RESUMO
OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.
Assuntos
Neoplasias do Endométrio , Proteína Supressora de Tumor p53 , Feminino , Humanos , Estudos de Coortes , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação , Recidiva Local de Neoplasia , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , População Negra/genética , População Branca/genéticaRESUMO
BACKGROUND: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation. METHODS: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival. RESULTS: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery. CONCLUSIONS: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Recidiva Local de Neoplasia/cirurgia , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Idoso , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Qualidade de Vida , Reoperação , Análise de SobrevidaRESUMO
Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have aimed to establish whether combination therapy can augment the response seen with PARP inhibitors or antiangiogenic agents alone. This review provides an overview of PARP inhibitors and antiangiogenics as monotherapy in women with advanced ovarian cancer, explores potential mechanisms of action of PARP inhibitor and antiangiogenic combination treatments, reviews efficacy and safety data from trials evaluating this combination, and outlines ongoing and future trials evaluating this combination, discussing these in the context of the current and future treatment landscape for women with advanced ovarian cancer. Sentinel studies evaluating PARP inhibitor (n = 8), antiangiogenic (n = 4), and combination (n = 7) therapy were identified in women with newly diagnosed (n = 7) and recurrent (n = 12) ovarian cancer. PARP inhibitors included olaparib (n = 9), niraparib (n = 4), rucaparib (n = 1), and veliparib (n = 1). Antiangiogenic agents included bevacizumab (n = 7) and cediranib (n = 4). PARP inhibitors combined with antiangiogenics demonstrated efficacy based on objective response rates and progression-free survival (PFS) in the relapsed disease setting. Maintenance therapy with the PARP inhibitor, olaparib, plus antiangiogenic therapy offered a significant PFS benefit versus the antiangiogenic alone in women with newly diagnosed advanced ovarian cancer who tested positive for homologous recombination deficiency. Combination therapy was tolerated, with no new safety signals reported compared with monotherapy trials. PARP inhibitors and antiangiogenics have changed the landscape of ovarian cancer treatment. The PARP inhibitor plus antiangiogenic combination is a novel treatment option that appears promising in the first-line advanced and recurrent ovarian cancer settings, although the role of this combination in recurrent disease requires further elucidation. Defining which patients are candidates for monotherapy or combination therapy is critical, taking into consideration safety profiles of therapies alone or in combination, and how these treatments should be sequenced in clinical practice.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/métodos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Seleção de Pacientes , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Reparo de DNA por RecombinaçãoRESUMO
OBJECTIVE: To identify novel immunologic targets and biomarkers associated with overall survival (OS) in high-grade serous ovarian cancer (HGSC). METHODS: In this retrospective study, microarray data from 51 HGSC specimens were analyzed (Affymetrix HG-U133A). A panel of 183 immune/inflammatory response related genes linked to 279 probe sets was constructed a priori and screened. Associations between gene expression and OS were assessed using logrank tests. Multiple testing was addressed within the False Discovery Rate (FDR) framework. For external validation, TCGA Ovarian dataset and five GSE publicly available HGSC datasets were evaluated. RESULTS: In Duke data, 110 probe sets linked to 83 immunologic/inflammatory-related genes were differentially expressed in tumors from long versus short-term HGSC survivors (adjusted p < 0.05). In TCGA, concordant with the results from the Duke discovery cohort, high expression of one probe (IL6R) demonstrated a consistent significance and concordant association with higher expression in long-term HGSC survivors (Duke q-value = 0.022) and improved OS in the TCGA dataset (p-value = 0.015, HR = 0.8). Thirteen genes in GSE14764 (N = 4) and GSE26712 (N = 9) datasets had significant p-values and consistent concordant with Duke Data. Despite the significant associations of gene expression and OS in the individual GSE datasets, in the GSE meta-analysis no genes were consistently concordant and significantly associated with survival. CONCLUSIONS: Evaluation of IL6R expression may be warranted based on higher expression in long-term survivors and association with improved survival in advanced HGSC. The other candidate genes may also be of worthy of further exploration to enhance immuno-oncology drug discovery.
Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/cirurgia , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/cirurgia , Bases de Dados Genéticas , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Receptores de Interleucina-6/biossíntese , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Estudos RetrospectivosRESUMO
OBJECTIVES: The COVID-19 pandemic has consumed considerable resources and has impacted the delivery of cancer care. Patients with cancer may have factors which place them at high risk for COVID 19 morbidity or mortality. Highly immunosuppressive chemotherapy regimens and possible exposure to COVID-19 during treatment may put patients at additional risk. The Society of Gynecologic Oncology convened an expert panel to address recommendations for best practices during this crisis to minimize risk to patients from deviations in cancer care and from COVID-19 morbidity. METHODS: An expert panel convened to develop initial consensus guidelines regarding anti-neoplastic therapy during the COVID-19 pandemic with respect to gynecologic cancer care and clinical trials. RESULTS: COVID-19 poses special risks to patients who are older, have medical co-morbidities, and cancer. In addition, this pandemic will likely strain resources, making delivery of cancer care or conduct of clinical trials unpredictable. Recommendations are to limit visits and contact with health care facilities by using telemedicine when appropriate, and choosing regimens which require less frequent visits and which are less immunosuppressive. Deviations will occur in clinical trials as a result of limited resources, and it is important to understand regulatory obligations to trial sponsors as well as to the IRB to ensure that clinical trial and patient safety oversight are maintained. CONCLUSIONS: The ongoing crisis will strain resources needed to deliver cancer care. When alterations to the delivery of care are mandated, efforts should be taken to minimize risks and maximize safety while approximating standard practice.
Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Infecções por Coronavirus/prevenção & controle , Neoplasias dos Genitais Femininos/terapia , Oncologia/métodos , Oncologia/normas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , COVID-19 , Infecções por Coronavirus/transmissão , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/virologia , Humanos , Pneumonia Viral/transmissão , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normasRESUMO
OBJECTIVE: To measure preferences of women with ovarian cancer regarding risks, side effects, costs and benefits afforded by maintenance therapy (MT) with a poly ADP ribose polymerase (PARP) inhibitor. METHODS: A discrete-choice experiment elicited preferences of women with ovarian cancer regarding 6 attributes (levels in parentheses) relevant to decisions for MT versus treatment break: (1) overall survival (OS; 36, 38, 42 months); (2) progression-free survival (PFS; 15, 17, 21 months); (3) nausea (none, mild, moderate); (4) fatigue (none, mild, moderate); (5) probability of death from myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML; 0% to 10%); (6) monthly out-of-pocket cost ($0 to $1000). Participants chose between 2 variable MT scenarios and a static scenario representing treatment break, with multiple iterations. Random-parameters logit regression was applied to model choices as a function of attribute levels. RESULTS: 95 eligible participants completed the survey; mean age was 62, 48% had recurrence, and 17% were ever-PARP inhibitor users. Participants valued OS (average importance weight 24.5 out of 100) and monthly costs (24.6) most highly, followed by risk of death from MDS/AML (17.9), nausea (14.7), PFS (10.5) and fatigue (7.8). Participants would accept 5% risk of MDS/AML if treatment provided 2.2 months additional OS or 4.8 months PFS. Participants would require gains of 2.6 months PFS to accept mild treatment-related fatigue and 4.4 months to accept mild nausea. CONCLUSIONS: When considering MT, women with ovarian cancer are most motivated by gains in OS. Women expect at least 3-4 months of PFS benefit to bear mild side effects of treatment.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Preferência do Paciente/psicologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Tomada de Decisões , Feminino , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/economia , Recidiva Local de Neoplasia/psicologia , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/psicologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Intervalo Livre de Progressão , Taxa de Sobrevida , Estados UnidosRESUMO
OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively pâ¯<â¯0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, pâ¯<â¯0.0001 in uterine and 3.5% vs 0.3% respectively, pâ¯=â¯0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48â¯months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.
Assuntos
Inibidores da Aromatase/administração & dosagem , Receptor alfa de Estrogênio/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Adulto , Inibidores da Aromatase/farmacologia , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transcrição Gênica/efeitos dos fármacos , Transcriptoma , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Predictive models are increasingly being used in clinical practice. The aim of the study was to develop a predictive model to identify patients with platinum-resistant ovarian cancer with a prognosis of less than 6 to 12 months who may benefit from immediate referral to hospice care. METHODS: A retrospective chart review identified patients with platinum-resistant epithelial ovarian cancer who were treated at our institution between 2000 and 2011. A predictive model for survival was constructed based on the time from development of platinum resistance to death. Multivariate logistic regression modeling was used to identify significant survival predictors and to develop a predictive model. The following variables were included: time from diagnosis to platinum resistance, initial stage, debulking status, number of relapses, comorbidity score, albumin, hemoglobin, CA-125 levels, liver/lung metastasis, and the presence of a significant clinical event (SCE). An SCE was defined as a malignant bowel obstruction, pleural effusion, or ascites occurring on or before the diagnosis of platinum resistance. RESULTS: One hundred sixty-four patients met inclusion criteria. In the regression analysis, only an SCE and the presence of liver or lung metastasis were associated with poorer short-term survival (P < 0.001). Nine percent of patients with an SCE or liver or lung metastasis survived 6 months or greater and 0% survived 12 months or greater, compared with 85% and 67% of patients without an SCE or liver or lung metastasis, respectively. CONCLUSIONS: Patients with platinum-resistant ovarian cancer who have experienced an SCE or liver or lung metastasis have a high risk of death within 6 months and should be considered for immediate referral to hospice care.
Assuntos
Técnicas de Apoio para a Decisão , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Cuidados Paliativos , Compostos de Platina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Cuidados Paliativos/métodos , Prognóstico , Encaminhamento e Consulta , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). METHODS: Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N=40 (19.9%), no gross disease/microscopically positive N=8 (4.0%), and gross disease N=153 (76.1%). RESULTS: The median PFS for patients with no gross disease/microscopically negative was 16.1months, no gross disease/microscopically positive was 13.5months and for gross disease was 11.7months, P=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5months, no gross disease/microscopically positive was 42.6months and for gross disease was 34.9months, P=0.018. CONCLUSION: Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Endometrioide/patologia , Procedimentos Cirúrgicos de Citorredução , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/patologia , Reoperação , Idoso , Carcinoma Endometrioide/cirurgia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Císticas, Mucinosas e Serosas/cirurgia , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVES: To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. METHODS: Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. RESULTS: The median TSIC was 62.5days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26days, p<0.001). TSIC was significantly associated (p=0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R2 -0.141, 95%CI -0.217, -0.064, p<0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. CONCLUSIONS: In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further.
Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Antineoplásicos/administração & dosagem , Carcinoma Endometrioide/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Infusões Parenterais/métodos , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Adenocarcinoma de Células Claras/patologia , Idoso , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
OBJECTIVES: To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). METHODS: 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. RESULTS: Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. CONCLUSIONS: Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.
Assuntos
Cistadenocarcinoma Seroso/irrigação sanguínea , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/genética , Adulto , Idoso , Antígenos CD/análise , Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/patologia , Endoglina , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Neovascularização Patológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Superfície Celular/análise , Taxa de SobrevidaRESUMO
BACKGROUND: The objective of this study was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen. METHODS: Women with advanced or recurrent ovarian cancer participated in a survey that included 3 methods to measure patient preferences (ratings, rankings, and a discrete-choice experiment) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort, and PFS. Participants were asked to choose between 2 unlabeled treatment scenarios that were characterized using the 7 attributes. Each participant completed 12 choice questions in which attribute levels were assigned according to an experimental design and a fixed-choice question representing 2 chemotherapy regimens for ovarian cancer. RESULTS: In total, 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (P < .0001 for all). The discrete-choice experiment revealed that the relative odds that a participant would choose a scenario with 18 months, 21 months, and 24 months of PFS versus 15 months of PFS were 1.5 (P = .01), 3.4 (P < .001), and 7.5 (P < .001), respectively. However, participants' choices indicated that they were willing to accept a shorter PFS to avoid severe side effects: 6.7 months to reduce nausea and vomiting from severe to mild, 5.0 months to reduce neuropathy from severe to mild, and 3.7 months to reduce abdominal symptoms from severe to moderate. CONCLUSIONS: PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in the current study were willing to trade significant PFS time for reductions in treatment-related toxicity.
Assuntos
Antineoplásicos/efeitos adversos , Comportamento de Escolha , Recidiva Local de Neoplasia/terapia , Neoplasias Ovarianas/tratamento farmacológico , Preferência do Paciente , Idoso , Intervalo Livre de Doença , Fadiga/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/psicologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/psicologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Vômito/induzido quimicamenteRESUMO
OBJECTIVE: The aim of this study is to determine whether a minimally invasive approach to hysterectomy is associated with an increased rate of lymph vascular space invasion (LVSI) and/or malignant pelvic peritoneal cytology in endometrial cancer. METHODS: We performed a single institution analysis of 458 women with endometrial cancer who underwent either total abdominal hysterectomy (TAH) or minimally invasive hysterectomy (MIH) with use of a disposable uterine manipulator. All patients had endometrial cancer diagnosed by endometrial biopsy at a single academic institution between 2002 and 2012. Exclusion criteria were pre-operative D&C and/or hysteroscopy, uterine perforation or morcellation, and conversion to laparotomy. Multivariate logistic regression models to determine if type of hysterectomy predicts either LVSI or presence of abnormal cytology were controlled for grade, stage, depth of invasion, tumor size, cervical and adnexal involvement. RESULTS: LVSI was identified in 39/214 (18%) MIH and 44/242 (18%) TAH (p=0.99). Pelvic washings were malignant in 14/203 (7%) MIH and 16/241 (7%) TAH (p=1.0). Washings were atypical or inconclusive in 16/203 (8%) MIH and 6/241 (2.5%) TAH (p=0.014). In multivariate analyses, type of hysterectomy was not a significant predictor of either LVSI (p=0.29) or presence of malignant washings (p=0.66), but was a predictor of atypical or inconclusive washings (p=0.03). CONCLUSION: Minimally invasive hysterectomy with use of a uterine manipulator for endometrial cancer is not associated with LVSI or malignant cytology. Algorithms that better determine the etiology and implications of inconclusive or atypical pelvic cytology are needed to inform the possible additional risk associated with a minimally invasive approach to endometrial cancer.
Assuntos
Adenocarcinoma/patologia , Líquido Ascítico/patologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Histerectomia/métodos , Excisão de Linfonodo , Miométrio/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Papilar/patologia , Adenocarcinoma Papilar/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Modelos Logísticos , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Pelve , Lavagem Peritoneal , Estudos RetrospectivosRESUMO
PURPOSE: To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review. RESULTS: Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills. CONCLUSION: The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.
Assuntos
Neoplasias Ovarianas , Paclitaxel , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Intervalo Livre de Progressão , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: The objective of this study was to evaluate the comparative effectiveness of strategies that incorporated bevacizumab into the primary platinum-based treatment of ovarian cancer: 1) no bevacizumab; 2) concurrent and maintenance bevacizumab for all; 3) bevacizumab for suboptimally debulked stage III and stage IV disease (high-risk cohort); and the evaluation of an alternative exploratory strategy of 4) directed bevacizumab therapy based on a predictive test for bevacizumab responsiveness. METHODS: A modified Markov state transition model with a 3-year time horizon that simulated publically available International Collaboration on Ovarian Neoplasms (ICON7) trial outcomes was used to evaluate the cost effectiveness of each strategy. Costs and adverse events were incorporated. An alternative strategy was used to model the impact on overall survival of a genetic-based predictive test. A Monte Carlo simulation simultaneously accounted for uncertainty in key parameters. RESULTS: The incorporation of bevacizumab for high-risk patients had an incremental cost-effectiveness ratio of $168,000 per quality-adjusted life-year (QALY) saved compared with chemotherapy alone and dominated a strategy of giving bevacizumab to all patients with ovarian cancer. Monte Carlo simulation acceptability curves indicated that, at a willingness-to-pay threshold of $200,000 per QALY, the treatment of high-risk women with bevacizumab was the strategy of choice in 84% of simulations. A predictive test had an incremental cost-effectiveness ratio of $129,000 per QALY compared with chemotherapy alone and dominated other bevacizumab treatment strategies. CONCLUSIONS: The selective treatment of women with suboptimal and/or stage IV ovarian cancer was a more cost-effective use of bevacizumab than universal treatment but still did not fall within the limits of common willingness-to-pay thresholds. Continued investigation of potentially cost-effective strategies, such as a predictive test, is necessary to optimize the use of this expensive treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/economia , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Carboplatina/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Humanos , Cadeias de Markov , Modelos Teóricos , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de SobrevidaRESUMO
OBJECTIVES: (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. METHODS: A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14 days of life, >1 hospitalization in the last 30 days, >1 ER visit in the last 30 days, intensive care unit (ICU) admission in the last 30 days, dying in an acute care setting, admitted to hospice ≤3 days. RESULTS: One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29 days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30 days before death was associated with a lower incidence of: chemotherapy in the last 14 days of life (p=0.003), >1 hospitalization in the last 30 days (p<0.001), ICU admission in the last 30 days (p=0.005), dying in acute care setting (p=0.01), admitted to hospice ≤3 days (p=0.02). EOL discussion as outpatient was associated with fewer patients hospitalized >1 in the last 30days of life (p<0.001). CONCLUSIONS: End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/psicologia , Assistência Terminal/métodos , Assistência Terminal/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/psicologia , Feminino , Recursos em Saúde , Humanos , Pessoa de Meia-Idade , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/psicologia , Qualidade de Vida , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVE: We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix. METHODS: Eligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m(2) day 1, topotecan 0.75 mg/m(2) days 1, 2 and 3 and bevacizumab 15 mg/kgday 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy. RESULTS: Twenty-seven eligible patients received a median of 3 treatment cycles (range, 1-19). Median follow-up was 10 months (range, 1.7-33.4). The 6-month PFS was 59% (80% CI: 46-70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4-14%) and 8 PR (31%; 80% CI: 19-45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25-53%) with median duration of 2.2 months. Median PFS was 7.1 months (80% CI: 4.7-10.1) and median OS was 13.2 months (80% CI: 8.0-15.4). All patients were evaluated for toxicity. Grade 3-4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities. CONCLUSION: The addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluordesoxiglucose F18 , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Neoplasias do Colo do Útero/diagnóstico por imagem , Adulto JovemRESUMO
Cyclin-dependent kinase inhibitors are approved in combination with hormonal therapy for treatment of hormone receptor expressing breast cancers. Activity in hormone receptor expressing gynecologic cancers has been postulated. Granulosa cell tumor of the ovary is one such cancer, which is relatively resistant to traditional cytotoxic chemotherapy. We report a case series of 7 heavily pre-treated patients with recurrent granulosa cell tumor of the ovary with a cyclin-dependent kinase inhibitor in combination with hormonal therapy, with 3 patients demonstrating partial response and 2 with stable disease. As of the data cutoff, 3 patients remained on treatment and 5 were alive, with true medians for duration of treatment and overall survival not reached (medians at data cutoff of 64 weeks and 62 months respectively). The treatment was generally well tolerated, with 1 patient choosing to discontinue treatment due to grade 3 fatigue. This regimen represents a possible option in the treatment of granulosa cell tumor of the ovary, warranting further prospective study for this unmet need in this indolent disease which often requires many lines of treatment.
RESUMO
BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction. METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450. FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group). INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction. FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
Assuntos
Obstrução Intestinal , Neoplasias , Estados Unidos , Humanos , Masculino , Feminino , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Projetos de Pesquisa , Seleção de PacientesRESUMO
BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2) on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC.