RESUMO
BACKGROUND: Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-ß1 and TGF-ß2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance. METHODS: This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1â×â107 cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747. FINDINGS: Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0-44·8) and from first dose of placebo was 39·8 months (35·5-44·6). Recurrence-free survival was 11·5 months (95% CI 7·5-not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9-15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44-1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups. INTERPRETATION: Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted. FUNDING: Gradalis.
Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma Endometrioide/terapia , Neoplasias Ovarianas/terapia , Idoso , Vacinas Anticâncer/efeitos adversos , Carcinoma Endometrioide/imunologia , Carcinoma Endometrioide/patologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BRCA1 and BRCA2 mutation carriers have an increased risk of developing breast and/or ovarian cancer. Technical advances in genetic testing have increased the need for genetic counseling services; therefore, we have developed a counseling program for these individuals. The purpose of this study is to characterize this population, assess level of interest in genetic testing, and evaluate our program over a 5-year period. Our Familial Cancer Genetic Counseling Program was established in November, 1994. Information was collected prospectively, with comprehensive evaluation including complete pedigree, risk assessment, and counseling by a genetic counselor, geneticist, and oncologist. Data were collected on risk level, and subsequent recommendations for screening and/or genetic testing. There were 824 contacts recorded from November, 1994, through August, 1999. To date, 162 families have undergone comprehensive genetic evaluation and counseling. 90 (56%) were seen for a concerning family history and 72 (44%) were seen due to a personal history of malignancy. The majority of families had a significant level of risk with 126 (78%) families having two and 70 (43%) families having three affected first-degree relatives. Of the 162 families who received full counseling, 125 (77%) met criteria to recommend BRCA1/BRCA2 genetic testing. At this time, 30 of the 162 (18%) have had genetic testing. A brief phone contact or clinic visit is useful to screen individuals so that counseling can be directed toward truly high-risk families. In our program, the majority of families counseled were eligible for BRCA1/BRCA2 testing, but only 18% have elected to proceed at this time.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/organização & administração , Neoplasias Ovarianas/genética , Neoplasias da Mama/epidemiologia , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/genética , Feminino , Aconselhamento Genético/tendências , Humanos , Neoplasias Ovarianas/epidemiologia , Fatores de Risco , WisconsinRESUMO
BACKGROUND: A prospective study was undertaken within the Gynecologic Oncology Group to determine whether serum levels of soluble tumor necrosis factor receptors I (sTNFR-I) and II (sTNFR-II), alone or in combination with CA 125, were associated with clinicopathologic characteristics or outcome in patients with epithelial ovarian malignancies. METHODS: Quantitative immunoassays were performed on valid pretreatment serum specimens obtained from patients with epithelial ovarian malignancies to assess levels of sTNFR-I, sTNFR-II, and CA 125. The authors then analyzed the results of these immunoassays for potential correlations with clinicopathologic characteristics and outcome. RESULTS: The median age of the 139 women evaluated was 59 years. Seventy-eight percent had Stage III or IV disease, and 58% had serous carcinomas. sTNFR-II was associated with age (P = 0.013), and CA 125 was associated with histologic subtype (P = 0.0009). In addition, sTNFR-I (P = 0.037) and CA 125 (P < 0.0001) were associated with extent of disease. After adjusting for patient age, histologic subtype, and extent of disease, all three biomarkers were predictive of progression-free survival, but not overall survival, when the combination was included in the model. The authors observed a 51% reduction (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24-0.99), a 2.9-fold increase (HR, 2.87; 95% CI, 1.15-7.20), and a 22% increase (HR, 1.22; 95% CI, 0.99-1.51) in the risk of progression for each unit increase in the log-transformed levels of sTNFR-I, sTNFR-II, and CA 125, respectively. CONCLUSIONS: The observations made in the current study-that among patients with low or high CA 125 levels, those with high sTNFR-I levels and low sTNFR-II levels had the lowest risk, that patients with low-low or high-high sTNFR-I and sTNFR-II levels, respectively, had an intermediate risk, and that patients with low sTNFR-I levels and high sTNFR-II levels had the highest risk of progression-suggested the potential value of simultaneous assessment of all three biomarkers in patients with epithelial ovarian malignancies.