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1.
Gynecol Oncol ; 165(1): 30-39, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35123771

RESUMO

BACKGROUND: There are limited treatment options for ovarian cancer patients with early relapse after platinum chemotherapy. In preclinical studies, we previously demonstrated the promising activity of ABT-737, a Bcl-2/Bcl-xL anti-apoptotic protein inhibitor, in chemo-resistant ovarian cancer cells and tumors, suggesting its potential activity in platinum-resistant patients. METHODS: We conducted a prospective multicenter single-arm phase II study to assess the efficacy of Navitoclax (orally available ABT-737 analogue) monotherapy in 46 heavily pretreated (2-12 lines, median = 4) patients with high-grade serous platinum-resistant ovarian tumors. Navitoclax was administered at the daily dose of 150 mg during a lead-in period (7-14 days) and then increased to 250 mg daily in the absence of dose-limiting thrombocytopenia (

Assuntos
Neoplasias Ovarianas , Trombocitopenia , Compostos de Anilina , Carcinoma Epitelial do Ovário/tratamento farmacológico , Feminino , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/uso terapêutico , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Platina/uso terapêutico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas
2.
Parasite Immunol ; 42(10): e12771, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32602946

RESUMO

AIMS: We evaluate whether the serum and aqueous humour (AH) level of IgG anti-Hsp70.1 antibodies improved the biological diagnosis of ocular toxoplasmosis. METHODS AND RESULTS: In this prospective cross-sectional and multicentre study, serum and AH were collected at the time of active uveitis. Anti-Hsp70.1-antibody levels were determined by ELISA. Patients with confirmed (Group A1, n = 21) or suspected ocular toxoplasmosis (group A2, n = 30) were enrolled, as well as a control group of patients with cataract (group B, n = 42). Serum IgG anti-Hsp70.1 antibody levels were not significantly different within the group of uveitis patients (A1, n = 21 vs A2, n = 30, P = .8) and were significantly associated with the affected retinal zone (P = .006) and with the size of the retinal lesion (P = .03). Serum anti-Hsp70.1 antibody level was positive in 10 out of the 18 patients of group A2. Significant anti-Hsp-70.1 antibody level in AH was reported in only three patients (3 eyes) with confirmed ocular toxoplasmosis. CONCLUSION: While the level of IgG anti-Hsp-70.1 antibody in AH did not improve the laboratory diagnosis of ocular toxoplasmosis, its level in serum was of major significance for retinal damage diagnosis.


Assuntos
Anticorpos Antiprotozoários/análise , Humor Aquoso/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Imunoglobulina G/análise , Toxoplasmose Ocular/imunologia , Adulto , Anticorpos Antiprotozoários/imunologia , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Toxoplasma/imunologia , Toxoplasmose Ocular/diagnóstico , Uveíte/diagnóstico , Uveíte/imunologia
3.
Int J Cancer ; 146(2): 439-448, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381147

RESUMO

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indóis/administração & dosagem , Neoplasias Ovarianas/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Ovário/cirurgia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Placebos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem
4.
Eur J Cancer ; 117: 99-106, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31279306

RESUMO

BACKGROUND: Platinum-resistant ovarian cancer (PROC) is associated with a variable prognosis and unpredictable survival times. We have developed and validated a prognostic nomogram with the objective of improving the prediction of overall survival (OS) in patients treated with chemotherapy. METHODS: The nomogram was developed using data from a training cohort of patients from two trials, including the chemotherapy-only arm in AURELIA and all randomised patients in CARTAXHY. Multivariable proportional hazards models were generated based on pretreatment characteristics to develop a nomogram that classifies patients based on OS. We subsequently assessed the performance of the nomogram in terms of discrimination and calibration in independent validation patient cohorts: PENELOPE and the bevacizumab-chemotherapy arm of AURELIA. RESULTS: The nomogram included six significant OS predictors, in order of importance: performance status, ascites, size of the largest tumour, CA-125, platinum-free interval and primary platinum resistance (C-statistic 0.69). In the training cohort, the median OS in the good, intermediate and poor prognosis groups was 25.3, 15.2 and 7.4 months, respectively. In the PENELOPE validation cohort (C-statistic 0.59), the median OS in the good, intermediate and poor prognosis groups was 18.5, 10.3 and 5.8 months, respectively. In the AURELIA bevacizumab-chemotherapy validation cohort (C-statistic 0.67), the median OS in good, intermediate and poor prognosis groups was 26.7, 13.8 and 10.0 months, respectively. CONCLUSIONS: This nomogram with six pretreatment characteristics allows prediction of OS in PROC and could be used for stratification of patients in clinical trials as well as for counselling patients about prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nomogramas , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida , Topotecan/administração & dosagem
5.
J Clin Oncol ; 37(32): 2968-2973, 2019 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-31173551

RESUMO

PURPOSE: In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS: A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (gBRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed gBRCAmut (non-gBRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to gBRCAmut status and response to their last platinum-based therapy. Ovarian cancer-specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy-Ovarian Symptom Index. RESULTS: Progression-free survival was improved in patients treated with niraparib compared with placebo in both the gBRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non-gBRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION: Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Indazóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Intervalo Livre de Progressão
6.
Gynecol Oncol ; 152(1): 68-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446275

RESUMO

BACKGROUND: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. METHODS: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. RESULTS: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. CONCLUSION: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos
7.
JAMA Oncol ; 5(1): e183773, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347019

RESUMO

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azepinas/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Europa (Continente) , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Fatores de Tempo , Estados Unidos
8.
PLoS One ; 13(10): e0204973, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30304013

RESUMO

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Gonanos/uso terapêutico , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Preparações de Ação Retardada , Feminino , Gonanos/efeitos adversos , Gonanos/farmacocinética , Meia-Vida , Humanos , Pessoa de Meia-Idade , Náusea/etiologia , Metástase Neoplásica , Recidiva Local de Neoplasia
9.
BMC Cancer ; 18(1): 775, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064401

RESUMO

BACKGROUND: The primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel (wP) administered in combination with oral metronomic cyclophosphamide (OMC). METHODS: Patients ≥ 18 years of age with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50 mg twice a day). A 3 + 3 design was used for dose escalation of wP (40 to 75 mg/m2) followed by an expansion cohort at RP2D. Dose-limiting toxicity (DLT) was defined over the first 28-day cycle as grade ≥ 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) or any toxicity leading to a dose reduction. RESULTS: In total, 28 pts. (18 in dose-escalation phase and 10 in expansion cohort) were included, and 16/18 pts. enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts. (hematological toxicity) at doses of 40, 60, 70 and 75 mg/m2 of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 patients in the expansion phase had a hematological DLT. At RP2D (n = 14), the maximal grade of drug-related adverse event was Gr1 in three patients, Gr2 in six patients, Gr3 in one patient and Gr4 in one patient (no AE in three patients). At RP2D, a partial response was observed in one patient with lung adenocarcinoma. CONCLUSION: The combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation. TRIAL REGISTRATION: TRN: NCT01374620 ; date of registration: 16 June 2011.


Assuntos
Antineoplásicos/administração & dosagem , Ciclofosfamida/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Metronômica , Administração Oral , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Adulto Jovem
10.
Bull Cancer ; 104 Suppl 1: S32-S38, 2017 May.
Artigo em Francês | MEDLINE | ID: mdl-28625313

RESUMO

OVARIAN CANCER: EARLY RELAPSE: Early relapse (primary or secondary) is defined by relapse of disease less than 6 months before the last infusion of chemotherapy (with a platinum compound). There is no carcinological surgical indication. Disease should be treated with a non-platinum single agent (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine or topotecan). Bevacizumab can be added if patients have not already received it (level of proof 1, grade A).


Assuntos
Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Paclitaxel/uso terapêutico , Topotecan/uso terapêutico , Gencitabina
11.
Eur J Cancer ; 70: 133-142, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27914243

RESUMO

AIM: To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma. METHODS: Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented. RESULTS: In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached. CONCLUSION: The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia
12.
J Minim Invasive Gynecol ; 23(5): 825-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27068278

RESUMO

A thorough laparoscopic assessment of the abdominopelvic cavity is a crucial step in the workup of primary advanced epithelial ovarian cancer to decide whether up-front cytoreductive surgery or neoadjuvant chemotherapy is the best option for adequate management. The purpose of our study was to compare single-port laparoscopy (SPL), classic laparoscopy (CL), and laparotomy using the peritoneal cancer index (PCI). Patients treated for Fédération Internationale de Gynécologie et d'Obstétrique stage 3 or 4 epithelial ovarian cancer were included in our study when they underwent a PCI evaluation by laparoscopy followed by laparotomy for cytoreduction. According to the technique used for the "noninvasive" procedure (SPL vs CL), 2 groups were compared retrospectively. The individual records of all patients were reviewed and analyzed. From 2011 to 2014, 21 patients were assessed for PCI by SPL plus laparotomy versus 21 by CL plus laparotomy. The clinicopathological features were similar in both groups (not significant [NS]), except for performance status >0, which was more frequent in the SPL group (39% vs 6%, p = .04). Quotation of PCI was possible for all patients. Nonbrowsing areas marked 3 procedures in the SPL group and 2 procedures in the CL group (NS). The mean PCI score and the score of each region assessed by SPL and CL were comparable with the evaluation by laparotomy (NS). Completeness of cytoreduction was achieved in 78% of cases in both groups (NS). SPL and widely mini-invasive procedures seem to be effective tools compared with laparotomy to adequately assess the resectability of a peritoneal carcinomatosis using the PCI.


Assuntos
Laparoscopia/métodos , Laparotomia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias/métodos , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos
13.
J Clin Oncol ; 34(7): 706-13, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26755507

RESUMO

PURPOSE: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Pteridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Pteridinas/administração & dosagem , Qualidade de Vida , Resultado do Tratamento
14.
Rep Pract Oncol Radiother ; 20(5): 385-92, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26549997

RESUMO

AIM: To report a single-institution experience using postoperative pelvic Intensity Modulation Radiation Therapy (IMRT) using tomotherapy accelerators (TA) in postoperative endometrial cancer (EC) regarding ICRU 83 recommendations. BACKGROUND: IMRT in gynecological malignancies provides excellent dosimetric data, lower rates of adverse events and clinical data similar to historical series. MATERIAL AND METHODS: Seventy-six patients with EC were postoperatively treated with adjuvant IMRT using TA. The IMRT dose was 45 Gy for patients without positive lymph nodes and Type I histology and 50.4 Gy for patients with positive lymph nodes and/or type II histology. RESULTS: With a median follow-up of 29 months, the 12- and 24-month Overall Survival (OS) and Disease-Free Survival (DFS) were 96%, 93%, 87%, and 74%, respectively. Age of less than 60 years was associated with better OS (HR: 8.9; CI: 1.1-68) and DFS (HR: 3.5; CI: 1.2-10.2). Patients with Type II and Type I Grade III histology had a worse OS (HR: 3.3; CI: 1.1-11). Five women (6.6%) presented in-field local vaginal recurrence, 2 (2.6%) presented non-in-field vaginal recurrence, 4 (5.2%) presented pelvic node and distant recurrence and 11 (14.4%) presented only distant metastases. One patient stopped radiation treatment due to Grade III acute diarrhea. No Grade III late toxicity was observed. Planning Target Volume (PTV) coverage showed mean D2, D50, D95, and D98 of 51.64-46.23 Gy, 49.49-44.97 Gy, 48.62-43.96 Gy, and 48.47-43.58 Gy for patients who received 45 and 50.4 Gy, respectively. CONCLUSIONS: IMRT with TA in postoperative EC shows excellent conformity and homogeneity of PTV dose. Without Grade III late toxicity, data from this cohort demonstrated the utility of IMRT.

15.
J Clin Oncol ; 32(30): 3374-82, 2014 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-25225436

RESUMO

PURPOSE: Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-ß, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy. PATIENTS AND METHODS: Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators. RESULTS: Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%). CONCLUSION: Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Indazóis , Neoplasias Ovarianas/mortalidade , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos
16.
J Clin Oncol ; 32(4): 320-6, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24366937

RESUMO

PURPOSE: This trial evaluated the efficacy of maintenance erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, after first-line chemotherapy. PATIENTS AND METHODS: Eligible patients had high-risk International Federation of Gynecology and Obstetrics stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first-line platinum-based chemotherapy (CT) and showed no signs of progression at the end of CT. Patients were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years or to observation. EGFR immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutation analyses were performed in 318 patients. RESULTS: Between October 2005 and February 2008, 835 patients were randomly assigned (median follow-up, 51 months). Twenty-six percent of the patients stopped erlotinib as a result of adverse effects (of these, 67% were due to rash). For erlotinib and observation, respectively, the median progression-free survival was 12.7 and 12.4 months (hazard ratio [HR], 1.05; 95% CI, 0.90 to 1.23), and the median overall survival was 50.8 and 59.1 months (HR, 0.99; 95% CI, 0.81 to 1.20 months), respectively. No subgroup could be identified with improved effect of erlotinib, based on IHC or FISH for EGFR, or mutations in genes related to the EGFR pathway, or on rash during erlotinib therapy. However, patients with a positive FISH EGFR score had a worse overall survival (46.1 months) than those with a negative score (67.0 months; HR, 1.56; 95% CI, 1.01 to 2.40; P = .044). Global health/quality-of-life scores showed a significant difference during the first year (P = .0102) in favor of the observation arm. CONCLUSION: Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Esquema de Medicação , Toxidermias/etiologia , Receptores ErbB/genética , Cloridrato de Erlotinib , Europa (Continente) , Neoplasias das Tubas Uterinas/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Compostos de Platina/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Qualidade de Vida , Quinazolinas/efeitos adversos , Transdução de Sinais/genética , Conduta Expectante
17.
Gynecol Oncol ; 105(2): 304-11, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17258799

RESUMO

BACKGROUND: Although cervical cancer is clinically staged, surgery has long been considered the best means to assess extrapelvic disease and remains the gold standard for the detection of both intraperitoneal spread and small volume nodal metastases. The objective of this study was to determine short- and long-term outcomes for patients with locally advanced cervical cancer who underwent pretherapeutic laparoscopic staging. METHODS: From 1997 to 2004, 184 patients with stages IB2-IVA cervical cancer underwent pretherapeutic laparoscopic staging procedure including transperitoneal abdomino-pelvic exploration and extraperitoneal bilateral infrarenal paraaortic lymph node dissection. Patients were then treated with definitive radiotherapy tailored according to the staging results. RESULTS: The median age and BMI were respectively 45.8 years old and 27.1 kg/m2. Most lesions were squamous (n=172) and clinical stage was evenly distributed. Median operative time was 155 min with an average of 20.8 lymph nodes removed. Postoperative hospital stay averaged 1.4 days. Major complications included 1 intraoperative ureteral injury and 1 postoperative bowel obstruction from an umbilical trocar site hernia. The final pathology revealed that 44 patients (24.3%) had metastatic disease within paraaortic lymph nodes. With a median follow-up of 26.8 months (average 32.9), 67 patients (36.4%) had recurrent disease. Overall 5-year survival rate was 58.3%. Successful resection of positive lymph node correlated with a survival advantage. CONCLUSIONS: Pretherapeutic laparoscopic assessment of patients with locally advanced cervical cancer offers valuable information for individualized treatment planning with minimal morbidity. This appears to be a therapeutic effect with resection of positive nodes followed by a tailored chemoradiation therapy.


Assuntos
Linfonodos/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Laparoscopia/métodos , Linfonodos/cirurgia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia
18.
Bull Cancer ; 93(4): 402-6, 2006 Apr.
Artigo em Francês | MEDLINE | ID: mdl-16627243

RESUMO

To prove feasibility of laparoscopic and vaginal surgical approach in obese patients with endometrial cancer, 81 patients were included retrospectively in 2 Cancer Centres : 41 obese and 40 non obese. We performed hysterectomy with oophorectomy and pelvic lymphadenectomy by laparoscopic and vaginal approach. Operative time was higher for obese patients vs non obese (150 vs 121 minutes, p = 0.01) but pelvic nodes (16.3 vs 16.2), postoperative stay (3.8 [2-8] vs 3.6 days [2-7]), complications and disease-free survival (93 % vs 83 %) were similar. Matching 41 obese patients treated by laparoscopy with 29 obese patients with endometrial cancer treated by laparotomy, hospital stay was shorter in the laparoscopic group (3.8 [2-8] vs 7.4 days [5-10] p < 0.001) and pelvic nodes (16.3 [3-50] vs 11.5 [2-34]), operative time (149.9 [80-300] vs 167.9 minutes [60-390]) and disease-free survival (93 vs 80 %) were similar. One patient treated by laparotomy never received intended radiotherapy because of a delay greater than 3 months caused by cutaneous necrosis. For obese patients with stage I endometrial adenocarcinoma, laparoscopic approach should be first choice because of similar operative complications and pelvic nodes, shorter hospital stay and less abdominal wall morbidity associated with lower risk to delay adjuvant radiotherapy.


Assuntos
Adenocarcinoma/cirurgia , Neoplasias do Endométrio/cirurgia , Procedimentos Cirúrgicos em Ginecologia/métodos , Laparoscopia/métodos , Obesidade/complicações , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Adulto , Idoso , Peso Corporal , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/fisiopatologia , Feminino , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valores de Referência , Resultado do Tratamento
19.
Bull Cancer ; 93(1): 43-9, 2006 Jan.
Artigo em Francês | MEDLINE | ID: mdl-16455505

RESUMO

General tendency of modern cancerology is the research of adequacy between extent of disease and treatments. This concept is of course valid for gynaecology and we saw these last months the promising results of fertility-sparing surgery: in initial cervical cancers and in ovarian cancer with good prognosis. Actual Studies should define a clear attitude in patient less than 40 with initial endometrial cancer. At the same time, the development of laparoscopic surgery has continued in cervical cancer staging. If use of sentinel node in endometrial or vulvar cancers remains discussed as for its reliability, importance of staging was stressed for cervical cancer and initial ovarian cancer. Laparoscopic surgery is confirmed in patient at risk with endometrial cancer but it is necessary to stress efforts of French teams which still push back the technical limits of laparoscopic approach like pelvic exenteration or intra-peritoneal chemohyperthermia in advanced ovarian cancer. The adventure continues....


Assuntos
Neoplasias dos Genitais Femininos/cirurgia , Procedimentos Cirúrgicos em Ginecologia/métodos , Laparoscopia/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Feminino , França , Neoplasias dos Genitais Femininos/tratamento farmacológico , Procedimentos Cirúrgicos em Ginecologia/tendências , Humanos , Hipertermia Induzida , Infusões Parenterais , Laparoscopia/tendências , Prognóstico , Fatores de Risco
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