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1.
Ann Oncol ; 34(8): 681-692, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37211045

RESUMO

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Bevacizumab , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Antineoplásicos/uso terapêutico , Ftalazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Quimioterapia de Manutenção
2.
Gynecol Oncol ; 158(3): 666-672, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32624235

RESUMO

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.


Assuntos
Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Ovarianas/terapia , Conduta Expectante , Adolescente , Adulto , Idoso , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Coriocarcinoma/cirurgia , Coriocarcinoma/terapia , Disgerminoma/tratamento farmacológico , Disgerminoma/patologia , Disgerminoma/cirurgia , Disgerminoma/terapia , Tumor do Seio Endodérmico/tratamento farmacológico , Tumor do Seio Endodérmico/patologia , Tumor do Seio Endodérmico/cirurgia , Tumor do Seio Endodérmico/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Retrospectivos , Teratoma/tratamento farmacológico , Teratoma/patologia , Teratoma/cirurgia , Teratoma/terapia , Adulto Jovem
3.
Ann Oncol ; 30(5): 845-852, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30851097

RESUMO

BACKGROUND: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women. PATIENTS AND METHODS: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS. RESULTS: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01). CONCLUSION: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Carcinoma Epitelial do Ovário/epidemiologia , Fadiga/epidemiologia , Neoplasias Ovarianas/epidemiologia , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/epidemiologia , Ansiedade/etiologia , Carcinoma Epitelial do Ovário/fisiopatologia , Carcinoma Epitelial do Ovário/psicologia , Carcinoma Epitelial do Ovário/terapia , Estudos de Casos e Controles , Terapia Combinada , Estudos Transversais , Depressão/epidemiologia , Depressão/etiologia , Fadiga/etiologia , Feminino , França/epidemiologia , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/fisiopatologia , Neoplasias Ovarianas/psicologia , Neoplasias Ovarianas/terapia , Inquéritos e Questionários , Adulto Jovem
4.
Br J Cancer ; 116(3): 303-309, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28072765

RESUMO

Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. METHODS: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. RESULTS: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. CONCLUSIONS: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Endometrioide/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Morfolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Quimioterapia Adjuvante , Progressão da Doença , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Inibidores de Fosfoinositídeo-3 Quinase , Recidiva , Resultado do Tratamento
5.
Ann Oncol ; 28(1): 103-109, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28177480

RESUMO

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/patologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Bevacizumab/administração & dosagem , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/sangue , Neoplasias Inflamatórias Mamárias/cirurgia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Taxoides/administração & dosagem , Trastuzumab/administração & dosagem , Adulto Jovem
6.
Eur J Cancer Care (Engl) ; 25(3): 458-65, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26891443

RESUMO

The question of returning to work and pursuing professional activity during cancer treatment is an increasingly important consideration. The present work focuses on factors affecting the feasibility of maintaining professional activity during treatment for breast cancer, for women who wished to do so. Written questionnaires were collected from 216 patients between March and November 2012. Since the onset of their treatment, 31.4% of the women (68/216) had not been on sick-leave. The main factors associated with the pursuit of professional activity were: considering the availability of their physician to answer questions as unimportant [OR = 18.83 (3.60-98.53); P ≤ 0.05]; considering the diagnosis of cancer as likely to have a weak impact on career perspectives [OR = 4.07 (2.49-6.64); P ≤ 0.05]; not having any children in the household [OR = 3.87 (2.38-6.28); P ≤ 0.05]; being in a managerial position [OR = 3.13 (1.88-5.21); P ≤ 0.05]. Negative predictive factors were: physician mentioning adverse effects of the treatment [OR = 0.31 (0.16-0.58); P ≤ 0.05], and patient rating workload as high [OR = 0.26 (0.15-0.46); P ≤ 0.05]. As a result of advances in therapeutic strategies, more patients will expect healthcare professionals, as well as employers and occupational health societies, to prioritise issues pertaining to the maintenance of professional activities during cancer treatment.


Assuntos
Neoplasias da Mama/terapia , Emprego/psicologia , Adulto , Idoso , Atitude Frente a Saúde , Neoplasias da Mama/psicologia , Escolha da Profissão , Feminino , Humanos , Intenção , Satisfação no Emprego , Pessoa de Meia-Idade , Relações Médico-Paciente , Retorno ao Trabalho/psicologia , Licença Médica/estatística & dados numéricos , Inquéritos e Questionários
7.
Ann Oncol ; 26(1): 120-125, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25361980

RESUMO

BACKGROUND: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. PATIENTS AND METHODS: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). RESULTS: A total of 55 primary tumor samples from the TAMRAD trial­25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group­were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. CONCLUSIONS: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Complexos Multiproteicos/genética , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Neoplasias da Mama/mortalidade , Proteínas de Ciclo Celular , Classe I de Fosfatidilinositol 3-Quinases , Everolimo , Feminino , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Análise de Sequência de DNA , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Tamoxifeno/uso terapêutico , Proteínas ras/genética
8.
Ann Oncol ; 25(11): 2191-2196, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25210017

RESUMO

BACKGROUND: Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. PATIENTS AND METHODS: Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. RESULTS: Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. CONCLUSIONS: Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. CLINICALTRIALSGOV: NCT01111903.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Neoplasias das Tubas Uterinas , Feminino , Humanos , Lenalidomida , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Platina/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos
9.
Ann Oncol ; 23(2): 346-52, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21562072

RESUMO

BACKGROUND: Platinum rechallenge or weekly topotecan in combination have not been evaluated in randomized trials for resistant recurrent ovarian cancer (ROC). METHODS: Patients with ROC after first- or second-line treatment including a platinum and taxane and progression within 6 months were randomized to weekly paclitaxel (wP, 80 mg/m(2)/week) alone or in combination with carboplatin (C, area under the curve of 5 mg/ml/min every 4 weeks) or weekly topotecan (wT, 3 mg/m(2)/week). Primary end point was progression-free survival (PFS) comparing wP and combination therapy. RESULTS: Patients (n = 165) received a median three cycles in each arm. Nonhematologic toxicity was not different, except increased hypersensitivity reactions with wP + C. Grade 3-4 hematologic toxic effects with wP, wP + C, and wP + wT, respectively, were neutropenia in 13%, 54%, and 42%; febrile neutropenia in 0%, 4%, and 5%; and anemia in 6%, 19%, and 29%. Response rates were 35%, 37%, and 39%, and median PFS times were 3.7, 4.8, and 5.4 months, respectively. PFS was not significantly different among the treatment arms [hazard ratio (HR) 0.922; 95% confidence interval (CI) 0.765-1.111; P = 0.46] or between monotherapy and combination therapy (HR 0.951; 95% CI 0.686-1.318; P = 0.76). CONCLUSIONS: Combination chemotherapy in platinum-resistant ROC was more toxic than weekly paclitaxel and did not significantly prolong PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Análise de Sobrevida , Topotecan/administração & dosagem
10.
Ann Oncol ; 23(10): 2552-2561, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22431701

RESUMO

BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.


Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fatores de Transcrição Forkhead/metabolismo , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , Humanos
11.
Ann Oncol ; 19(7): 1255-1260, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18381372

RESUMO

BACKGROUND: Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC. PATIENTS AND METHODS: Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated. RESULTS: One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%). CONCLUSIONS: Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Coortes , Diarreia/induzido quimicamente , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Neutropenia/induzido quimicamente , Estudos Prospectivos , Taxoides/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
12.
J Med Genet ; 43(9): e49, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16950820

RESUMO

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.


Assuntos
Genes BRCA2 , Mutação em Linhagem Germinativa/genética , Éxons/genética , Feminino , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Deleção de Sequência/genética
13.
Eur J Cancer ; 82: 230-236, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28648618

RESUMO

HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life. RESULTS: Hundred and thirteen patients were randomised and treated. H-s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8-93.0]; p < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0-21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6-73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade ≥ III, 3 (2.8%) and 2 (1.8%) were serious. CONCLUSION: The safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Preferência do Paciente , Trastuzumab/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/secundário , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Qualidade de Vida
14.
J Clin Oncol ; 17(4): 1105, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10561167

RESUMO

PURPOSE: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU. PATIENTS AND METHODS: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance. RESULTS: The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25. CONCLUSION: The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Uracila/análogos & derivados , Uracila/sangue , Adulto , Idoso , Área Sob a Curva , Distribuição de Qui-Quadrado , Cromatografia Líquida , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Leucovorina/administração & dosagem , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos
15.
J Clin Oncol ; 19(2): 558-67, 2001 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11208851

RESUMO

PURPOSE: Two identical, concurrent, parallel, multicenter, randomized, double-blind, double-dummy trials were conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM). PATIENTS AND METHODS: Patients with moderate to severe HCM (corrected serum calcium [CSC] > or = 3.00 mmol/L [12.0 mg/dL]) were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or pamidronate (90 mg) via 2-hour infusion. A protocol-specified pooled analysis of the two parallel trials was performed. Clinical end points included rate of complete response by day 10, response duration, and time to relapse. RESULTS: Two hundred eighty-seven patients were randomized and evaluated for safety; 275 were evaluated for efficacy. Both doses of zoledronic acid were superior to pamidronate in the treatment of HCM. The complete response rates by day 10 were 88.4% (P = .002), 86.7% (P = .015), and 69.7% for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively. Normalization of CSC occurred by day 4 in approximately 50% of patients treated with zoledronic acid and in only 33.3% of the pamidronate-treated patients. The median duration of complete response favored zoledronic acid 4 and 8 mg over pamidronate 90 mg with response durations of 32, 43, and 18 days, respectively. CONCLUSION: Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.


Assuntos
Difosfonatos/uso terapêutico , Hipercalcemia/tratamento farmacológico , Imidazóis/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Hipercalcemia/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Pamidronato , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Zoledrônico
16.
J Clin Oncol ; 16(4): 1470-8, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9552054

RESUMO

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Neoplasias Retais/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Feminino , Fluoruracila/sangue , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
17.
J Gynecol Obstet Biol Reprod (Paris) ; 34(1 Pt 1): 41-6, 2005 Feb.
Artigo em Francês | MEDLINE | ID: mdl-15767916

RESUMO

Endometrial stromal sarcoma is a rare malignant uterine tumor. We report 4 cases of low-grade endometrial stromal sarcoma, corresponding to the form with a mitotic index at less than 10 mitoses per 10 high power fields (HPF), from which we carried out a review of the literature and defined the potential interest of hormone therapy and chemotherapy by etoposide. Generally diagnosed in pre-menopause, the main clinical signs, which are not very specific, are metrorrhagia and pelvic pain. The etiologic diagnosis is established from the pathology analysis. Intravascular extension, which is observed in nearly 50% of patients, should evoke the disease. The initial treatment is mainly based open surgery, generally total hysterectomy with annexectomy. There is no effective adjuvant treatment. The potential of reccurences remains around 50% with a 34-month median. Several therapeutic options are possible after recurrence but no standard treatment has been established. We are mainly interested in three medical options but the surgery remains an alternative of choice. Chemotherapy by oral etoposide offers easy administration, good compliance and acceptable toxicity with median 20-month remission in 3 patients before progression. Hormone therapy with progestogens (hormone receptor expression of the tumor is 71% for estrogens and 95% for progesterone) is widely studied in the literature with a 46% response rate and 46% rate of disease stabilization. Hormone therapy with an anti-aromatase appears to be a promising treatment according to the bibliographic references on this subject. Overall, prognosis of low-grade endometrial sarcoma is relatively good with 100% survival at 5 years. The progression pattern is slow, requiring regular and prolonged surveillance.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Etoposídeo/uso terapêutico , Progestinas/uso terapêutico , Sarcoma/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez
18.
Presse Med ; 34(17): 1235-6, 2005 Oct 08.
Artigo em Francês | MEDLINE | ID: mdl-16230965

RESUMO

INTRODUCTION: Esomeprazole, the pure S isomer form of omeprazole, is indicated for the treatment of peptic esophagitis. We report here a major episode of cytolytic hepatitis following a single administration. CASE: A 41-year-old woman with infiltrating ductal carcinoma of the breast was undergoing chemotherapy with paclitaxel and trastuzumab. On the fourth day of the second course, she took 1 tablet of esomeprazole 20 mg for epigastric pain. Liver pain and asthenia followed, and liver function tests showed substantial cytolysis. These tests returned to normal levels despite continuation of the chemotherapy. DISCUSSION: This cytolytic hepatitis is very probably imputable to esomeprazole, but a synergistic hepatic toxicity of the chemotherapy with esomeprazole cannot be ruled out.


Assuntos
Antiulcerosos/efeitos adversos , Antiulcerosos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Esomeprazol/efeitos adversos , Esomeprazol/uso terapêutico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Esofagite/induzido quimicamente , Esofagite/tratamento farmacológico , Feminino , Humanos , Paclitaxel/administração & dosagem , Trastuzumab
19.
Breast ; 24(4): 376-83, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25913287

RESUMO

PURPOSE: The LORHA study described the clinical features of patients and tumours in long-term responders from a subset of breast cancer patients who responded to 1st-line trastuzumab and without disease progression. METHODS: This was an ambispective, multicentre, non-interventional study conducted in 57 centres in France. Eligible patients were women with HER2+metastatic or locally-advanced breast cancer, treated with 1st-line therapy, progression-free for ≥3 years after starting trastuzumab, and followed-up for 12 months. RESULTS: 160 patients were recruited, 128 were included in the efficacy analysis subset (median age: 61 years; [34-95 years]). A majority (88%) had invasive ductal carcinoma; 53% had SBR grade III carcinoma, and 58% were positive for hormonal receptors. The median time since diagnosis was 8 years [3-26 years]. The most frequent metastatic sites were the bone, liver, lymph nodes, and lungs in 43%, 35%, 20% and 19% of patients, respectively. The median duration of 1st-line trastuzumab was 4.5 years [0.8-12.1], combined with paclitaxel and docetaxel in 35 and 72 patients, respectively. Median PFS (progression-free survival) was 6.4 years [5.7; Not Reached]. No trastuzumab-related deaths were observed. In the safety analysis subset (N = 134), 3 cardiac adverse events considered related to trastuzumab were recorded in 3 patients (2.2%), and only one prospective congestive cardiac failure was of grade ≥3. CONCLUSIONS: The LORHA study showed that long term responders to 1st-line trastuzumab for locally advanced or metastatic breast cancer could achieve a median PFS of more than 6 years, with an acceptable safety profile.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Sobreviventes , Trastuzumab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Docetaxel , Feminino , Seguimentos , França , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos Prospectivos , Receptor ErbB-2 , Estudos Retrospectivos , Taxoides/administração & dosagem
20.
J Bone Miner Res ; 14(9): 1557-61, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10469284

RESUMO

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.


Assuntos
Difosfonatos/administração & dosagem , Hipercalcemia/complicações , Hipercalcemia/tratamento farmacológico , Imidazóis/administração & dosagem , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Difosfonatos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Zoledrônico
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