RESUMO
The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.
Assuntos
Oncologia , Neoplasias Ovarianas , Humanos , Feminino , Sociedades Médicas , Espanha , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Biologia MolecularRESUMO
BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Difosfato de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Progressão da Doença , Feminino , Humanos , Quimioterapia de Manutenção , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ribose/uso terapêuticoRESUMO
OBJECTIVE: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. METHODS: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300â¯mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18â¯months after the last patient received their first dose. RESULTS: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2â¯months (95% confidence interval [CI], 7.6-10.9) in the overall population. At 12 and 18â¯months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3â¯months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. CONCLUSION: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.
Assuntos
Recidiva Local de Neoplasia , Neoplasias Ovarianas , Ftalazinas , Piperazinas , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Feminino , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Quimioterapia de Manutenção , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Platina/uso terapêuticoRESUMO
Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
BACKGROUND: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. MATERIALS AND METHODS: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. RESULTS: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. CONCLUSIONS: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Biomarcadores , Carcinoma Epitelial do Ovário , Feminino , Recombinação Homóloga , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
BACKGROUND: We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. RESULTS: 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms. CONCLUSIONS: This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used. CLINICAL TRIAL REGISTRATION: Clinicaltrials.govNCT01610869.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Neoplasias das Tubas Uterinas/tratamento farmacológico , Indóis/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Administração Metronômica , Administração Oral , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Neoplasias das Tubas Uterinas/diagnóstico , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Indóis/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão , Qualidade de VidaRESUMO
BACKGROUND: Potentially platinum sensitive recurrent ovarian cancer (PPS ROC) is defined by a platinum-free interval of >6 months, and usually treated with platinum-based chemotherapy with variable response and benefit in women who have had 3 or more lines of chemotherapy(≥3). We identified baseline characteristics (health-related quality of life[HRQL] and clinicopathological factors), associated with PFS, OS and early progression (within 8 weeks). The goal is to improve patient selection for chemotherapy based on a nomogram predicting PFS. METHODS: HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with PFS and OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis were included in multivariable analyses using backward elimination to select those significant. Associations with stopping chemotherapy early were assessed with logistic regression. RESULTS: 378 women were enrolled, with median(m)OS and PFS of 16.6 months and 5.3 months, respectively. The majority had ECOGPS 0-1. Chemotherapy was stopped early in 45/378 participants (12%); with mOS 3.4 months (95% CI: 1.7-7.2). Physical function(PF), role function(RF), cognitive function(CF), social function(SF), Global Health Status(GHS) and abdominal/GI symptoms(AGIS) were significant univariable predictors of PFS(p < 0.030). SF remained significant after adjusting for clinicopathological factors; p = 0.03. PF, RF, CF, SF, GHS and AGIS were significant univariable predictors of OS (p < 0.007); PF, RF, SF and GHS remained significant predictors of OS in multivariable models; p < 0.007. Poor baseline PF and GHS were significant univariable predictors of stopping chemotherapy early (p < 0.007) but neither remained significant after adjusting for clinicopathological factors. CONCLUSION: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.
Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/sangue , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Qualidade de Vida , Taxa de SobrevidaRESUMO
OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.
Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Indazóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Indazóis/efeitos adversos , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.
Assuntos
Recidiva Local de Neoplasia , Neoplasias Ovarianas , Feminino , Humanos , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Terapia Combinada , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Taxa de SobrevidaRESUMO
BACKGROUND: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. PATIENTS AND METHODS: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of ≥3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. CONCLUSIONS: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. CLINICAL TRIAL NUMBER: Clinicaltrials.gov, NCT02674061.
Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/patologia , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Estudos de Coortes , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de SobrevidaRESUMO
The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on April 12-14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.
RESUMO
For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of antiangiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed. We review key trials that have led to the approval of three PARP inhibitors-olaparib, niraparib and rucaparib-as maintenance therapy for platinum-sensitive recurrent ovarian cancer. We discuss the efficacy and safety of these agents in the populations studied in clinical trials. We then provide an overview of the numerous avenues of ongoing research for PARP inhibitors in different treatment settings: as treatment rather than maintenance strategies and in combination with other anticancer approaches, including antiangiogenic and immunotherapeutic agents. Three phase III trials (NOVA, SOLO2 and ARIEL3) demonstrated remarkable improvement in progression-free survival (PFS) with PARP inhibitors given as maintenance therapy in patients with complete or partial response after platinum-based therapy for platinum-sensitive ovarian cancer. Differences in trial design and patient populations influence the conclusions that can be drawn from these trials. Overall survival data are pending and there is a limited experience regarding long-term safety. PARP inhibitors have transformed the management of ovarian cancer and have changed the course of disease for many patients. Although recent approvals are irrespective of BRCA mutation or homologous repair deficiency status, genetic profiles, as well as dosing schedules, tolerability and affordability, may influence patient selection and the setting in which PARP inhibitors are used. The development and evolution of PARP inhibitors continue, with new agents, strategies, combinations and indications under intensive evaluation.
Assuntos
Desenvolvimento de Medicamentos , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/química , Animais , Feminino , Humanos , Neoplasias Ovarianas/enzimologia , PrognósticoAssuntos
Neoplasias da Mama , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Humanos , Feminino , Detecção Precoce de Câncer , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Comportamento de Redução do Risco , Predisposição Genética para DoençaRESUMO
Background: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). Patients and methods: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL). Results: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone. Conclusion: In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy. Clinical trial number: clinicaltrials.gov, NCT01622543.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário/mortalidade , Cisplatino/administração & dosagem , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Intervalo Livre de ProgressãoRESUMO
Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose â¼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.
Assuntos
Indazóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Trombocitopenia/epidemiologia , Administração Oral , Adulto , Peso Corporal , Relação Dose-Resposta a Droga , Feminino , Humanos , Incidência , Indazóis/efeitos adversos , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/métodos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Piperidinas/efeitos adversos , Contagem de Plaquetas , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamenteRESUMO
BACKGROUND: The 5-year survival of ovarian cancer has slowly increased but to date much of this has been due to the use of more lines of treatment rather than better first-line therapy. In this setting, there has been little improvement over the past 15 years. The introduction of new treatments to extend time to first progression and overall survival remains a key objective of clinical research. DESIGN: The focus of research in the previous decade has been on the incorporation of anti-angiogenic therapy or dose-dense scheduling of paclitaxel (Taxol) to improve outcome. The new trials being conducted build on the knowledge gained and are focussing on two new areas of research, the use of PARP (poly-ADP ribose polymerase) inhibitors and immunotherapy. RESULTS: Ongoing randomised trials using PARP inhibitors or immune checkpoint inhibits are reviewed and the potential benefits and challenges of using these agents are discussed. CONCLUSIONS: Improvements in outcome from some of the many open trials may present challenges; interpretation of the outcome data needs to be taken in the context of clinical benefit and a health-economic assessment. The latter is becoming ever-more important as the cost of trials with combinations of targeted therapy is very great.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/imunologia , Paclitaxel/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The Gynecologic Cancer InterGroup (GCIG) Fifth Ovarian Cancer Consensus Conference (OCCC) was held in Tokyo, Japan from 7 to 9 November 2015. It provided international consensus on 15 important questions in 4 topic areas, which were generated in accordance with the mission statement to establish 'International Consensus for Designing Better Clinical Trials'. The methodology for obtaining consensus was previously established and followed during the Fifth OCCC. All 29 clinical trial groups of GCIG participated in program development and deliberations. Draft consensus statements were discussed in topic groups as well as in a plenary forum. The final statements were then presented to all 29 member groups for voting and documentation of the level of consensus. Full consensus was obtained for 11 of the 15 statements with 28/29 groups agreeing to 3 statements, and 27/29 groups agreeing to 1 statement. The high acceptance rate of the statements among trial groups reflects the fact that we share common questions, and recognise important unmet needs that will guide future research in ovarian cancer.
Assuntos
Neoplasias Ovarianas/terapia , Feminino , Humanos , Avaliação das Necessidades , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included.