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Clinical management of gynecological cancer begins by optimal debulking with first-line platinum-based chemotherapy. However, in ~80% patients, ovarian cancer will recur and is lethal. Prognostic gene signature panel identifying platinum-resistance enables better patient stratification for precision therapy. Retrospectively collected serum from 11 "poor" (<6 months progression free interval [PFI]) and 22 "favorable" (>24 months PFI) prognosis patients, were evaluated using circulating cell-free DNA (cfDNA). DNA from both groups showed 50 to 10 000 bp fragments. Pairwise analysis of sequenced cfDNA from patients showed that gene dosages were higher for 29 genes and lower for 64 genes in poor than favorable prognosis patients. Gene ontology analysis of higher dose genes predominantly grouped into cytoskeletal proteins, while lower dose genes, as hydrolases and receptors. Higher dosage genes searched for cancer-relatedness in Reactome database indicated 15 genes were referenced with cancer. Among them 3 genes, TGFBR2, ZMIZ2, and NRG2, were interacting with more than 4 cancer-associated genes. Protein expression analysis of tumor samples indicated that TGFBR2 was downregulated and ZMIZ2 was upregulated in poor prognosis patients. Our results indicate that the cfDNA gene dosage combined with protein expression in tumor samples can serve as gene signature panel for prognosis determination amongst ovarian cancer patients.
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OBJECTIVE: Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1MET (APR246) on mebendazole activity were evaluated. METHODS: Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model. RESULTS: Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism. CONCLUSION: This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance.
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Mebendazol/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Fenbendazol/farmacología , Humanos , Mebendazol/administración & dosificación , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Quinuclidinas/administración & dosificación , Quinuclidinas/farmacología , Distribución Aleatoria , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND OBJECTIVE: In diagnosis of cervical cancer patients, lymph node (LN) metastasis is a highly important indicator for the following treatment management. Although CT/PET (i.e., computed tomography/positron emission tomography) examination is the most effective approach for this detection, it is limited by the high cost and low accessibility, especially for the rural areas in the U.S.A. or other developing countries. To address this challenge, this investigation aims to develop and test a novel radiomics-based CT image marker to detect lymph node metastasis for cervical cancer patients. METHODS: A total of 1,763 radiomics features were first computed from the segmented primary cervical tumor depicted on one CT image with the maximal tumor region. Next, a principal component analysis algorithm was applied on the initial feature pool to determine an optimal feature cluster. Then, based on this optimal cluster, the prediction models (i.e., logistic regression or support vector machine) were trained and optimized to generate an image marker to detect LN metastasis. In this study, a retrospective dataset containing 127 cervical cancer patients were established to build and test the model. The model was trained using a leave-one-case-out (LOCO) cross-validation strategy and image marker performance was evaluated using the area under receiver operation characteristic (ROC) curve (AUC). RESULTS: The results indicate that the SVM based imaging marker achieved an AUC value of 0.841 ± 0.035. When setting an operating threshold of 0.5 on model-generated prediction scores, the imaging marker yielded a positive and negative predictive value (PPV and NPV) of 0.762 and 0.765 respectively, while the total accuracy is 76.4%. CONCLUSIONS: This study initially verified the feasibility of utilizing CT image and radiomics technology to develop a low-cost image marker to detect LN metastasis for assisting stratification of cervical cancer patients.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Neoplasias del Cuello Uterino/diagnóstico por imagenRESUMEN
[This corrects the article DOI: 10.1016/j.gore.2019.100532.].
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PURPOSE: NRG Oncology conducted a phase II trial to assess the antitumor activity and tolerability of copanlisib, a selective inhibitor of PIK3CA, in persistent or recurrent endometrial carcinoma harboring hotspot PIK3CA mutations. PATIENTS AND METHODS: Eligible patients had endometrial cancer with endometrioid, serous or mixed histology, a somatic PIK3CA gene mutation, measurable disease, and GOG performance status ≤2. Treatment consisted of IV copanlisib (60â¯mg weekly, day 1, 8 and 15 of 28-day cycle) until disease progression or prohibitive toxicity. The primary endpoints of the study were objective tumor response as assessed by RECIST 1.1 and to determine the nature and degree of toxicity of copanlisib as assessed by CTCAE version 4. The study used a 2-stage group sequential design. RESULTS: Eleven patients were enrolled onto stage I of the treatment trial. Five patients had endometrioid, four serous and two had a tumor of mixed histology. The most common PIK3CA mutation was Q546X (nâ¯=â¯3) in exon 9. The most common grade 3 or 4 AE was hyperglycemia. No grade 5 adverse events were reported. No clinical responses were detected. Six patients had a best overall response of stable disease. Of 11 who initiated treatment, 10 progressed on treatment. One patient with stable disease on copanlisib withdrew from treatment secondary to relocation. The median progression-free survival (PFS) was 2.8â¯months; at 6â¯months 27% were alive, progression-free. The median overall survival (OS) was 15.2â¯months. Due to the lack of CR/PR continuation of accrual to the second stage of accrual was not warranted. CONCLUSION: Copanlisib is well tolerated but has limited activity as a single agent in this population.
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BACKGROUND: Prospective, randomized trials are needed to determine optimal treatment approaches for palliative care problems such as malignant bowel obstruction (MBO). Randomization poses unique issues for such studies, especially with divergent treatment approaches and varying levels of equipoise. We report our experience accruing randomized patients to the Prospective Comparative Effectiveness Trial for Malignant Bowel Obstruction (SWOG S1316) study, comparing surgical and nonsurgical management of MBO. METHODS: Patients with MBO who were surgical candidates and had treatment equipoise were accrued and offered randomization to surgical or nonsurgical management. Patients choosing nonrandomization were offered prospective observation. Trial details are listed on www.clinicaltrials.gov (NCT #02270450). An accrual algorithm was developed to enhance enrollment. RESULTS: Accrual is ongoing with 176 patients enrolled. Most (89%) patients chose nonrandomization, opting for nonsurgical management. Of 25 sites that have accrued to this study, 6 enrolled patients on the randomization arm. Approximately 59% (20/34) of the randomization accrual goal has been achieved. Patient-related factors and clinician bias have been the most prevalent reasons for lack of randomization. An algorithm was developed from clinician experience to aid randomization. Using principles in this tool, repeated physician conversations discussing treatment options and goals of care, and a supportive team-approach has helped increase accrual. CONCLUSIONS: Experience gained from the S1316 study can aid future palliative care trials. Although difficult, it is possible to randomize patients to palliative studies by giving clinicians clear recommendations utilizing an algorithm of conversation, allotment of necessary time to discuss the trial, and encouragement to overcome internal bias.
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Obstrucción Intestinal/etiología , Obstrucción Intestinal/terapia , Neoplasias/complicaciones , Cuidados Paliativos/organización & administración , Proyectos de Investigación , Algoritmos , Humanos , Obstrucción Intestinal/cirugía , Neoplasias/patología , Selección de Paciente , Estudios ProspectivosRESUMEN
OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12â¯months after primary platinum chemotherapy have worse prognosis than those recurring in >12â¯months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12â¯months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12â¯months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2â¯months (95% CI 8-9â¯months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3â¯months, pâ¯=â¯0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3â¯months pâ¯=â¯0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6â¯months (pâ¯=â¯0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12â¯months leads to worse survival.
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Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Platino/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/mortalidad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Ováricas/mortalidad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3â¯+â¯3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUCâ¯=â¯5â¯mg/ml·min) and P (175â¯mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPAâ¯ââ¯C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1)â¯ââ¯C/P(D3) (2 & 4â¯mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6â¯mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3â¯months (95% CI 8.5-14.2) and OS 33â¯months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Receptores Acoplados a Proteínas G/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Anciano , Antineoplásicos Fitogénicos , Huesos/efectos de los fármacos , Carboplatino/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/farmacología , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
BACKGROUND: The Multinational Association of Supportive Care of Cancer (MASCC) risk-index score has been validated as a stratification tool for febrile neutropenia (FN) risk in a heterogeneous group of cancer patients; recently, it has been deemed a suitable tool in gynecologic oncology patients in a retrospective study. This is a prospective multi-institutional study wherein we sought to validate MASCC score for stratifying FN morbidity in gynecologic oncology patients. METHODS: IRB approval was obtained at 4 institutions for prospective data collection of gynecologic cancer patients admitted with FN from 3/1/2013 to 9/1/2014. Participating institutions have a policy of inpatient management of FN patients receiving chemotherapy. Deidentified data was compiled and processed at the leading institution. RESULTS: In total, 31 patients met inclusion criteria. Most had advanced stage disease (67%). 100% of patients were receiving chemotherapy (57% for primary, 43% for recurrent disease). 55% had a positive culture. Median MASCC score was 21 (range, 10 to 26); 58% of patients were considered low risk. High risk patients more often had one (11% vs. 38%, P=0.09) or multiple (6% vs. 23%, P=0.28) severe complications, ICU admission (0% vs. 15%, P=0.17), and delay in next chemotherapy cycle (33% vs. 54%, P=0.25). No patients died from FN during the study period. CONCLUSIONS: This pilot data suggests that MASCC score may be a promising tool for determining suitability of outpatient management of FN in gynecologic oncology patients. Larger studies are warranted to achieve statistically significant results, which may enable us to effectively utilize this risk stratification tool for cost containment and avoidance of nosocomial infections.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neutropenia Febril/terapia , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Cuidados Paliativos , Medición de Riesgo/métodos , Índice de Severidad de la Enfermedad , Anciano , Neutropenia Febril/inducido químicamente , Neutropenia Febril/diagnóstico , Femenino , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/patología , Hospitalización , Humanos , Agencias Internacionales , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
PURPOSE OF REVIEW: This review will provide an update of recently presented clinical data as well as discuss ongoing trials focused on the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into the treatment paradigm for ovarian cancer. RECENT FINDINGS: As of this publication, PARPi have indications in many parts of the globe as maintenance therapy following response to platinum-based chemotherapy in the setting of platinum-sensitive recurrence. In addition, in the United States, two PARPi have indications as monotherapy treatment for recurrent ovarian cancer in patients with a BRCA mutation and at least two prior lines of therapy. Exciting data was published in October 2018, demonstrating an unprecedented benefit to utilization of olaparib following response to front-line platinum-based chemotherapy among patients with a BRCA mutation and this data is expected to expand the indication for olaparib globally. SUMMARY: Ongoing studies will seek to expand the benefit of PARPi beyond the BRCA population in front-line therapy as well as to overcome inherent and acquired resistance to PARPi with studies of novel combinations with antiangiogenesis agents, immune-oncology agents and chemotherapy. These efforts may identify more settings and populations in which PARPi provide clinical benefit.
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Carcinoma Epitelial de Ovario/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Proteína BRCA2 , Carcinoma Epitelial de Ovario/patología , Femenino , Humanos , Neoplasias Ováricas/patología , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
This study aimed to investigate the feasibility of integrating image features computed from both spatial and frequency domain to better describe the tumor heterogeneity for precise prediction of tumor response to postsurgical chemotherapy in patients with advanced-stage ovarian cancer. A computer-aided scheme was applied to first compute 133 features from five categories namely, shape and density, fast Fourier transform, discrete cosine transform (DCT), wavelet, and gray level difference method. An optimal feature cluster was then determined by the scheme using the particle swarm optimization algorithm aiming to achieve an enhanced discrimination power that was unattainable with the single features. The scheme was tested using a balanced dataset (responders and non-responders defined using 6 month PFS) retrospectively collected from 120 ovarian cancer patients. By evaluating the performance of the individual features among the five categories, the DCT features achieved the highest predicting accuracy than the features in other groups. By comparison, a quantitative image marker generated from the optimal feature cluster yielded the area under ROC curve (AUC) of 0.86, while the top performing single feature only had an AUC of 0.74. Furthermore, it was observed that the features computed from the frequency domain were as important as those computed from the spatial domain. In conclusion, this study demonstrates the potential of our proposed new quantitative image marker fused with the features computed from both spatial and frequency domain for a reliable prediction of tumor response to postsurgical chemotherapy.
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Carcinoma Epitelial de Ovario/tratamiento farmacológico , Interpretación de Imagen Asistida por Computador/métodos , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Área Bajo la Curva , Carcinoma Epitelial de Ovario/diagnóstico por imagen , Análisis por Conglomerados , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico por imagenRESUMEN
The tumor-stroma ratio (TSR) reflected on hematoxylin and eosin (H&E)-stained histological images is a potential prognostic factor for survival. Automatic image processing techniques that allow for high-throughput and precise discrimination of tumor epithelium and stroma are required to elevate the prognostic significance of the TSR. As a variant of deep learning techniques, transfer learning leverages nature-images features learned by deep convolutional neural networks (CNNs) to relieve the requirement of deep CNNs for immense sample size when handling biomedical classification problems. Herein we studied different transfer learning strategies for accurately distinguishing epithelial and stromal regions of H&E-stained histological images acquired from either breast or ovarian cancer tissue. We compared the performance of important deep CNNs as either a feature extractor or as an architecture for fine-tuning with target images. Moreover, we addressed the current contradictory issue about whether the higher-level features would generalize worse than lower-level ones because they are more specific to the source-image domain. Under our experimental setting, the transfer learning approach achieved an accuracy of 90.2 (vs. 91.1 for fine tuning) with GoogLeNet, suggesting the feasibility of using it in assisting pathology-based binary classification problems. Our results also show that the superiority of the lower-level or the higher-level features over the other ones was determined by the architecture of deep CNNs.
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Neoplasias de la Mama/patología , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador , Neoplasias Ováricas/patología , Bases de Datos Factuales , Femenino , Humanos , Análisis de Matrices TisularesRESUMEN
OBJECTIVES: Age imposes a disparity in the treatment of and outcomes with gynecologic cancer. Older patients are underrepresented in primary treatment trials, but little is known about their ability to withstand trial-based treatment for recurrent or refractory disease. This study sought to examine treatment-related toxicities and outcomes of older versus younger patients participating in phase 1 clinical trials. METHODS: A retrospective analysis of patients enrolled in phase 1 clinical trials for gynecologic malignancies from 2010 to 2016 was performed. Demographic and clinic-pathologic data was abstracted. Toxicities were defined as either grade III or IV by CTCAE criteria. Best response was calculated using RECIST criteria. Associations between categorical variables were determined using Fisher's exact test and continuous variables using Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. RESULTS: 237 patients were included with 22% (n=51) comprising the older cohort (≥70years). The vast majority (98%) were treated for recurrent disease. Older patients incurred similar grade III/IV hematologic (21% vs 16%, p=0.38) and non-hematologic toxicities (26% vs 29%, p=0.64). Older patients discontinued treatment due to toxicity only 8% of the time. Median survival was 13.0 and 10.3months in the <70 and ≥70 groups, respectively (p=0.35). 63% of patients ≥70 achieved clinical benefit. CONCLUSIONS: Although historically older patients have not been routinely considered for enrollment in phase 1 trials, our data demonstrates similar toxicity profiles to that of younger patients and 63% clinical benefit rate. Thus, with careful selection, patients ≥70 should be considered when facing recurrent or refractory gynecologic cancer.
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Ensayos Clínicos Fase I como Asunto/métodos , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Disparidades en Atención de Salud/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Selección de Paciente , Estudios Retrospectivos , Adulto JovenRESUMEN
Health disparities are defined as the preventable difference in the burden of disease, injury, and violence, or opportunity to achieve optimal health that socially disadvantaged populations experience compared to the population as a whole. Disparities in incidence and cancer outcomes for women with gynecologic malignancies have been well described particularly for American women of Black race. The etiology of these disparities has been tied to socio-economics, cultural, educational and genetic factors. While access to high quality treatment has been primarily linked to survival from cervical and ovarian cancer, innate biologic distinctions have been principally cited as reasons for differences in incidence and mortality in cancers of the uterine corpus. This article will update the framework of disparities to incorporate a broader understanding of the social determinants of health and how they affect health equity by addressing the root causes of disparities within the health care system. Special populations are identified who are at risk for health inequities which include but are not limited to Black race, underserved racial and ethnic minorities (e.g. indigenous peoples, low English fluency), trans/gender nonconforming people and rural populations. Each of these populations at risk have unique structural barriers within the healthcare system impacting gynecologic cancer outcomes. The authors provide practical recommendations for practitioners aimed at eliminating cancer related outcome disparities.
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Neoplasias de los Genitales Femeninos/terapia , Equidad en Salud , Disparidades en Atención de Salud , Práctica Clínica Basada en la Evidencia , Femenino , Ginecología/normas , Humanos , Oncología Médica/normas , Estados Unidos , Poblaciones VulnerablesRESUMEN
As precision medicine has become a focus in oncology in recent years, many targeted and biologic agents are being used along with or in place of traditional cytotoxic chemotherapy. As these drugs have been developed and some have received FDA approval, we have gained substantial data about the adverse event profiles. However, the management and approach to the toxicities incurred and subsequent complications are often not well understood, especially for physicians who have a varied clinical practice. The purpose of this review is to provide an overview of the frequency and types of adverse events and appropriate management steps when prescribing modern targeted therapies for gynecologic cancers in the classes of anti-angiogenic agents, poly-ADP-ribose polymerase (PARP) inhibitors, and immunotherapy drugs.
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Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Anemia/inducido químicamente , Anemia/terapia , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/terapia , Bevacizumab/efectos adversos , Diarrea/inducido químicamente , Diarrea/terapia , Epistaxis/inducido químicamente , Epistaxis/terapia , Fatiga/inducido químicamente , Fatiga/terapia , Femenino , Cefalea/inducido químicamente , Cefalea/terapia , Hemorragia/inducido químicamente , Hemorragia/terapia , Humanos , Hipertensión/inducido químicamente , Hipertensión/terapia , Indazoles , Perforación Intestinal/inducido químicamente , Perforación Intestinal/terapia , Terapia Molecular Dirigida , Náusea/inducido químicamente , Náusea/terapia , Neutropenia/inducido químicamente , Neutropenia/terapia , Medicina de Precisión , Proteinuria/inducido químicamente , Proteinuria/terapia , Pirimidinas/efectos adversos , Medición de Riesgo , Sulfonamidas/efectos adversos , Vómitos/inducido químicamente , Vómitos/terapia , Desequilibrio Hidroelectrolítico/inducido químicamente , Desequilibrio Hidroelectrolítico/terapiaRESUMEN
OBJECTIVE: To characterize patients who did not enroll on a clinical trial and identify barriers that may limit enrollment among patients with advanced epithelial ovarian cancer (EOC) presenting for first-line chemotherapy. METHODS: We conducted a retrospective review of patients diagnosed with stage II-IV EOC from 10/2009-4/2013, a time period during which multiple trials were available to all EOC patients, including optimally debulked, suboptimally debulked, or undergoing neoadjuvant chemotherapy. Enrollment status, demographics, tumor characteristics, and treatment details were recorded. SAS version 9.3 was used for all analyses. RESULTS: 144 patients met study criteria; 67% were enrolled on a trial. Enrolled patients were significantly younger (median 61 vs 68years, p=0.002). Stage (p=0.30), race (p=0.75), and performance status (p=0.38) were similar between enrolled and non-enrolled patients. Distance did not impact enrollment, as nearly half of patients in both groups lived >50miles from the treatment center (39.0% vs 47.8%, p=0.36). Mode of chemotherapy administration significantly differed based on participation (all p<0.05). Despite similar residual disease status (p=1.00) and number of chemotherapy regimens received (p=0.59), patients treated on trial had a higher 3-year survival rate (70.7% vs 51.7%, p=0.031). The difference in median progression-free survival approached significance (20.2 vs 9.2months, p=0.091). CONCLUSION: In an institution where the culture is to offer clinical trials to all eligible patients, 33% of front-line EOC patients did not participate. Increasing age was associated with non-participation. Modifiable barriers must be overcome so that trial enrollment can better reflect true EOC demographics.
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Ensayos Clínicos como Asunto , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Participación del Paciente , Selección de Paciente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Carcinoma Epitelial de Ovario , Quimioterapia Adyuvante , Procedimientos Quirúrgicos de Citorreducción , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
RATIONALE AND OBJECTIVES: The study aimed to investigate the role of applying quantitative image features computed from computed tomography (CT) images for early prediction of tumor response to chemotherapy in the clinical trials for treating ovarian cancer patients. MATERIALS AND METHODS: A dataset involving 91 patients was retrospectively assembled. Each patient had two sets of pre- and post-therapy CT images. A computer-aided detection scheme was applied to segment metastatic tumors previously tracked by radiologists on CT images and computed image features. Two initial feature pools were built using image features computed from pre-therapy CT images only and image feature difference computed from both pre- and post-therapy images. A feature selection method was applied to select optimal features, and an equal-weighted fusion method was used to generate a new quantitative imaging marker from each pool to predict 6-month progression-free survival. The prediction accuracy between quantitative imaging markers and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was also compared. RESULTS: The highest areas under the receiver operating characteristic curve are 0.684 ± 0.056 and 0.771 ± 0.050 when using a single image feature computed from pre-therapy CT images and feature difference computed from pre- and post-therapy CT images, respectively. Using two corresponding fusion-based image markers, the areas under the receiver operating characteristic curve significantly increased to 0.810 ± 0.045 and 0.829 ± 0.043 (P < 0.05), respectively. Overall prediction accuracy levels are 71.4%, 80.2%, and 74.7% when using two imaging markers and RECIST, respectively. CONCLUSIONS: This study demonstrated the feasibility of predicting patients' response to chemotherapy using quantitative imaging markers computed from pre-therapy CT images. However, using image feature difference computed between pre- and post-therapy CT images yielded higher prediction accuracy.
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Procesamiento de Imagen Asistido por Computador , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/tratamiento farmacológico , Tomografía Computarizada por Rayos X/métodos , Anciano , Femenino , Humanos , Curva ROC , Estudios RetrospectivosRESUMEN
OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.
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Adenocarcinoma de Células Claras/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Platino (Metal)/uso terapéutico , Estudios RetrospectivosRESUMEN
Intravenous leiomyomatosis is a benign smooth muscle tumor which despite its histology can have devastating consequences. Furthermore, the clinical manifestations are variable and nonspecific, typically leading to delayed or missed diagnosis. Thus, it is critical for clinicians to be aware of this condition and have a high index of suspicion in a middle-aged woman with a history of uterine leiomyoma presenting with an inferior vena cava mass to enable early diagnosis and treatment. We report a case of a large intravenous leiomyoma which was initially considered to be a very large deep venous thrombosis; with thorough preoperative planning, it was successfully removed intact and in entirety with a single-stage operation.
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Leiomiomatosis/diagnóstico por imagen , Músculo Liso Vascular/patología , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Vasculares/diagnóstico por imagen , Vena Cava Inferior/patología , Diagnóstico Diferencial , Femenino , Humanos , Leiomiomatosis/patología , Leiomiomatosis/cirugía , Persona de Mediana Edad , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugía , Neoplasias Vasculares/patología , Neoplasias Vasculares/cirugíaRESUMEN
OBJECTIVES: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. METHODS: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. CONCLUSIONS: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach.