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1.
Lancet Oncol ; 25(4): 518-528, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38547895

RESUMO

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Docetaxel , Cisplatino/efeitos adversos , Fluoruracila/efeitos adversos , Antígeno B7-H1 , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Ânus/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
Br J Cancer ; 130(5): 769-776, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38184691

RESUMO

BACKGROUND: Standard care for non-metastatic squamous cell carcinoma of the anus (SCCA) is chemoradiotherapy, data about elderly patients are scarce. METHODS: All consecutive patients treated for non-metastatic SCCA from the French multicenter FFCD-ANABASE cohort were included. Two groups were defined according to age: elderly (≥75 years) and non-elderly (<75). RESULTS: Of 1015 patients, 202 (19.9%) were included in the elderly group; median follow-up was 35.5 months. Among the elderly, there were more women (p = 0.015); frailer patients (p < 0.001), fewer smokers (p < 0.001) and fewer HIV-infected (p < 0.001) than in the non-elderly group. Concomitant chemotherapy and inguinal irradiation were less frequent (p < 0.001 and p = 0.04). In the elderly group; 3-year overall survival (OS), recurrence-free survival (RFS) and colostomy-free survival (CFS) were 82.9%, 72.4% and 78.0%, respectively; complete response rate at 4-6 months was 70.3%. There were no differences between groups for all outcomes and toxicity. In multivariate analyses for the elderly, PS ≥ 2 and locally-advanced tumors were significantly associated with poor OS (HR = 3.4 and HR = 2.80), RFS (HR = 2.4 and HR = 3.1) and CFS (HR = 3.8 and HR = 3.0); and treatment interruption with poor RFS (HR = 1.9). CONCLUSION: In the FFCD-ANABASE cohort, age did not influence tumor and tolerance outcomes of non-metastatic SCCA. Optimal curative treatment should be offered to elderly patients.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Quimiorradioterapia/efeitos adversos , Estudos Prospectivos , Estudos Multicêntricos como Assunto
3.
Oncologist ; 25(2): e266-e275, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043796

RESUMO

BACKGROUND: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting. MATERIALS AND METHODS: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR). RESULTS: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007). CONCLUSION: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF. IMPLICATIONS FOR PRACTICE: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.


Assuntos
Anticorpos Monoclonais , Neoplasias Colorretais , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila/uso terapêutico , Humanos , Masculino , Estudos Retrospectivos
4.
BMC Cancer ; 20(1): 352, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334548

RESUMO

BACKGROUND: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. METHODS: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy. DISCUSSION: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA. TRIAL REGISTRATION: NCT03519295.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
5.
Rev Prat ; 69(3): 311-317, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30983261

RESUMO

Canal anal carcinoma. Anal carcinomas are rare, but their incidence has increased in recent years. They are induced by the Human papillomas virus (mostly genotype 16). The prevalence is high among HIV-infected men who have sex with men (MSM) and primary prevention by vaccination against HPV is a source of hope in this population. Screening is based on the detection and treatment of precancerous lesions, called anal intra-epithelial neoplasia, which can be of low grade or high grade. It concerns a category of HIV-infected patients: MSM, history of condyloma or precancerous/cancerous lesions of the cervix. Treatment, based on a combination of simultaneous chemotherapy and radiation therapy, allows a complete response rate of 80%. In case of persistence or tumor recurrence, abdominoperineal resection remains the treatment of choice. Advanced diseases can benefit from highly effective chemotherapy combinations or even in the future, combination of chemotherapy and immunotherapy.


Carcinomes du canal anal. Les carcinomes anaux sont des tumeurs rares, dont l'incidence a augmenté durant les dernières années. Ils sont viro-induits par le human papillomavirus [HPV) [génotype 16 essentiellement]. La prévalence est élevée chez les hommes homosexuels infectés par le virus de l'immunodéficience humaine (VIH), dont la prévention primaire par vaccination anti-HPV constitue une source d'espoir. Le dépistage repose sur la détection et le traitement des lésions précancéreuses : néoplasies intraépithéliales anales qui peuvent être de bas grade ou de haut grade, chez une certaine catégorie de patients séropositifs pour le VIH : homme ayant des relations sexuelles avec les hommes, antécédents de condylome ou de lésion tumorale cervicale utérine. Le traitement, fondé sur une association de chimio- et de radiothérapie concomitantes permet une rémission complète dans 80 % des cas. En cas de persistance ou de récidive tumorale, l'amputation abdomino-pelvienne reste le traitement de choix. Les maladies avancées peuvent bénéficier de combinaisons de chimiothérapies très efficaces, voire dans le futur de combinaisons de chimiothérapie et d'immunothérapie.


Assuntos
Neoplasias do Ânus/virologia , Infecções por HIV , Homossexualidade Masculina , Infecções por Papillomavirus , Canal Anal , Neoplasias do Ânus/epidemiologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Masculino , Recidiva Local de Neoplasia , Prevalência , Minorias Sexuais e de Gênero
6.
Lancet Oncol ; 19(8): 1094-1106, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30042063

RESUMO

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. METHODS: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. FINDINGS: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. INTERPRETATION: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. FUNDING: Besançon University Hospital and Ligue contre le cancer Grand-Est.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
7.
BMC Cancer ; 17(1): 574, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28841909

RESUMO

BACKGROUND: The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. METHODS: This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon's optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. DISCUSSION: Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. TRIAL REGISTRATION: NCT02402842 , EudraCT: 2014-001789-81.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Recidiva Local de Neoplasia , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Docetaxel , França , Humanos , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Adulto Jovem
8.
BMC Cancer ; 16: 384, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27378078

RESUMO

BACKGROUND: Cetuximab is a commonly used antibody agent in the treatment of colorectal or head and neck cancer. Although it is generally well tolerated in most patients, cetuximab has been associated with some rare but serious adverse events. Aseptic meningitis is one such distinctly uncommon adverse drug reaction. CASE PRESENTATION: We present the case of a middle-aged Caucasian patient, who presented with fever and headache within a few hours of starting cetuximab therapy and was diagnosed with cetuximab-induced aseptic meningitis after a complete workup. CONCLUSION: To our knowledge, this is the ninth case of cetuximab-induced aseptic meningitis reported in literature. Because of a nonspecific clinical presentation, this adverse drug reaction can be easily misdiagnosed. It is important to increase awareness of this potentially severe reaction among oncologists.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Meningite Asséptica/induzido quimicamente , Administração Intravenosa , Idoso , Antibacterianos/uso terapêutico , Cetuximab/administração & dosagem , Feminino , Humanos , Meningite Asséptica/tratamento farmacológico , Resultado do Tratamento
9.
Mol Diagn Ther ; 28(2): 201-214, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38267771

RESUMO

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk human papillomavirus (HPV) and is currently one of the fastest-growing causes of cancer incidence and mortality in developed countries. Although next-generation sequencing technologies (NGS) have revolutionized cancer and immuno-genomic research in various tumor types, a limited amount of clinical research has been developed to investigate the expression and the functional characterization of genomic data in ASCC. Herein, we comprehensively assess recent advancements in "omics" research, including a systematic analysis of genome-based studies, aiming to identify the most relevant ASCC cancer driver gene expressions and their associated signaling pathways. We also highlight the most significant biomarkers associated with anal cancer progression, gene expression of potential diagnostic biomarkers, expression of therapeutic drug targets, and emerging treatment opportunities. This review stresses the urgent need for developing target-specific therapies in ASCC. By illuminating the molecular characteristics and drug-target expression in ASCC, this study aims to provide insights for the development of precision medicine in anal cancer.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Biomarcadores , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/genética , Neoplasias do Ânus/epidemiologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Genômica , Recidiva Local de Neoplasia/patologia
10.
Biomedicines ; 11(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36979770

RESUMO

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

11.
Radiother Oncol ; 183: 109542, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36813175

RESUMO

INTRODUCTION: International guidelines regarding the treatment of squamous cell carcinoma of the anus (SCCA) recommend intensity-modulated radiotherapy (IMRT) combined with mitomycin-based chemotherapy (CT). The French FFCD-ANABASE cohort aimed at evaluating clinical practices, treatment, and outcomes of SCCA patients. METHODS: This prospective multicentric observational cohort included all non-metastatic SCCA patients treated in 60 French centers from January 2015 to April 2020. Patients and treatment characteristics, colostomy-free survival (CFS), disease-free survival (DFS), overall survival (OS), and prognostic factors were analyzed. RESULTS: Among 1015 patients (male: 24.4 %; female: 75.6 %; median age: 65 years), 43.3 %presented with early-stage(T1-2, N0) and 56.7 % with locally advanced stage (T3-4 or N + ) tumors. IMRT was used for 815 patients (80.3 %) and a concurrent CT was administered in 781 patients, consisting of mitomycin-based CT for 80 %. The median follow-up was 35.5 months. DFS, CFS, and OS at 3 years were 84.3 %, 85.6 %, and 91.7 % respectively in the early-stage group compared to 64.4 %, 66.9 %, and 78.2 % in the locally-advanced group (p < 0.001). In multivariate analyses, male gender, locally-advanced stage, and ECOG PS ≥ 1 were associated with poorer DFS, CFS, and OS. IMRT was significantly associated with a better CFS in the whole cohort and almost reached significance in the locally-advanced group. CONCLUSION: Treatment of SCCA patients showed good respect for current guidelines. Significant differences in outcomes advocate for personalized strategies by either de-escalation for early-stage tumors or treatment intensification for locally-advanced tumors.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Radioterapia de Intensidade Modulada , Idoso , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Quimiorradioterapia/métodos , Estudos de Coortes , Fluoruracila , Mitomicina , Prognóstico , Estudos Prospectivos , Radioterapia de Intensidade Modulada/métodos , Resultado do Tratamento
12.
Eur J Cancer ; 162: 138-147, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34995900

RESUMO

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line. PATIENTS AND METHODS: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol. RESULTS: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy. CONCLUSION: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Canal Anal/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Cisplatino/uso terapêutico , Docetaxel , Epitopos , Fluoruracila/uso terapêutico , Humanos , Paclitaxel/uso terapêutico , Estudos Prospectivos
13.
Cureus ; 13(7): e16604, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34447643

RESUMO

Palbociclib (Ibrance™) has been marketed since 2015 for patients with metastatic hormone-receptor-positive breast cancer. We report here the case of a patient who presented with a posterior reversible encephalopathy syndrome (PRES) during treatment with this new targeted therapy. The 67-year-old woman presented prodromal headaches followed by occurrences of two episodes of generalized convulsive seizures. The brain MRI revealed a bilateral, globally symmetrical, sub-cortical parietooccipital fluid-attenuated inversion recovery (FLAIR) hypersignal of the white matter. The patient recovered after palbociclib discontinuation with no further neurological signs. A follow-up MRI performed one month upon palbociclib discontinuation showed a decrease in the FLAIR signal abnormalities. Altogether, the clinical presentation was consistent with PRES. This case report aims to encourage physicians whom patients are treated with cyclin-dependent kinase 4/6 inhibitors to cautiously monitor symptoms suggesting PRES in contexts known to promote its occurrence such as that of arterial hypertension, immunosuppression, and/or autoimmune disease. PRES should be considered in the event of seizure, headache, and/or visual disturbances.

14.
Dig Liver Dis ; 53(6): 776-784, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33867291

RESUMO

INTRODUCTION: for localized T1N0 squamous cell carcinoma of the anus (SCCA) standard radiotherapy (RT) may result in overtreatment and alternative strategies are debated. METHODS: T1N0M0 SCCA treated between 2015 and 2020 by local excision (LE) or RT were analyzed from the French prospective FFCD ANABASE cohort. Treatment strategies, recurrence-free and colostomy-free survivals (RFS, CFS) and prognostic factors were reported. RESULTS: among 1135 SCCA patients, 99 T1N0M0 were treated by LE(n = 17,17.2%), or RT (n = 82,82.8%) including RT alone (n = 65,79.2%) or chemo-RT (n = 17, 20.7%). Median follow-up was 27.2 months [0.03-54.44]. Median tumor size were 11.4 mm [0.9-20] and 15.3 mm [2-20] in the LE and RT groups respectively. Mean RT tumor dose was 59.4 Gy [18-69.4 Gy]. One patient in LE group and 9 in RT group had a pelvic recurrence, either local (60%), nodal (10%) or both (30%). RFS and CFS at 24 months were 92.2%[95%CI,83.4-96.4] and 94.6%[95%CI,86.1-98.0], at 36 months 88.1%[95%CI,77.1-94.2] and 88.5%[95%CI,77.0-94.5], in LE and RT group respectively, without any significative difference (HR = 0.57;[95%CI,0.07-4.45];p = 0.60). By univariate analysis, male gender was the only prognostic factor(HR = 5.57;95%CI, 1.76-17.63; p = 0.004). CONCLUSION: this cohort confirms the heterogeneity of T1N0M0 SCCA management, questioning the place of RT alone, reduced dose or RT volume, and the safety of LE.


Assuntos
Canal Anal/cirurgia , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Radioterapia , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Ther Adv Med Oncol ; 12: 1758835920975356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329760

RESUMO

AIMS: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies. PATIENTS & METHODS: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen. RESULTS: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6-16.1] [11.0 months (9.3-16.0) in -HPV02, and 15.6 months (11.2-34.5) in -HPV01, (p = 0.06)]. The median overall survival was 39.2 months (26.0-109.1) [36.3 in -HPV02 (25.2-NR), and 61.1 months (21.4-120.0) in -HPV01 (p = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF (n = 54) and mDCF (n = 58) in terms of OS (p = 0.57) and PFS (p = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed. CONCLUSION: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.

16.
Clin Cancer Res ; 25(7): 2109-2115, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30504426

RESUMO

PURPOSE: Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA. EXPERIMENTAL DESIGN: According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses. RESULTS: Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1; P = 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5; P < 0.001) and a reduction of 1-year overall survival rate (OR = 7.0; P = 0.02). CONCLUSIONS: This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.See related commentary by Morris, p. 2030.


Assuntos
DNA Tumoral Circulante , Papillomaviridae/genética , Infecções por Papillomavirus , Epitopos , Humanos , Estudos Prospectivos
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