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OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.
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Fulvestrant , Recurrencia Local de Neoplasia , Receptores de Estrógenos , Humanos , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Fulvestrant/administración & dosificación , Fulvestrant/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Femeninos/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Tumores de los Cordones Sexuales y Estroma de las Gónadas/tratamiento farmacológico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patologíaRESUMEN
Background: Stabilized mutant p53 protein (mutp53) is a novel target in epithelial ovarian cancer. Due to aberrant conformation, mutp53 proteins depend on folding support by the Hsp90 chaperone. Hsp90 blockade induces degradation of mutp53, resulting in tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor ganetespib combined with paclitaxel provided the rationale for testing the combination in platinum-resistant ovarian cancer (PROC) patients in the GANNET53 trial (NCT02012192). Methods: Eligible patients had high-grade PROC with ≤ 4 prior lines of chemotherapy. Weekly paclitaxel (80 mg/m2) and increasing doses of ganetespib (100, 150 mg/m2) were given i.v. on days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. Endpoints were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity (with exceptions) occurring in cycles 1&2. Results: Ten patients (median age 59 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with paclitaxel + ganetespib 100 mg/m2), nor in cohorts 2 and 3 (6 patients treated with paclitaxel + ganetespib 150 mg/m2). The most common adverse event (AE) related to ganetespib was transient grade 1/2 diarrhea (n = 6). Related grade 1/2 AEs in >2 patients included QTc prolongation (n = 4), nausea (n = 3), anemia (n = 3), headache (n = 3), fatigue (n = 3), and dyspnoea (n = 3). Most frequently related grade 3/4 AEs were diarrhea (n = 3) and neutropenia (n = 2). There was 1 death on study due to hemorrhage from a duodenal ulcer. Three patients discontinued study treatment due to serious AEs (digestive hemorrhage n = 1, cardiac failure n = 1, abdominal pain and vomiting n = 1), 6 due to progressive disease, one due to investigator and patient decision. Two patients achieved a partial response (ORR 20%) and 4 patients a stable disease (disease control rate of 60%). Median PFS was 2.9 months (1.6 months in cohort 1 at 100 mg/m2 ganetespib, 5.1 months in cohorts 2+3 at 150 mg/m2 ganetespib). Conclusions: The combination of ganetespib 150 mg/m2 with paclitaxel 80 mg/m2 once weekly for 3 out of 4 weeks was generally well-tolerated with no DLTs, and therefore chosen for the randomized phase II trial.
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BACKGROUND: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations. METHODS: This phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75 years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance ≥ 81, 51-80 or 31-50 mL/min, respectively). Blood was collected for 96 h, and urine samples collected for 24 h post-dose. Patients could continue taking olaparib 300 mg twice daily for a long-term safety assessment. RESULTS: Overall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment. CONCLUSIONS: In patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200 mg twice daily. CLINICAL TRIALS REGISTRATION: NCT01894256.
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Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Insuficiencia Renal/etiología , Administración Oral , Adulto , Anciano , Femenino , Humanos , Riñón/fisiopatología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/patología , Nivel sin Efectos Adversos Observados , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , SeguridadRESUMEN
INTRODUCTION: The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours. METHODS: During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1-5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10-13, 20 mg qd days 14-26; cohort 2, anastrozole 1 mg qd days 10-19; cohort 3, letrozole 2.5 mg qd days 10-38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B. RESULTS: Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0-τ decreased by 20% (90% CI 0.71-0.90) and 27% (0.63-0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0-τ increased by 13% (1.06-1.22) and 16% (1.11-1.21), respectively]; however, the 90% CI fell within the 0.7-1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable. CONCLUSIONS: The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified. FUNDING: AstraZeneca. CLINICAL TRIAL REGISTRATION: NCT02093351.
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Neoplasias de la Mama , Quimioterapia Combinada , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Adulto , Anciano , Anastrozol/administración & dosificación , Anastrozol/farmacocinética , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Monitoreo de Drogas/métodos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Humanos , Letrozol/administración & dosificación , Letrozol/farmacocinética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/clasificación , Neoplasias/patología , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Tamoxifeno/administración & dosificación , Tamoxifeno/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors. METHODS: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors <10 cm and 2 blocks/cm diameter in tumors >10 cm) were performed in all cases. RESULTS: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months. CONCLUSIONS: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent.
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Adenocarcinoma Mucinoso/patología , Recurrencia Local de Neoplasia , Estadificación de Neoplasias/métodos , Neoplasias Ováricas/patología , Lesiones Precancerosas/patología , Salpingooforectomía/métodos , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/cirugía , Lesiones Precancerosas/cirugía , Embarazo , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Despite excellent per-lesion performance for peritoneal staging, the additional clinical value of diffusion-weighted magnetic resonance imaging (DWI/MRI) compared to computed tomography (CT) remains to be established in ovarian cancer. Our purpose was to evaluate whole body (WB)-DWI/MRI for diagnosis, staging and operability assessment of patients suspected for ovarian cancer compared to CT. METHODS: One hundred and sixty-one patients suspected for ovarian carcinoma underwent 3 T WB-DWI/MRI and contrast-enhanced CT. WB-DWI/MRI and CT were compared for confirmation of the malignant nature and primary origin of the ovarian mass, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging and prediction of incomplete resection using institutional operability criteria. Interobserver agreement between two readers was determined for WB-DWI/MRI and CT. RESULTS: WB-DWI/MRI showed a significantly higher accuracy than CT (93 versus 82%, p = 0.001) to confirm the malignant nature of the ovarian mass and correctly identified 26 of 32 (81%) cancers of non-ovarian origin compared to 10/32 (31%) for CT (p < 0.001). WB-DWI/MRI assigned more ovarian carcinoma patients to the correct FIGO stage (82/94, 87%) compared with CT (33/94, 35%). For prediction of incomplete resection, WB-DWI/MRI showed significantly higher sensitivity (94 versus 66%), specificity (97.7 versus 77.3%) and accuracy (95.7 versus 71.3%) compared to CT (p < 0.001). Interobserver agreement was almost perfect (κ = 0.90) for WB-DWI/MRI and moderate (κ = 0.52) for CT for prediction of incomplete resection. CONCLUSIONS: WB-DWI/MRI was superior to CT for primary tumour characterisation, staging and prediction of incomplete resection in patients suspected for ovarian cancer.
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Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias Ováricas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Variaciones Dependientes del Observador , Neoplasias Ováricas/patología , Estándares de Referencia , Adulto JovenRESUMEN
OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by surgery in cervical cancer is widely studied with paclitaxel-ifosfamide-cisplatinum 3 weekly (TIP). Although the response rates with TIP are high, the toxicity is substantial. Therefore, this study evaluates dose-dense paclitaxel-carboplatin (TC) as an alternative. METHODS: In this prospective phase 2 study trial, we included 36 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IIB cervical cancer, who received 9 weeks' NACT dose-dense TC (median weekly dose paclitaxel 60 mg/m, carboplatinum area under the curve 2.7). Radiological response was evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Optimal pathologic response (OPT) was defined as complete disappearance of tumor (complete response [CR]) or residual disease with less than 3-mm stromal invasion (PR1). Suboptimal pathologic response consisted of persistent residual disease with more than 3-mm stromal invasion (PR2). RESULTS: Nine patients had a FIGO stage IB1 (25%), 7 had stage IB2(19%), 3 had stage IIA (8%), and 17 had stage IIB disease (47%). Evaluation by magnetic resonance imaging after NACT showed 32 RECIST responses (89%) (CR in 11, PR in 21). Patients who were inoperable had insufficient reduction of the tumor to be operable (4 patients), progressive disease (1 patient), or stable disease (1 patient). Thirty patients were suitable for surgery after NACT. Pathology showed OPT in 50% (CR in 10, PR1 in 5). Thirteen patients had pathologic lymph nodes on radiological evaluation before start of chemotherapy. After chemotherapy, the lymph nodes were negative in 6 (47%) of these patients (pathologic complete remission). Postoperative chemoradiotherapy was administered in 11 patients (2 because of close resection margins, 5 because of metastatic lymph node after surgery, 2 because of close resection margins and metastatic lymph nodes after surgery, and 1 tumor >4 cm after NACT). Hematologic toxicity was acceptable with no febrile neutropenia and a low nonhematologic toxicity. The estimated 5-year overall survival was 70.8%. CONCLUSIONS: Neoadjuvant TC dose-dense in cervical carcinoma has a high response rate, comparable with TIP, and an acceptable toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Conización , Esquema de Medicación , Femenino , Humanos , Ifosfamida/administración & dosificación , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Prospectivos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugíaRESUMEN
Purpose: Chromosomal instability is a hallmark of ovarian cancer. Here, we explore copy-number alteration (CNA) profiling in cell-free DNA as a potential biomarker to detect malignancy in patients presenting with an adnexal mass.Experimental Design: We prospectively enrolled 68 patients with an adnexal mass, of which 57 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by low-coverage whole-genome sequencing.Results: Patterns of chromosomal instability were detectable in cell-free DNA using 44 healthy individuals as a reference. Profiles were representative of those observed in matching tumor tissue and contained CNAs enriched in two large datasets of high-grade serous ovarian cancer (HGSOC). Quantitative measures of chromosomal instability, referred to as genome-wide z-scores, were significantly higher in patients with ovarian carcinoma than in healthy individuals or patients with benign disease. Cell-free DNA testing improved malignancy detection (AUC 0.89) over serum CA-125 (AUC 0.78) or the risk of malignancy index (RMI, AUC 0.81). AUC values of cell-free DNA testing even further increased for HGSOC patients specifically (AUC 0.94). At a specificity of 99.6%, a theoretical threshold required for ovarian cancer screening, sensitivity of cell-free DNA testing was 2- to 5-fold higher compared with CA-125 and RMI testing.Conclusions: This is the first study evaluating the potential of cell-free DNA for the diagnosis of primary ovarian cancer using chromosomal instability as a read-out. We present a promising method to increase specificity of presurgical prediction of malignancy in patients with adnexal masses. Clin Cancer Res; 23(9); 2223-31. ©2016 AACR.
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Enfermedades de los Anexos/sangre , Biomarcadores de Tumor/sangre , Inestabilidad Cromosómica/genética , Neoplasias Ováricas/sangre , Enfermedades de los Anexos/complicaciones , Enfermedades de los Anexos/patología , Adulto , Anciano , Antígeno Ca-125/sangre , Ácidos Nucleicos Libres de Células/sangre , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/patologíaRESUMEN
PURPOSE: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). FINDINGS: In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. IMPLICATIONS: Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).
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Itraconazol/farmacología , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Rifampin/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Área Bajo la Curva , Inhibidores del Citocromo P-450 CYP3A/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Femenino , Humanos , Itraconazol/administración & dosificación , Masculino , Persona de Mediana Edad , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Rifampin/administración & dosificaciónRESUMEN
OBJECTIVE: To assess the clinical feasibility of whole-body diffusion-weighted MRI (WB-DWI/MRI) for diagnosis and prediction of complete tumour resection in patients with suspected recurrent ovarian cancer. METHODS: 51 females clinically suspected for ovarian cancer recurrence underwent 3-T WB-DWI/MRI in addition to contrast-enhanced CT. WB-DWI/MRI was assessed for detection of tumour recurrence, prediction of tumour extent and complete resection compared with CT. Tumour presence was confirmed by pathology obtained by surgery or biopsy, or by imaging follow-up. RESULTS: WB-DWI/MRI showed 94% accuracy for detecting ovarian cancer recurrence, compared with 78% for CT (p = 0.008). WB-DWI/MRI showed better sensitivity [% (95% confidence interval)] than CT for detecting involvement of surgically critical tumour sites including mesenteric root infiltration [92 (62-100) vs 31 (10-61)], small bowel [93 (64-100) vs 21 (6-51)], colon carcinomatosis [91 (57-100) vs 27 (7-61)] and unresectable distant metastases [90 (54-99) vs 20 (4-56)]. WB-DWI/MRI correctly predicted complete resection in 33 of 35 (94%) patients eligible for salvage surgery compared with 17 of 35 (49%) for CT (p < 0.001). CONCLUSION: WB-DWI/MRI allowed better detection of ovarian cancer recurrence and better prediction of complete resection than CT. Advances in knowledge: WB-DWI/MRI could assist in optimizing treatment planning for recurrent ovarian cancer, particularly by improving patient selection for salvage surgery, thus giving eligible patients the highest chance on prolonged survival and refraining patients who would not benefit from extensive surgery reducing related morbidity and mortality.
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Imagen de Difusión por Resonancia Magnética , Recurrencia Local de Neoplasia/diagnóstico por imagen , Neoplasias Ováricas/diagnóstico por imagen , Imagen de Cuerpo Entero , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Medios de Contraste , Estudios de Factibilidad , Femenino , Humanos , Ácido Yotalámico/análogos & derivados , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Estudios Prospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X , Ácidos TriyodobenzoicosRESUMEN
OBJECTIVE: This study aimed to assess the role and complications of extensive cytoreduction with PlasmaJet (Plasma Surgical, Roswell, Ga) in ovarian cancer with peritoneal carcinomatosis. MATERIALS: All patients undergoing primary, secondary, or interval debulking surgery for ovarian cancer and treated with PlasmaJet between October 2013 and February 2015 were analyzed. RESULTS: Nineteen patients were enrolled. The median operative time was 270 minutes, median blood loss was 700 mL, and median length of stay was 9 days. In all patients, complete resection of all macroscopic disease was achieved.We used PlasmaJet to remove peritoneal carcinomatosis on the abdominal peritoneum, intestinal mesentery, bowel serosa, and diaphragmatic region. Overall, we treated 66 organs with PlasmaJet in our series. No bowel or urological fistulas were observed. According to the Clavien-Dindo classification, 13 adverse events were recorded at grade 2 or lesser. We observed only 1 grade 3 adverse event. No postoperative mortality was recorded. CONCLUSIONS: In our series, the PlasmaJet seems to be an efficient device for tumor ablation or dissection to obtain complete resection of all macroscopic disease in patients with peritoneal carcinomatosis.
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Coagulación con Plasma de Argón/métodos , Carcinoma/cirugía , Procedimientos Quirúrgicos de Citorreducción/métodos , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Laparotomía/métodos , Persona de Mediana EdadRESUMEN
OBJECTIVES: This study aimed to determine the overall survival (OS) and progression-free interval and the influence of fertility-preserving surgery (FPS) versus radical surgery (RS) in patients with serous borderline ovarian tumor (BOT). METHODS: Clinical parameters of patients with serous BOT treated between 1993 and 2013 in one institution were retrospectively investigated. All tumors were examined by one pathologist with experience in gynecological pathology. RESULTS: One hundred thirty-two patients with serous BOT (inclusive 16 microinvasive) were analyzed (45% were ≤40 years), with a median follow-up of 6 years. Thirty-two percent (42/132) of the patients received FPS; 14% (18/132) relapsed (invasive or borderline). The 5-year progression-free survival was 89%. The risk of recurrence was higher in patients 40 years or younger (P = 0.019), after FPS (P = 0.002), in patients with a higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.016), for bilateral BOT (P = 0.0132), and for the micropapillary variant (P = 0.067). The OS at 5 years was 97%. There was no statistically significant difference in OS between FPS and RS [all (6 of 90) patients, except for 1, with RS died]. One patient died of relapsed BOT. Among the recurrences, low-grade invasive carcinoma was diagnosed in 4 patients. Three of these 4 patients were originally operated radically, 2 had a micropapillary variant FIGO stage III, and 1 had a papillary pattern FIGO stage II with microinvasion; all 3 had noninvasive implants and are alive. One patient with a micropapillary variant, FIGO stage IIIC with microinvasion and invasive implants, received FPS and died of disease. CONCLUSIONS: The risk of recurrence is higher after FPS compared with RS; however, no influence on OS was observed. This was because most of the patients relapsed as BOT. Fertility preservation is justified in young patients with serous borderline tumors.
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Cistadenocarcinoma Seroso/cirugía , Preservación de la Fertilidad/métodos , Neoplasias Ováricas/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/patología , Supervivencia sin Enfermedad , Femenino , Preservación de la Fertilidad/efectos adversos , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to report the experience and oncological outcome of robot-assisted radical hysterectomies (RRHs) for cervical cancer performed in Belgium. METHODS: Patients undergoing RRH for cervical cancer (n = 109) were prospectively collected between July 2007 and April 2014 in the 5 Belgian centers performing RRH for cervical cancer. RESULTS: The median age of the patients was 46 years (range, 31-80 years). Histological types included squamous cell carcinoma in 61 patients, adenocarcinoma in 22 patients, adenosquamous in 8 patients, endometrioid carcinoma in 2 patients, and other types (n = 16). The International Federation of Gynecology and Obstetrics stage distribution was IA (n = 9), stage IB1 (n = 71), stage IB2 (n = 4), stage II (n = 24), and unknown (n = 1). Twenty-four patients received adjuvant therapy, 17 patients underwent radiochemotherapy, and 7 underwent adjuvant radiation. Eighteen patients relapsed, and 5 died of disease. The median follow-up was 27.5 months (range, 3-82 months). The 2- and 5-year overall survivals were 96% and 89%, respectively. The 2- and 5-year disease-free survivals (DFSs) were 88% and 72%, respectively. The 2-year DFS per stage was 100% for IA, 88% for IB1, 100% for IB2, and 83% for II. The 5-year DFS per stage was 100% for stage IA and 75% for IB1. The complications were as expected for radical hysterectomy. CONCLUSIONS: This series confirms the feasibility and safety of RRH not only in cervical cancer stage IA to IB1, but also after neoadjuvant chemotherapy in stage IB2 to IIB.
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Carcinoma/terapia , Histerectomía/métodos , Recurrencia Local de Neoplasia/terapia , Procedimientos Quirúrgicos Robotizados , Neoplasias del Cuello Uterino/terapia , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Pérdida de Sangre Quirúrgica , Carcinoma/secundario , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Histerectomía/efectos adversos , Persona de Mediana Edad , Estadificación de Neoplasias , Tempo Operativo , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Tasa de Supervivencia , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. RESULTS: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. CONCLUSIONS: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.
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Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Química Farmacéutica , Estudios Cruzados , Dieta Alta en Grasa/efectos adversos , Esquema de Medicación , Femenino , Semivida , Humanos , Absorción Intestinal , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/sangre , Ftalazinas/efectos adversos , Ftalazinas/química , Ftalazinas/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/química , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , ComprimidosRESUMEN
BACKGROUND: Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. METHODS: In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel-ifosfamide-carboplatin or a combination of paclitaxel-carboplatin was used as neoadjuvant chemotherapy. RESULTS: Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58months with all patients alive and no evidence of disease until now. CONCLUSIONS: Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Cuello del Útero/cirugía , Conización , Preservación de la Fertilidad , Escisión del Ganglio Linfático , Terapia Neoadyuvante , Neoplasias del Cuello Uterino/terapia , Aborto Retenido/etiología , Adenocarcinoma/secundario , Adulto , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/secundario , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Ifosfamida/administración & dosificación , Metástasis Linfática , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pelvis , Embarazo , Índice de Embarazo , Nacimiento Prematuro/etiología , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: To investigate the addition of prophylactic G-CSF to each weekly paclitaxel/carboplatin course in patients with recurrent platinum-resistant ovarian (OC), or recurrent or advanced endometrial (EC) or cervical carcinoma (CC). METHODS: 108 patients were enrolled i.e. 36 in each cohort. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatin (AUC 2.7) were administered weekly. G-CSF (filgrastim) was given to all patients on day 5 (and if needed on day 6). RESULTS: For patients with OC, 91% had platinum-resistant and 9% platinum-refractory disease. Median number of prior chemotherapy lines was 3 for OC, 1 for EC, and 1 for CC. Grade 3-4 neutropenia was observed in 34% of patients (95% CI: 26%-44%, P<0,0001) (OC 29%, EC 36%, CC 38%). This is lower compared to historical data in all cohorts (84%). Confirmed sepsis was observed in 5%, grade 3-4 thrombocytopenia in 41%, grade 2-3 peripheral neuropathy in 17% of patients. In 71% of patients dose was delayed. Dose reduction was necessary for carboplatin in 47% and paclitaxel in 18% of patients. ORR was 51% (OC 48%, EC 45%, CC 58%). Median (95% CI) PFS and OS was 7.1 (5.1-8.1) and 12.7 (10.2-16.3) months, respectively (OC 7 and 13, EC 6 and 19, CC 6 and 14). CONCLUSION: Weekly paclitaxel/carboplatin with G-CSF is an effective treatment with acceptable toxicity in patients with platinum-resistant or platinum-refractory OC, advanced or recurrent EC and CC. The incidence of grade 3-4 neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without routine use of prophylactic G-CSF.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. METHODS: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. RESULTS: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high-fat meal). CONCLUSIONS: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. FUNDING: AstraZeneca.
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Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Estudios Cruzados , Femenino , Absorción Gastrointestinal , Humanos , Masculino , Persona de Mediana Edad , Ftalazinas/uso terapéutico , Piperazinas/uso terapéuticoRESUMEN
OBJECTIVE: Compare surgical staging with imaging (PET-CT, PET or CT) of the para-aortic lymph nodes (PAOLN) in locally advanced cervical cancer (LACC). METHODS: Monocentric retrospective study of 336 patients with cervical cancer FIGO stage IB2-IVA. All patients underwent staging of the PAOLN using imaging by PET-CT, PET or CT. Two hundred and four patients with normal or not overtly malignant PAOLN on imaging underwent surgical PAOLN staging up to the inferior mesenteric artery (189 endoscopy and 15 laparotomy). RESULTS: The patients were divided into 4 groups: 16 with positive surgical staging and negative PAOLN imaging (sPAOLN+), 172 negative surgical staging (sPAOLN-), 20 positive imaging without surgical staging (iPAOLN+) and 128 negative imaging without surgical staging (iPAOLN-). Median operative time of staging was 70 (40-160) min and median number of removed PAOLN was 5 (0-24). Operative complications were 10 peroperative bleedings, 2 ureteral traumas, 1 carbon dioxide retention and 1 retroperitoneal abscess. The median follow-up was 31 (1-218) months. Overall survival at 2 years was for sPAOLN+, sPAOLN-, iPAOLN+, and iPAOLN- 40%, 83%, 58%, and 69%, respectively (p<0.001 for sPAOLN+ and iPAOLN+ versus sPAOLN- and iPAOLN-). The most frequent site of recurrence was distant LN metastases (outside the pelvic and PAO area) (36%) for sPAOLN+. For sPAOLN-, iPAOLN+, and iPAOLN- the most frequent site of recurrence was the cervix (27%, 66% and 26%, respectively). CONCLUSION: Despite negative imaging, PAOLN metastases were present in 8% at surgical staging. Overall survival is significantly influenced by the presence of PAOLN metastases.
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Ganglios Linfáticos/patología , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Aorta , Femenino , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Metástasis Linfática , Persona de Mediana Edad , Imagen Multimodal , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Adulto JovenRESUMEN
BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Polimorfismo de Nucleótido Simple , Neoplasias de la Mama/química , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Pronóstico , Receptores de Estrógenos/análisis , Análisis de Supervivencia , Población Blanca/genéticaRESUMEN
BACKGROUND: This study aimed to determine whether single nucleotide polymorphisms (SNPs) in genes involved in DNA repair or metabolism of taxanes or platinum could predict toxicity or response to first-line chemotherapy in ovarian cancer. METHODS: Twenty-six selected SNPs in 18 genes were genotyped in 322 patients treated with first-line paclitaxel-carboplatin or carboplatin mono-therapy. Genotypes were correlated with toxicity events (anemia, neutropenia, thrombocytopenia, febrile neutropenia, neurotoxicity), use of growth factors and survival. RESULTS: The risk of anemia was increased for variant alleles of rs1128503 (ABCB1, C > T; p = 0.023, OR = 1.71, 95% CI = 1.07-2.71), rs363717 (ABCA1, A > G; p = 0.002, OR = 2.08, 95% CI = 1.32-3.27) and rs11615 (ERCC1, T > C; p = 0.031, OR = 1.61, 95% CI = 1.04-2.50), while it was decreased for variant alleles of rs12762549 (ABCC2, C > G; p = 0.004, OR = 0.51, 95% CI = 0.33-0.81). Likewise, increased risk of thrombocytopenia was associated with rs4986910 (CYP3A4, T > C; p = 0.025, OR = 4.99, 95% CI = 1.22-20.31). No significant correlations were found for neurotoxicity. Variant alleles of rs2073337 (ABCC2, A > G; p = 0.039, OR = 0.60, 95% CI = 0.37-0.98), rs1695 (ABCC1, A > G; p = 0.017, OR = 0.55, 95% CI 0.33-0.90) and rs1799793 (ERCC2, G > A; p = 0.042, OR = 0.63, 95% CI 0.41-0.98) associated with the use of colony stimulating factors (CSF), while rs2074087 (ABCC1, G > C; p = 0.011, OR = 2.09, 95% CI 1.18-3.68) correlated with use of erythropoiesis stimulating agents (ESAs). Homozygous carriers of the rs1799793 (ERCC2, G > A) G-allele had a prolonged platinum-free interval (p = 0.016). CONCLUSIONS: Our data reveal significant correlations between genetic variants of transport, hepatic metabolism, platinum related detoxification or DNA damage repair and toxicity or outcome in ovarian cancer.