitabina/uso terapêutico , Fluoruracila/uso terapêutico , Estudos de Coortes , Estudos Prospectivos , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapiaRESUMO
Importance: Only 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting. Objectives: To determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC. Design, Setting, and Participants: The SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis. Interventions: Patients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal. Main Outcome and Measures: The primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population). Results: A total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months. Conclusions: The SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03186326.
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BACKGROUND: The optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma (OGA) remains challenging. METHODS: Patients treated with trastuzumab (T) plus platinum salts and fluoropyrimidine (F) as first-line chemotherapy between 2010 and 2020 for HER2-positive advanced OGA at 17 academic care centers in France, Italy, and Austria were included. The primary objective was the comparison of F + T vs T alone as maintenance regimen in terms of progression-free survival (PFS) and overall survival (OS) after a platinum-based chemotherapy induction + T. As secondary objective, PFS and OS between patients treated with reintroduction of initial chemotherapy or standard second-line chemotherapy at progression were assessed. RESULTS: Among the 157 patients included, 86 (55%) received F + T and 71 (45%) T alone as a maintenance regimen after a median of 4 months of induction chemotherapy. Median PFS from start of maintenance therapy was 5.1 months in both groups (95% CI 4.2-7.7 for F + T and 95% CI 3.7-7.5 for T alone; p = 0.60) and median OS was 15.2 (95% CI 10.9-19.1) and 17.0 months (95% CI 15.5-21.6) for F + T and T alone, respectively (p = 0.40). Of 112/157 patients (71%) receiving systemic therapy after progression under maintenance, 26/112 (23%) were treated with a reintroduction of initial chemotherapy + T and 86/112 (77%) with a standard second-line regimen. Here, median OS was significantly longer with the reintroduction (13.8 (95% CI 12.1-19.9) vs 9.0 months (95% CI 7.1-11.9); p = 0.007) as confirmed by multivariate analysis (HR 0.49; 95% CI 0.28-0.85; p = 0.01). CONCLUSION: No additional benefit of adding F to T monotherapy as a maintenance treatment could be observed. Reintroduction of initial therapy at first progression may be a feasible approach to preserve later treatment lines.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Quimioterapia de Indução , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica , Trastuzumab/uso terapêuticoRESUMO
Extra-cellular galectins 1, 3 and 9 (gal-1, -3 and -9) are known to act as soluble immunosuppressive agents in various malignancies. Previous publications have suggested that their expression is dependent on the metabolic status of producing cells and reciprocally that they can influence metabolic pathways in their target cells. Very little is known about the status of gal-1, -3 and -9 in patients bearing head and neck squamous cell carcinomas (HNSCC) and about their relationships with the systemic metabolic condition. This study was conducted in plasma samples from a prospective cohort of 83 HNSCC patients with advanced disease. These samples were used to explore the distribution of gal-1, -3 and -9 and simultaneously to profile a series of 87 metabolites assessed by mass spectrometry. We identified galectin and metabolic patterns within five disease categories defined according to the primary site and human papillomavirus (HPV) status (HPV-positive and -negative oropharyngeal carcinomas, carcinomas of the oral cavity, hypopharynx and larynx carcinomas). Remarkably, samples related to hypopharyngeal carcinomas displayed the highest average concentration of gal-9 (p = .017) and a trend toward higher concentrations of kynurenine, a potential factor of tumor growth and immune suppression. In contrast, there was a tendency toward higher concentrations of fatty acids in samples related to oral cavity. These observations emphasize the diversity of HPV-negative HNSCCs. Depending on their primary site, they evolve into distinct types of immune and metabolic landscapes that seem to be congruent with specific oncogenic mechanisms.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Hipofaríngeas , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Estudos Prospectivos , GalectinasRESUMO
BACKGROUND: Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available. AIM: To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time. METHODS: A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups. RESULTS: Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors. CONCLUSION: This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.
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BACKGROUND: Prognosis of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) remains poor. The addition of cetuximab, to platinum and fluorouracil chemotherapy (EXTREME regimen) has been shown to improve patients' outcomes in first-line settings. METHODS: We conducted a retrospective, multicenter study, including HNSCC that progressed after a first line of platinum-based chemotherapy and cetuximab, treated either by paclitaxel + cetuximab (PC) or paclitaxel alone (P), between January 2010 and April 2018. The end points were overall survival (OS), progression-free survival (PFS), and overall response rates (ORR). Patients were matched according to their propensity scores, estimated with a logistic regression model. The secondary objectives were to study the safety profile and to look for prognostic and predictive factors of effectiveness. RESULTS: Of the 340 identified patients, 262 were included in the analysis, 165 received PC, and 97 received P. In unmatched population, ORR was 16.4% with PC and 6.2% for P. Median PFS was 2.9 months [95% Confidence Interval 2.7-3.0] for PC versus 2.5 months [2.2-2.7] for P, hazard ratio (HR) = 0.770 [0.596-0.996]. Median OS was 5.5 months [4.4-6.9] for PC versus 4.2 months [3.4-4.8] for P, HR = 0.774 [0.590-1.015]. In multivariate analysis, PC was associated with better PFS and OS. These results were consistent in matched-paired population. Previous cetuximab maintenance for more than 3 months was predictive of better OS with PC. CONCLUSION: Although the continuation of cetuximab in combination with paclitaxel after EXTREME provides moderate benefit, it could be an interesting option for selected patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Intervalos de Confiança , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Compostos de Platina/uso terapêutico , Intervalo Livre de Progressão , Pontuação de Propensão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10â¯mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12â¯vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.