RESUMEN
INTRODUCTION: Niraparib first-line maintenance (1LM) therapy has demonstrated clinical benefit for patients with ovarian cancer (OC) in clinical trial and real-world settings, but data on factors associated with real-world patient outcomes remain limited. This analysis identified patient characteristics associated with time to next treatment (TTNT), a proxy for real-world progression-free survival, in patients with OC treated with 1LM niraparib monotherapy. METHODS: This retrospective observational study used a USA nationwide electronic health record-derived deidentified database and included adult patients diagnosed with OC who initiated 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Patients were followed until the earliest occurrence of last clinical activity, death, or end of study period. TTNT was measured from 1LM niraparib initiation to the start of second-line treatment or death. Cox proportional hazards models assessed univariable and multivariable associations between baseline characteristics and TTNT. RESULTS: Of 7872 patients diagnosed with OC, 526 met the eligibility criteria and were included in this analysis. Median (IQR) duration of follow-up was 14.1 (7.4-23.6) months. In univariable analyses, age, BRCA/homologous recombination deficiency (HRD) status, socioeconomic status, stage at initial diagnosis, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT and were introduced into the multivariable model with other clinically relevant variables. In the multivariable analysis, BRCA/HRD status, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT after covariate adjustment. Conversely, age, Eastern Cooperative Oncology Group performance status, disease stage, niraparib starting dose status, and first-line bevacizumab use were not associated with observed TTNT. CONCLUSION: This real-world, retrospective, observational analysis offers valuable insights on prognostic factors associated with TTNT in patients with OC treated with 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Future studies are needed to examine how additional patient characteristics associated with clinical outcomes may guide treatment decisions and improve outcomes.
RESUMEN
INTRODUCTION: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. METHODS: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011-30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan-Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). RESULTS: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60-72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7-25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0-53.9 days). Median TTD was 9.3 months (95% CI 6.1-11.3 months). Median TTNT was 12.9 months (95% CI 11.5-19.0 months). CONCLUSIONS: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC.
RESUMEN
Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.
RESUMEN
OBJECTIVE: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.
Asunto(s)
Neoplasias Ováricas , Neoplasias Peritoneales , Femenino , Humanos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Progresión de la Enfermedad , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patología , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
OBJECTIVE: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC). METHODS: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses. RESULTS: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo). CONCLUSIONS: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS.
Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
OBJECTIVE: Evaluate systemic therapy utilization patterns and outcomes by line of therapy among patients with advanced/recurrent endometrial cancer (EC) treated in the United States. METHODS: This retrospective observational study used the Optum Clinformatics Extended Data Mart Date of Death database (1 January 2004-31 December 2019) and included de-identified data from adult patients with advanced/recurrent EC who were treated with first-line (1L) platinum-based chemotherapy and initiated second-line (2L) anti-neoplastic therapy. The index date was the date of 1L therapy initiation. The number and sequence of treatments received and the proportion of patients who received each type of treatment for each line of therapy were evaluated. To account for new drug approvals, patients first treated in 2018 or 2019 were also assessed separately. RESULTS: Among the 1317 patients who met all eligibility criteria, 520 (39.5%) and 235 (17.8%) patients received 3 or 4+ lines of treatment, respectively, during a median total follow-up time of 25.2 months (range, 2.5-173.3 months) following the index date. Chemotherapy, including platinum- and non-platinum-based regimens, was the most common treatment across all lines of therapy: 2L, 80.0%; 3L, 66.2%; 4L+, 80.4%. Overall, 2.5%, 2.3%, and 8.9% of 2L, 3L, and 4L + patients, respectively, received anti-program death 1 (anti-PD-1) immunotherapies. In patients first treated in 2018 and 2019 (n = 163), 9.8% of patients received anti-PD-1 immunotherapy in the 2L. In the overall population, median time to next treatment (TTNT) was 19.3, 10.5, and 8.1 months for patients undergoing 2L, 3L, and 4L treatment, respectively. CONCLUSIONS: Among patients with advanced/recurrent EC treated with 1L platinum-based therapy in clinical practice, chemotherapy was the most common treatment choice across all lines of therapy. Immunotherapy use was low overall but increased in patients who started treatment in 2018 or 2019. Overall, median TTNT decreased as lines of therapy increased.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Adulto , Humanos , Estados Unidos , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inmunoterapia , Estudios Retrospectivos , Neoplasias Endometriales/tratamiento farmacológicoRESUMEN
OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Anciano , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/patología , Quimioterapia Adyuvante , Estudios de Cohortes , Procedimientos Quirúrgicos de Citorreducción , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de TiempoRESUMEN
OBJECTIVE: This study aims to determine the rate of postoperative venous thromboembolism (VTE) in endometrial cancer patients undergoing robotic hysterectomy with or without extended pharmacologic VTE prophylaxis. METHODS/MATERIALS: A retrospective chart review of women undergoing robotic hysterectomy with or without other procedures for endometrial cancer from January 2010 to February 2015 was conducted at 2 institutions. Charts were manually abstracted, and rates of VTE within 30 and 60 days after surgery were determined. Patients were then stratified by those who did and did not receive extended VTE prophylaxis. RESULTS: A total of 403 patients were included, of which 367 patients (91%) received extended pharmacologic prophylaxis and 36 patients (9%) did not. Low molecular weight heparin prescriptions ranged from 7 to 30 days. Patients receiving extended prophylaxis (EP) were older (63 ± 11 vs 57 ± 12; P = 0.004), more frequently underwent lymphadenectomy (67% vs 34%; P < 0.001), and had higher-grade tumors compared with patients not receiving EP. Overall 30-day and 60-day VTE rates were 0.7% and 1.2%, respectively. There were no significant differences in 30-day and 60-day VTE rates among patients that did and did not receive EP, although a trend toward lower VTE rates in the EP group was observed (30-day rates 0.5% vs 2.8% respectively, P = 0.25; 60-day rates 0.8% vs 5.6%, P = 0.07). CONCLUSIONS: In this study, 30-day and 60-day VTE rates after minimally invasive surgery for endometrial cancer were low. Rates were also similar to those of previous reports in this setting in which the majority of patients did not receive extended VTE prophylaxis. Given the consistent finding that postoperative VTE in this population is rare regardless of prophylaxis use and the variability in practice patterns for VTE prophylaxis, the development of best practice guidelines for EP use specific to this setting is warranted.
Asunto(s)
Neoplasias Endometriales/sangre , Neoplasias Endometriales/cirugía , Tromboembolia Venosa/epidemiología , Estudios de Cohortes , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/patología , Femenino , Humanos , Histerectomía/efectos adversos , Histerectomía/métodos , Histerectomía/estadística & datos numéricos , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/estadística & datos numéricos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.
Asunto(s)
Adenocarcinoma de Células Claras/tratamiento farmacológico , Carcinosarcoma/tratamiento farmacológico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Anciano , Carcinosarcoma/mortalidad , Carcinosarcoma/patología , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Estudios de Seguimiento , Humanos , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Squamous cell carcinoma of the ovary is a rare complication of mature cystic teratoma. The epidemiology, pathology, diagnosis, and management of this rare tumor are reviewed. Clinical characteristics, preoperative imaging, and tumor markers may help to predict malignancy preoperatively. Complete cytoreduction should be the aim of surgery. The prognosis for stage 1A disease is good, but for women with advanced or recurrent disease, it is very poor and has not improved in recent years. At present, there are insufficient data to provide clear guidance on the optimal management strategy for advanced disease, and there is a need to gain an understanding of the biology and to develop novel effective therapies. This will require coordinated international collaboration.
Asunto(s)
Carcinoma de Células Escamosas/patología , Oncología Médica , Neoplasias Ováricas/patología , Guías de Práctica Clínica como Asunto , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Consenso , Femenino , Humanos , Neoplasias Ováricas/terapia , Sociedades MédicasRESUMEN
Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (Ld ). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in Ld (% fold-increase > 50%, p-value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with micro-RNA expression data.
Asunto(s)
Transformación Celular Neoplásica , Cuello del Útero/patología , Endometrio/patología , Neoplasias Ováricas/patología , Anciano , Células Epiteliales/patología , Femenino , Humanos , Persona de Mediana Edad , Nanotecnología , Neoplasias Ováricas/etiologíaRESUMEN
OBJECTIVE: There is growing evidence that progestins and nonsteroidal antiinflammatory drugs (NSAIDs) may prevent ovarian cancer. Because both induce apoptosis, we investigated the potential for synergistic impact of combined drug treatment on cell death. STUDY DESIGN: Using normal and malignant human ovarian epithelial cells and an NSAID-sensitive human colon cancer cell line, we evaluated the effects of progestins and NSAIDs alone and in combination on apoptosis. RESULTS: Both progestins and NSAIDs dose dependently inhibited cell growth (P < .0001). Doses of NSAIDs or progestins that independently reduced cell viability by less than 30% synergistically reduced cell viability by 70-95% when combined. Similarly, the NSAID/progestin combination conferred 4- to 18-fold (P < .05) increased apoptosis over either treatment alone. CONCLUSION: Our results suggest it may be possible to combine progestins and NSAIDs to achieve ovarian cancer prevention at lower doses of each than are required for single administration, thereby lessening the risk of side effects posed by these agents.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Ováricas/prevención & control , Ovario/efectos de los fármacos , Ovario/patología , Progestinas/farmacología , Antiinflamatorios no Esteroideos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Progestinas/administración & dosificaciónRESUMEN
OBJECTIVES: Protein kinase C (PKC) activation contributes to proliferation and angiogenesis in epithelial ovarian or primary peritoneal carcinoma (EOC/PPC). A multi-institutional phase II trial was conducted to evaluate the efficacy and safety of PKCß inhibitor enzastaurin in persistent or recurrent EOC/PPC and to explore potential prognostic and predictive biomarkers. METHODS: Eligible women with measurable platinum-sensitive and resistant EOC/PPC were treated with continuous administration of oral enzastaurin until disease progression or unacceptable toxicity. A two-stage sequential design was used to evaluate progression-free survival (PFS) ≥6-months, tumor response, and toxicity. Translational studies included sequencing of the TP53, PTEN, PIK3CA and PKCßII genes for somatic mutations, quantitative PCR assays for AKT2 and PTEN copy number alterations, and measurement of circulating VEGF-A plasma levels. RESULTS: Among 27 eligible and evaluable patients, 3 women with PFS≥6-months (11%) and 2 women with partial responses (7%) were observed. One of them achieved a durable response and remains on the study. No grade 4 adverse events were observed. Most common grade 3 adverse events were constitutional (4) and gastrointestinal (3). Mutations in the TP53 gene and abnormal copy number in the PTEN gene were common (56% and 48% of cases, respectively). CONCLUSIONS: Enzastaurin was tolerable but had insufficient activity to proceed with the second stage of accrual. However, 1 patient has been progression-free for 44 months. No association between a biomarker and response to enzastaurin has been found. Exploratory analysis suggested an association between survival and PTEN copy number losses.
Asunto(s)
Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma Epitelial de Ovario , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Genes p53 , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/genética , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/enzimología , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/genética , Fosfohidrolasa PTEN/genética , Neoplasias Peritoneales/enzimología , Neoplasias Peritoneales/genética , Fosfatidilinositol 3-Quinasas/genética , Proteína Quinasa C/genética , Proteína Quinasa C beta , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-akt/genética , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC). METHODS: Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum. RESULTS: Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS. CONCLUSION: Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.
Asunto(s)
Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Tamoxifeno/uso terapéutico , Talidomida/uso terapéutico , Administración Oral , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Antígeno Ca-125/sangre , Supervivencia sin Enfermedad , Determinación de Punto Final , Neoplasias de las Trompas Uterinas/sangre , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/sangre , Neoplasias Peritoneales/sangre , Tamoxifeno/efectos adversos , Taxoides/administración & dosificación , Talidomida/efectos adversos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Disease metastatic to the heart from cervical carcinoma is rare and associated with a poor prognosis. Multimodality treatment has been shown to provide palliative benefit. CASE: A woman presented with stage Ib2 cervical cancer metastatic to the tricuspid valve. She presented with small bowel obstruction from a small bowel metastasis 4 years after initial treatment with chemoradiation. Computed tomographic imaging revealed a small bowel mass as well as a pericardial effusion. Cardiac magnetic resonance imaging showed a tricuspid mass. Endomyocardial biopsy confirmed metastatic disease consistent with a cervical primary. The patient was treated with bowel resection, systemic chemotherapy and cardiac radiation. She died of cardiac failure 8 months after diagnosis of the cardiac lesion. CONCLUSION: Cervical cancer metastatic to the heart is rare and associated with a poor prognosis. Selected patients may benefit from multimodality treatment.
Asunto(s)
Carcinoma/secundario , Neoplasias Cardíacas/secundario , Válvula Tricúspide/patología , Neoplasias del Cuello Uterino/patología , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma/terapia , Resultado Fatal , Femenino , Neoplasias Cardíacas/terapia , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/terapiaRESUMEN
The current management of advanced ovarian cancer consists of aggressive primary cytoreductive surgery (PCS) followed by combination platinum based chemotherapy. Recent studies have suggested that platinum-based chemotherapy may be of benefit in patients with advanced ovarian cancer prior to cytoreductive surgery (neoadjuvant chemotherapy, NACT). The concept of NACT has not been completely validated in the treatment of ovarian cancer. This review will discuss the role of NACT in patients with advanced epithelial ovarian cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Ováricas/terapia , Quimioterapia Adyuvante , Femenino , Humanos , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Ovariectomía , Selección de PacienteRESUMEN
OBJECTIVES: To evaluate the response rate and toxicity of a regimen comprised of monthly carboplatin and weekly paclitaxel for recurrent ovarian cancer. METHODS: We performed a retrospective chart review of patients with recurrent ovarian cancer treated between 2001 and 2006 at a single institution with carboplatin AUC 5 (day 1), and paclitaxel 80 mg/m(2) (days 1, 8, 15) of a 28-day cycle. Primary endpoints were response rate, progression-free survival and overall survival. RESULTS: Twenty patients were treated with this regimen from 2001 to 2006. Stage ranged from stages IC to IV. All received intravenous platinum and taxane as their initial therapy. Histologic subtypes included papillary serous (17), carcinosarcoma (1), and clear cell (2). The median number of prior regimens was 1 (range 1-3). The overall response rate was 85.0% (15 complete responses, 2 partial responses). Patients with tumors categorized as platinum sensitive had a response rate of 93.3% (14/15) and those with tumors deemed platinum resistant had a response rate of 60.0% (3/5). The median survival has not yet been reached after a median follow-up of 28 months. Neutropenia was the only grade 3/4 toxicity, occurring in 7 patients (35.0%). Platinum hypersensitivity reactions occurred in 5 patients (25.0%) who all successfully continued treatment using a carboplatin desensitization protocol. CONCLUSIONS: A monthly carboplatin and weekly paclitaxel regimen is highly active for women with recurrent platinum-sensitive and platinum-resistant epithelial ovarian cancer. The regimen is well tolerated. This pilot series demonstrates the potential for this regimen as treatment of choice among doublet first salvage regimens for patients with recurrent epithelial ovarian cancer, thus warranting multi-institutional study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/patología , Estudios RetrospectivosRESUMEN
OBJECTIVE: We previously demonstrated that omega-3 fatty acids (OM-3FAs) have definitive inhibitory effects on ovarian cancer cell lines. We sought to determine whether the inhibitory effects of OM-3FAs were mediated by the transforming growth factor (TGF)-beta1 signaling pathway. STUDY DESIGN: Ovarian cancer cell lines were grown at 37 degrees C in 5% CO(2) and treated with OM-3FAs, omega-6 fatty acids, and control at different concentrations for 24-72 hours. Enzyme-linked immunosorbent assay (ELISA) assay and Western blot analysis were used to measure TGF-beta1, phosphorylated mothers against decapentaplegic (Smad)-3 and p21 protein levels. RESULTS: An ELISA assay demonstrated that OM-3FA treatment increased TGF-beta1 in all 3 Hey cell lines (P < .05). In both SKOV-3 and OVCAR-3 cells, TGF-beta1 levels were not significantly increased. Western blots confirmed increases in TGF-beta1, Smad-3 and p21 protein levels in Hey and HeyC2 but not SKOV-3 and OVCAR-3 cells. CONCLUSION: OM-3FAs increased the level of TGF-beta1, Smad-3, and p21 protein in ovarian cancer cells known to be more sensitive to their inhibitory effect.