RESUMEN
OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Inmunoconjugados , Maitansina , Neoplasias Ováricas , Trombocitopenia , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Gemcitabina , Neoplasias Ováricas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/etiología , Trompas Uterinas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/etiología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Diarrea/inducido químicamente , Trombocitopenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Maitansina/análogos & derivadosRESUMEN
Background/objectives: Patients hospitalized with alcohol withdrawal syndrome (AWS) are typically treated with CIWA-directed benzodiazepines to prevent complications, such as seizures and delirium tremens. Gabapentin is an evidence-based alternative to benzodiazepines in the outpatient setting, but there is limited data for hospitalized patients with AWS. This study compared fixed-dose gabapentin to CIWA-directed benzodiazepines for AWS in the hospital setting. Methods: This open-label, randomized controlled trial enrolled 88 adults from February 1, 2017 to August 16, 2020 with a risk of complicated alcohol withdrawal as defined by the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) ≥4. Patients were randomized within 16 h of admission to either fixed-dose gabapentin taper or continued CIWA-directed benzodiazepine administration. The primary outcome was the length of stay (LOS). Secondary outcomes included seizure, delirium tremens, ICU transfer, and patient-reported symptoms (alcohol cravings, anxiety, sleepiness). Results: LOS was shorter, but not statistically different in the gabapentin group compared to the benzodiazepine group. Because benzodiazepines were received in both gabapentin and benzodiazepine groups before randomization, the mean amount of benzodiazepines received in each group was also not statistically different, although the amount received by the gabapentin group was less than half of that received by the benzodiazepine group (4.3 vs. 10.6 mg, p = 0.146 by per protocol analysis). There were no statistical differences in secondary measures. Conclusions: Fixed-dose gabapentin taper showed similar outcomes compared to CIWA-directed benzodiazepines for the treatment of hospitalized patients with mild/moderate AWS, but the interpretation of the results is limited due to under-enrollment and the use of benzodiazepines in both groups pre-enrollment.Clinical trial registration: NCT03012815.
Asunto(s)
Delirio por Abstinencia Alcohólica , Alcoholismo , Síndrome de Abstinencia a Sustancias , Adulto , Humanos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/diagnóstico , Alcoholismo/tratamiento farmacológico , Alcoholismo/complicaciones , Gabapentina/uso terapéutico , Delirio por Abstinencia Alcohólica/tratamiento farmacológico , Delirio por Abstinencia Alcohólica/complicaciones , Delirio por Abstinencia Alcohólica/prevención & control , Benzodiazepinas/uso terapéutico , Hospitales , Estudios RetrospectivosRESUMEN
OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.
Asunto(s)
Fibrilación Atrial , Trastorno Bipolar , Enfermedades Cardiovasculares , Trastorno Depresivo Mayor , Trastorno Bipolar/epidemiología , Enfermedades Cardiovasculares/complicaciones , Estudios de Cohortes , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/epidemiología , Humanos , Factores de RiesgoRESUMEN
BACKGROUND: SERCA [sarco(endo)plasmic reticulum calcium ATPase] is regulated by oxidative posttranslational modifications at cysteine 674 (C674). Because sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species, we hypothesized that SERCA oxidation at C674 would modulate the effects of reactive oxygen species on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes. METHODS: Adult rat ventricular myocytes expressing wild-type SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to H2O2 (100 µmol/Lµ). Free mitochondrial calcium concentration was measured in adult rat ventricular myocytes with a genetically targeted fluorescent probe, and SR calcium content was assessed by measuring caffeine-stimulated release. Mice with heterozygous knock-in of the SERCA C674S mutation were subjected to chronic ascending aortic constriction. RESULTS: In adult rat ventricular myocytes expressing wild-type SERCA, H2O2 caused a 25% increase in mitochondrial calcium concentration that was associated with a 50% decrease in SR calcium content, both of which were prevented by the ryanodine receptor inhibitor tetracaine. In cells expressing the C674S mutant, basal SR calcium content was decreased by 31% and the H2O2-stimulated rise in mitochondrial calcium concentration was attenuated by 40%. In wild-type cells, H2O2 caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SERCA knock-in mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis in vivo, SERCA knock-in mice were subjected to chronic ascending aortic constriction. In wild-type mice, ascending aortic constriction caused myocyte apoptosis, LV dilation, and systolic failure, all of which were inhibited in SERCA knock-in mice. CONCLUSIONS: Redox activation of SERCA C674 regulates basal SR calcium content, thereby mediating the pathologic reactive oxygen species-stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.
Asunto(s)
Apoptosis , Calcio/metabolismo , Insuficiencia Cardíaca/enzimología , Mitocondrias Cardíacas/enzimología , Miocitos Cardíacos/enzimología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Apoptosis/efectos de los fármacos , Señalización del Calcio , Células Cultivadas , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Peróxido de Hidrógeno/toxicidad , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/patología , Mutación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Oxidantes/toxicidad , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
Vulvar cancer is a rare malignancy with high curability in early-stage disease, yet poor outcomes for advanced-stage and recurrent disease. Surgical management is at the cornerstone of treatment for most vulvar cancers, and includes conservative and radical resection of the primary vulvar tumor and excision of local lymph nodes, which are major prognostic factors and drive adjuvant treatment. This review summarizes the surgical management of primary squamous cell carcinoma of the vulva, specifically initial treatment guidelines by stage, based on the 2017 NCCN Clinical Practice Guidelines in Oncology for Vulvar Cancer.
Asunto(s)
Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia/cirugía , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugía , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/radioterapia , Femenino , Humanos , Conducto Inguinal , Estadificación de Neoplasias , Exenteración Pélvica , Guías de Práctica Clínica como Asunto , Radioterapia Adyuvante , Factores de Riesgo , Biopsia del Ganglio Linfático Centinela , Vulva/cirugía , Neoplasias de la Vulva/diagnóstico , Neoplasias de la Vulva/radioterapiaRESUMEN
BACKGROUND: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia; however, rigorous monitoring is required to prevent or detect adverse drug events that contribute to morbidity and mortality. In addition to the Food and Drug Administration (FDA) boxed safety warnings specific to clozapine (agranulocytosis, hypotension, seizures, and cardiomyopathy/myocarditis), other adverse events such as pneumonia and gastrointestinal hypomotility have been reported in the literature to result in hospitalization. OBJECTIVE: To explore the reasons for medical hospitalization in patients prescribed clozapine, a retrospective chart review was completed. METHODS: Adults with schizophrenia or schizoaffective disorder prescribed clozapine were identified if they had a nonpsychiatric medical admission between 1/1/2003 and 8/1/2015. Demographics, admitting diagnosis, admitting service type, psychiatric consult information, clozapine dosing, and drug interactions were collected. RESULTS: Overall, 104 patients, representing 248 hospitalizations, were admitted to a medical unit during the study period. The predominant admission types were for the management of either pulmonary (32.2%) or gastrointestinal (19.8%) illnesses. The most common pulmonary diagnosis was pneumonia, accounting for 58% of pulmonary admissions. Further, 61.2% of the gastrointestinal admissions were related to hypomotility, ranging from constipation to death. Clozapine was discontinued owing to neutropenia in 2 patients; however, in both cases concomitant chemotherapy had been given. CONCLUSION: In patients prescribed clozapine admitted to nonpsychiatric medical settings, gastrointestinal and pulmonary illnesses were common, but not illnesses related to boxed warnings. Additional research is needed to better assess the causality and true incidence of gastrointestinal or pulmonary events associated with clozapine. Furthermore, clinicians must be prepared to prevent, detect, and manage potentially life-threatening events associated with clozapine.
Asunto(s)
Clozapina/uso terapéutico , Enfermedades Gastrointestinales/epidemiología , Hospitalización/estadística & datos numéricos , Enfermedades Pulmonares/epidemiología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/epidemiología , Antipsicóticos/uso terapéutico , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minnesota/epidemiología , Estudios RetrospectivosRESUMEN
This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.
Asunto(s)
Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Femenino , HumanosRESUMEN
BACKGROUND: With advances such as next-generation sequencing (NGS) increasing understanding of the basis of cancer and its response to treatment, NCCN believes it is important to understand how molecular profiling/diagnostic testing is being performed and used at NCCN Member Institutions and their community affiliates. METHODS: The NCCN Oncology Research Program's Investigator Steering Committee and the NCCN Best Practices Committee gathered baseline information on the use of cancer-related molecular testing at NCCN Member Institutions and community members of the NCCN Affiliate Research Consortium through 2 separate surveys distributed in December 2013 and September 2014, respectively. RESULTS: A total of 24 NCCN Member Institutions and 8 affiliate sites provided quantitative and qualitative data. In the context of these surveys, "molecular profiling/diagnostics" was defined as a panel of at least 10 genes examined as a diagnostic DNA test in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. CONCLUSIONS: Results indicated that molecular profiling/diagnostics are used at 100% of survey respondents' institutions to make patient care decisions. However, challenges relating to reimbursement, lack of data regarding actionable targets and targeted therapies, and access to drugs on or off clinical trials were cited as barriers to integration of molecular profiling into patient care. Frameworks for using molecular diagnostic results based on levels of evidence, alongside continued research into the predictive value of biomarkers and targeted therapies, are recommended to advance understanding of the role of genomic biomarkers. Greater evidence and consensus regarding the clinical and cost-effectiveness of molecular profiling may lead to broader insurance coverage and increased integration into patient care.
Asunto(s)
Biomarcadores de Tumor , Perfilación de la Expresión Génica , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Investigación Cualitativa , Encuestas y CuestionariosRESUMEN
Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.
Asunto(s)
Apoptosis/fisiología , Citosol/metabolismo , Insuficiencia Cardíaca/metabolismo , Peróxido de Hidrógeno/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Miocitos Cardíacos/patología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Retículo Sarcoplasmático/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.
Asunto(s)
Biomarcadores/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Ensayos Clínicos como Asunto , Humanos , Medicina de Precisión/métodos , Proyectos de InvestigaciónRESUMEN
OBJECTIVES: Hospital-based behavioral emergency response teams (BERT) respond to acute behavioral disturbances among hospitalized patients. We aimed to examine associations between altered mental status in postanesthesia care unit (PACU) and behavioral disturbances on surgical wards requiring BERT activation. METHODS: Electronic medical records of patients who underwent general anesthesia and were admitted to the PACU between May 2018-December 2020 were reviewed for episodes of BERT activations on surgical wards. Characteristics of BERT patients were compared with the rest of surgical population during the same period to examine risk factors for BERT. RESULTS: Of 56,275 adult surgical patients, 133 patients had 178 BERT activations (incidence 2.4, 95% confidence interval [CI] 2.0-2.8 per 1000 admissions), with 21 being for physical assault. The risk for BERT activation was increased with each decade over age of 50 as well as younger age (30 versus 50 y), male sex (odds ratio [OR] = 2.48, 95% CI 1.69, 3.62), longer procedures (OR = 1.08 per 30 minutes, 95% CI 1.05, 1.11), and alterations in mental status in PACU, with both moderate/deep sedation (OR = 1.63, 95% CI 1.04, 2.57) and agitation/combative state (OR = 8.47, 95% CI 5.13, 14.01), P < 0.001 for all comparisons. CONCLUSIONS: Early postoperative agitation and oversedation are associated with BERT activation on surgical wards. Altered mental status in PACU should be conveyed to accepting hospital units so healthcare staff can be vigilant for the potential development of behavioral disturbances.
RESUMEN
These NCCN Guidelines Insights focus on the major updates to the 2013 NCCN Guidelines for Ovarian Cancer. Four updates were selected based on recent important updates in the guidelines and on debate among panel members about recent clinical trials. The topics include 1) intraperitoneal chemotherapy, 2) CA-125 monitoring for ovarian cancer recurrence, 3) surveillance recommendations for less common ovarian histopathologies, and 4) recent changes in therapy for recurrent epithelial ovarian cancer. These NCCN Guidelines Insights also discuss why some recommendations were not made.
Asunto(s)
Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Femenino , Humanos , RecurrenciaAsunto(s)
Mutismo Acinético/diagnóstico , Delirio/diagnóstico , Epilepsia del Lóbulo Frontal/diagnóstico , Mutismo Acinético/tratamiento farmacológico , Mutismo Acinético/epidemiología , Anticonvulsivantes/uso terapéutico , Comorbilidad , Delirio/epidemiología , Electroencefalografía , Epilepsia del Lóbulo Frontal/tratamiento farmacológico , Epilepsia del Lóbulo Frontal/epidemiología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: We aim to compare the psychiatric antecedents of schizophrenia (SZ) and bipolar disorder (BD). METHODS: Using the Rochester Epidemiology Project, we searched for residents of Olmsted County that had a diagnosis of SZ or BD. We confirmed each case using DSM-5 criteria and obtained the psychiatric antecedents. RESULTS: We identified 205 cases with first episode psychosis or mania (SZ = 131; BD = 74). The mean age at first visit for mental health reasons was 12.3 ± 6.3 years for SZ and 13.9 ± 5.6 years for BD. The duration of the initial prodrome (time from first mental health visit to first episode) was similar for both groups (SZ 8.3 ± 6.2 years vs BD 7.3 ± 5.9 years). We found that SZ and BD have overlapping antecedents, but SZ was more common in males and in foreign born and had more learning deficits before the first episode. BD was more common in white population and had higher rates of depressive and adjustment disorders prior to first episode. BD also had more affective symptoms, nightmares, and panic attacks before the first episode. Both groups had similarly high rates of substance use (SZ 74 % vs BD 74.3 %), prescription of antidepressants (SZ 46.6 % vs BD 55.4 %) and stimulants (SZ 30.5 % vs BD 22.9 %). CONCLUSIONS: The psychiatric antecedents of SZ and BD usually start during adolescence, overlap, and present in unspecific ways. The initial prodromes are more alike than distinct. Further studies are encouraged to continue looking for specific factors that distinguish the antecedents of these two disorders.
Asunto(s)
Trastorno Bipolar , Trastornos Psicóticos , Esquizofrenia , Masculino , Adolescente , Humanos , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiología , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , Manía , Estudios Retrospectivos , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiologíaRESUMEN
BACKGROUND: The California Cancer Consortium has performed a Phase II trial of infusional bryostatin, a protein kinase C inhibitor isolated from the marine invertebrate bryozoan, Bugula Neritina, a member of the phylum Ectoprocta, in combination with cisplatin, in patients (pts) with recurrent platinum-sensitive or resistant ovarian cancer (OC). METHODS: Pts received bryostatin 45 mcg/m(2) as a 72 h continuous infusion followed by cisplatin 50 mg/m(2). Cycles were repeated every 3 weeks. Dosages were chosen based on phase I data obtained by the CCC in a population of pts with mixed tumor types. RESULTS: Eight pts with recurrent or persistent epithelial OC received 23 cycles of treatment. All pts had received previous platinum-based chemotherapy; two pts had received one prior course, five had received two prior courses, and one had received three prior courses of chemotherapy. The median age was 64 (range 32-72), and Karnofsky performance status 90 (range 80-100). A median of 3 cycles of chemotherapy were delivered (range: 1-5). The median progression-free and overall survivals were 3 and 8.2 months respectively. Best responses included two partial responses (one in a platinum-resistant pt), three pts with stable disease, and three progressions. All pts experienced Grade 3 or 4 toxicities including severe myalgias/pain/fatigue/asthenia in six pts, and severe nausea/vomiting/constipation in two other pts. One pt experienced a seizure and liver function tests were elevated in one other. CONCLUSIONS: A modest response rate is observed in pts with recurrent or persistent ovarian cancer treated with the combination of bryostatin and cisplatin. The toxicity profile, however, observed in this pt population (primarily severe myalgias), precludes tolerability and prevents this combination from further investigation at this dose and schedule. It is possible that platinum pre-exposure in OC patients exacerbates observed toxicity. Phase II dosages of investigational agents in OC pts that are determined by phase I trials in pts with other tumor types should be chosen cautiously.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brioestatinas/administración & dosificación , California , Carcinoma Epitelial de Ovario , Cisplatino/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/enzimología , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Factores de Tiempo , Resultado del TratamientoRESUMEN
These NCCN Guidelines Insights focus on the major updates for the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer by describing how and why the new recommendations were made. The 6 update topics were selected based on recent important updates in the guidelines and on debate among panel members about recent clinical trials, and include: 1) screening, 2) diagnostic tests for assessing pelvic masses, 3) primary treatment using neoadjuvant chemotherapy, 4) primary adjuvant treatment using bevacizumab in combination with chemotherapy, 5) therapy for recurrent disease, and 6) management of drug/hypersensitivity reactions. These NCCN Guidelines Insights also discuss why some recommendations were not made (eg, panel members did not feel the new data warranted changing the guideline). See "Updates" in the NCCN Guidelines for Ovarian Cancer for a complete list of all the recent revisions.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/terapia , Neoplasias Ováricas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Detección Precoz del Cáncer , Femenino , Humanos , Terapia Molecular Dirigida , Terapia Neoadyuvante , Neoplasias Ováricas/diagnósticoRESUMEN
PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.