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Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
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Antígenos de Neoplasias/inmunología , Inmunoglobulina A/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Linfocitos T Citotóxicos/inmunología , Transcitosis , Especificidad de Anticuerpos , Antígenos CD/inmunología , Línea Celular , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Ováricas/prevención & control , Receptores Fc/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Transcitosis/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
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OBJECTIVES: To determine clinical significance of preoperative and pre-chemotherapy CA-125 in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients with stage IA/IB and grade 3, stage IC, clear cell, or completed resected stage II cancer were enrolled in a phase III trial and treated with chemotherapy. Kaplan-Meier method and Cox proportional hazards model were used for statistical analyses. RESULTS: 427 patients with high-risk early-stage ovarian cancer were enrolled. Of 213 patients with preoperative CA-125 data, 79% had elevated CA-125. Median preoperative CA-125 level was 103 U/mL. Patients with ≤10, 11-15, and > 15 cm tumors had median preoperative CA-125 levels of 62, 131 and 158 U/mL, respectively (p = 0.002). For the 350 patients with data for pre-chemotherapy CA-125 level, 69% had elevated pre-chemotherapy CA-125 above 35 U/mL with median value of 65 U/mL. However, age, race, stage, cell type and grade of disease were not correlated with CA-125 levels before and after surgery. On multivariate analysis, elevated pre-chemotherapy CA-125 independently predicted worse recurrence-free survival (HR = 2.13, 95% CI: 1.23-3.69; p = 0.007) and overall survival (HR = 1.99, 95% CI: 1.10-3.59; p = 0.022) after adjusting for age, stage, cell type and grade of disease. Compared to those with normal CA-125, patients with elevated pre-chemotherapy CA-125 had lower recurrence-free survival (RFS, 87% vs. 75%; p = 0.007) and overall survival (OS, 88% vs. 82%; p = 0.02). However, preoperative CA-125 was not prognostic of RFS (p = 0.699) or OS (p = 0.701). CONCLUSIONS: Preoperative CA-125 was elevated in nearly 80% of high-risk early-stage ovarian cancer patients. Pre-chemotherapy CA-125 was associated with recurrence-free and overall survival; however, preoperative CA-125 was not prognostic.
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Neoplasias Ováricas , Femenino , Humanos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.
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Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Ftalazinas , Piperazinas , Quinazolinas , Humanos , Femenino , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Recombinación Homóloga , Supervivencia sin Progresión , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , IndolesRESUMEN
Ovarian cancer is considered the most fatal and costly gynecologic cancer. Although personalized therapies have improved ovarian cancer prognosis, they have resulted in increased financial toxicity concerns among this population. This study evaluated financial toxicity in patients with advanced ovarian cancer. Using secondary data from a study of barriers to palliative care, financial toxicity (FT) was measured through the Comprehensive Score for Financial Toxicity scale. Univariate and bivariate analyses were used to assess the relationship between selected demographic (i.e., age, race, ethnicity, education, place of birth, insurance type, yearly household income, employment status) and treatment-specific variables (i.e., years since diagnosis, surgery, chemotherapy, radiation, hormonal and targeted therapy) with clinically relevant financial toxicity. Characteristics were compared using Fisher's exact or chi squared tests. A total of 38 participants with advanced ovarian cancer were included in this study; 24% (n = 9) reported clinically significant FT. Income (p = .001), place of birth (p = .048) and employment status (p = .001) were related to FT. Study findings highlight that advanced ovarian cancer patients experience high FT, particularly those with low income, who are not able to work and were born outside the US. Further research using larger datasets and more representative samples is needed to inform intervention development and implementation.
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Estrés Financiero , Renta , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/terapia , Neoplasias Ováricas/patología , Persona de Mediana Edad , Anciano , Estrés Financiero/psicología , Renta/estadística & datos numéricos , Cuidados Paliativos , Factores Socioeconómicos , Empleo/estadística & datos numéricos , Adulto , Anciano de 80 o más Años , Factores SociodemográficosRESUMEN
OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.
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Neoplasias Endometriales , Paclitaxel , Humanos , Femenino , Paclitaxel/efectos adversos , Resultado del Tratamiento , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).
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Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Antígeno Ca-125 , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carboplatino , Paclitaxel , Doxorrubicina , Polietilenglicoles , Recurrencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
OBJECTIVE: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. METHODS: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared. RESULTS: We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. CONCLUSIONS: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.
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Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Femenino , Humanos , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carboplatino , Neoplasias Ováricas/patología , Supervivencia sin Enfermedad , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Paclitaxel , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de NeoplasiasRESUMEN
OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.
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Neoplasias Ováricas , Femenino , Humanos , Carboplatino , Creatinina , Tasa de Filtración Glomerular , Pruebas de Función Renal , Neoplasias Ováricas/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
PURPOSE: Palliative care aims to provide symptom relief and general support for patients with serious illness. Despite experiencing significant treatment side effects, specialty palliative care is under-utilized by patients with advanced ovarian cancer. We explored barriers to palliative care in this population. METHODS: We conducted a sequential mixed-methods study. Qualitative: we interviewed patients with advanced ovarian cancer (N = 7). Guided by the Social Ecological Model (SEM), interviews assessed intrapersonal, interpersonal, organizational, and policy-level barriers to receipt of specialty palliative care. Interviews were audio-recorded, transcribed, and analyzed with directed content analysis. Quantitative: patients with advanced ovarian cancer (N = 38) completed self-report surveys assessing knowledge about, attitudes towards, and prior experiences with specialty palliative care. Descriptive statistics were used to characterize survey responses. RESULTS: Qualitative analysis identified barriers to specialty palliative care at each SEM level. Intrapersonal factors (e.g., knowledge, attitudes) were most frequently discussed. Other common barriers included insurance coverage and distance/travel time. Survey responses indicated most participants were aware of palliative care (74%) but had mixed attitudes towards palliative care and did not feel they needed for palliative care. No survey respondents had received a physician recommendation for palliative care, and a sizable minority (29%) thought palliative care referral should only take place when patients have no remaining treatment options. CONCLUSION: Among patients with advanced ovarian cancer, barriers to specialty palliative care exist at multiple levels. Our results underscore the potential value of a multilevel intervention to support receipt of palliative care in this population.
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Enfermería de Cuidados Paliativos al Final de la Vida , Neoplasias Ováricas , Médicos , Humanos , Femenino , Cuidados Paliativos/métodos , Pacientes , Neoplasias Ováricas/terapiaRESUMEN
OBJECTIVE: To determine the effect of distance to closest negative margin on survival after pelvic exenteration (PE). METHODS: In this retrospective analysis of PE at Moffitt Cancer Center from 2000 to 2019, baseline characteristics, clinical details, and outcomes were ascertained. Distance to closest negative margin was measured. Close and distant negative margins were defined as <3 mm and ≥3 mm from malignancy to nearest surgical margin, respectively. Overall survival (OS) and progression-free survival (PFS) were determined, and Kaplan-Meier curves were compared. Cox proportional hazards regression was used to examine the association of margin status with OS and PFS. RESULTS: Of 124 PEs with malignancy, 80 (64.5%) had negative margins. Median survival was 62 (95% confidence interval [CI] 27-70) months for negative and 21 (95% CI 15-29) months for positive margins. Of 76 with negative margins and documented margin length, 26 had close and 50 had distant margins. Median survival was 32 (95% CI 14-62) months for close and 111 (95% CI 42-166) months for distant margins. Distant margins were associated with improved OS (p = 0.0054) and PFS (p = 0.0099) compared to close margins. After adjusting for other prognostic factors, patients with distant margins had significantly decreased risk of all-cause mortality (HR 0.39, 95% CI 0.19-0.78; p = 0.008) and progression (HR 0.48, 95% CI 0.23-0.99; p = 0.04) compared to positive margins. No significant differences in OS or PFS were observed between close and positive margins. This survival benefit remained among those with cervical cancer. Median survival in this cohort was 34.1 (95% CI 2.0-69.8) months for close and 165.7 (95% CI 24.5-165.7) for distant margins. CONCLUSIONS: Distant margins following PE are associated with improved OS and PFS compared to close margins.
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Exenteración Pélvica , Neoplasias del Cuello Uterino , Femenino , Humanos , Márgenes de Escisión , Recurrencia Local de Neoplasia/cirugía , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias del Cuello Uterino/cirugíaRESUMEN
OBJECTIVES: To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4). CONCLUSIONS: Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.
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Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estadificación de Neoplasias , Antígeno Ca-125 , Carboplatino , PaclitaxelRESUMEN
OBJECTIVE: To describe the incidence, complications, and trends associated with ureteral surgeries on a gynecologic oncology service in the context of a fellowship training program over a 24-year period. METHODS: We conducted a retrospective cohort analysis of ureteral surgeries by gynecologic oncologists at either Moffitt Cancer Center or Tampa General Hospital from 1997 to 2020. Patient characteristics, predisposing factors, location and type of injury, repair method, postoperative management and complications were abstracted from the medical record. The recent cohort (2005-2020) was compared to our prior series (1997-2004). RESULTS: Eighty-eight cases were included. The average number of ureteral surgeries per year decreased from 5.75 (1997-2004) to 2.63 (2005-2020). Of 46 iatrogenic injuries, 45 were recognized and repaired intraoperatively. Ureteral transection was the most common type (85% [39 of 46]) and the distal 5 cm was the most common location of injury (63% [29 of 46]). Ureteroneocystostomy was the most common method of repair (83% [73 of 88]). Postoperative management, including stenting and imaging, has not changed significantly. Length of urinary catheter usage decreased in the recent cohort without associated complications. Five patients had major postoperative complications and 4 involved the urinary tract. Of those with follow-up, 96% (66 of 69) of ureteroneocystostomies and 75% (9 of 12) of ureteroureterostomies had radiologically normal urinary tracts. CONCLUSIONS: Ureteral surgery is necessary in the case of injury or involvement with invasive disease. There has been a decrease in number of procedures. Ureteroneocystostomy has remained the most common method of reconstruction for both injury and resection with acceptable postoperative complication rates.
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Neoplasias de los Genitales Femeninos/cirugía , Uréter/cirugía , Estudios de Cohortes , Cistostomía/métodos , Cistostomía/tendencias , Femenino , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Ginecológicos/tendencias , Humanos , Estudios Retrospectivos , Uréter/lesiones , Ureterostomía/métodos , Ureterostomía/tendenciasRESUMEN
OBJECTIVES: Older women have a worse prognosis with advanced epithelial ovarian cancer (EOC) and comorbidities likely contribute to poor outcomes. We sought to identify comorbid conditions and treatment-related factors in older women. METHODS: A retrospective chart review identified 351 patients who underwent cytoreductive surgery (CRS). 100/351 (28.5%) were ≥ 70 years old. Demographic and clinicopathologic information was collected. Crude progression-free (PFS) and overall survival (OS) estimates were calculated using Kaplan-Meier method. Cox proportional hazards regression model was used to estimate hazard ratios and adjustments for confounders. RESULTS: Study subjects ≥70 years old had significantly: higher Cumulative Illness Rating Scale-Geriatric (CIRS-G) score (5.9 vs 4.3; p = 0.0001), less completion of adjuvant chemotherapy (24% vs 15.1%; p = 0.049), less intraperitoneal (IP) therapy (18.2% vs 35.5%; p = 0.002), less clinical trial participation (16% vs 26.3%; p = 0.040), decreased platinum sensitivity (60% vs 73.7%; p = 0.012) and lacked BRCA mutations (0% vs 12%; p = 0.0006). They were less likely to have optimal CRS (75% vs 86.9%; p = 0.007) with same surgical complexity (p = 0.89). Patients ≥70 had significantly worse PFS and OS. In a multivariate analysis, better OS was associated with younger age (<70 years old), any IP therapy, completion of adjuvant chemotherapy, and platinum sensitivity. CONCLUSION: The older cohort had worse CIRS-G scores (5.9 vs 4.3; p = 0.0001), but no strong associations between comorbidities and treatment characteristics, but less optimal CRS rates (75% vs 86.9%; p = 0.007) with similar surgical complexity and less platinum sensitivity. Our results show comorbid conditions in older patients with advanced EOC may have less impact than tumor biology.
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Carcinoma Epitelial de Ovario/cirugía , Anciano Frágil , Neoplasias Ováricas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Comorbilidad , Femenino , Florida , Humanos , Registros Médicos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: Identify predisposing, enabling, and reinforcing factors impacting genetic counseling/testing among ovarian cancer patients guided by Green and Kreuter's PRECEDE-PROCEED model. METHODS: Gynecologic oncology providers (N = 4), genetic counselors (N = 4), and ovarian cancer patients (N = 9) completed semi-structured qualitative interviews exploring participants' knowledge of and experiences with genetic counseling/testing. Interviews were audio recorded, transcribed verbatim, and analyzed using inductive content analysis by two independent raters. RESULTS: Thematic analysis identified predisposing, enabling, and reinforcing factors impacting referral for and uptake of genetic counseling/testing. Predisposing factors included participant's knowledge, beliefs, and attitudes related to genetic counseling/testing. Both patients and providers also cited that insurance coverage and out-of-pocket cost are major concerns for ovarian cancer patients considering genetic testing. Finally, both patients and providers emphasized that genetic counseling/testing would provide additional information to an ovarian cancer patient. While providers emphasized that genetic testing results were useful for informing a patient's personal treatment plan, patients emphasized that this knowledge would be beneficial for their family members. CONCLUSION: Barriers to genetic testing for ovarian cancer patients exist at multiple levels, including the patient (e.g., knowledge, attitudes), the provider (e.g., workload, availability of services), the institution (e.g., difficulty with referrals/scheduling), and the healthcare system (e.g., insurance/cost). Interventions aiming to increase genetic testing among ovarian cancer patients will likely need to target multiple levels of influence. Future quantitative studies are needed to replicate these results. This line of work will inform specific multilevel intervention strategies that are adaptable to different practice settings, ultimately improving guideline concordant care.
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Asesoramiento Genético/métodos , Pruebas Genéticas/métodos , Neoplasias Ováricas/diagnóstico , Relaciones Médico-Paciente , Femenino , Humanos , Neoplasias Ováricas/genéticaRESUMEN
Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Derivación y Consulta/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Demografía , Femenino , Pruebas Genéticas/normas , Personal de Salud , Humanos , Aseguradoras , Modelos Logísticos , Persona de Mediana Edad , National Cancer Institute (U.S.) , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/fisiopatología , Neoplasias Ováricas/terapia , Estudios Retrospectivos , Estados Unidos , Población Blanca/genéticaRESUMEN
INTRODUCTION: To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer. METHODS: In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test. RESULTS: Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19â¯months (3-52â¯months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2-44); pâ¯=â¯0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, pâ¯=â¯0.09). Grade 3-4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66â¯Gy (pâ¯=â¯0.03) and prior pelvic radiotherapy (pâ¯=â¯0.002) predicted grade 3-4 toxicity. CONCLUSION: High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.
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Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/uso terapéutico , Neoplasias de la Vulva/tratamiento farmacológico , Neoplasias de la Vulva/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/diagnóstico por imagen , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias de la Vulva/diagnóstico por imagenRESUMEN
OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Método Doble Ciego , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Quimioterapia de Mantención , Persona de Mediana Edad , Supervivencia sin Progresión , Piridinas/administración & dosificación , Piridinas/efectos adversos , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , GemcitabinaRESUMEN
OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07). CONCLUSIONS: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.
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Neoplasias de los Genitales Femeninos/epidemiología , Terapia de Reemplazo de Hormonas/métodos , Salpingooforectomía/métodos , Adolescente , Adulto , Femenino , Predisposición Genética a la Enfermedad , Neoplasias de los Genitales Femeninos/cirugía , Humanos , Persona de Mediana Edad , Conducta de Reducción del Riesgo , Adulto JovenRESUMEN
BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood. METHODS: GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy - Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time. RESULTS: Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO. CONCLUSIONS: HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.