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2.
Cancer Res Commun ; 2(10): 1293-1303, 2022 10.
Article in English | MEDLINE | ID: mdl-36388466

ABSTRACT

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.


Subject(s)
Adenocarcinoma , Carcinoma , Endometrial Neoplasms , Lung Neoplasms , Female , Humans , Aged , Carboplatin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Paclitaxel/adverse effects , Carcinoma/chemically induced , Endometrial Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma/drug therapy
3.
Sci Adv ; 8(2): eabh3375, 2022 Jan 14.
Article in English | MEDLINE | ID: mdl-35020422

ABSTRACT

Preclinical studies of primary cancer cells are typically done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3 to 10% range, with most tumors in a hypoxic or 1 to 2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anticancer agents is routinely examined at ambient O2. Here, we demonstrate that tumors collected, processed, and propagated at physiologic O2 compared to ambient air display distinct differences in key signaling networks including LGR5/WNT, YAP, and NRF2/KEAP1, nuclear reactive oxygen species, alternative splicing, and sensitivity to targeted therapies. Therefore, evaluating cancer cells under physioxia could more closely recapitulate their physiopathologic status in the in vivo microenvironment.

4.
Case Rep Obstet Gynecol ; 2021: 6986768, 2021.
Article in English | MEDLINE | ID: mdl-34603808

ABSTRACT

The prevalence of cervical cancer has dropped significantly since introduction of the Papanicolaou (Pap) screen. The greatest risk factor for cervical cancer is inadequate screening. Altered pelvic anatomy can limit the ability to collect a Pap smear. In the presented case, a woman with a history of fibroids and bleeding presented for an exam under anesthesia. Traditional approaches for collecting a Pap smear failed. A GlideScope video laryngoscope was used to visualize the cervix, and a Pap smear was collected. The specimen was satisfactory, negative for intraepithelial lesion or malignancy, and HPV negative. A laryngoscope can be repurposed to visualize collection of a challenging Pap smear. Novel approaches for Pap smear collection and cervical cancer screening are needed and have the potential to save lives.

5.
Cancers (Basel) ; 10(11)2018 Nov 12.
Article in English | MEDLINE | ID: mdl-30424539

ABSTRACT

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85⁻90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically-and genetically-cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.

6.
Gynecol Oncol ; 151(2): 257-263, 2018 11.
Article in English | MEDLINE | ID: mdl-30177462

ABSTRACT

PURPOSE: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). PATIENTS AND METHODS: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. RESULTS: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. CONCLUSION: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Fallopian Tube Neoplasms/drug therapy , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Carcinoma, Ovarian Epithelial , Disease-Free Survival , Double-Blind Method , Everolimus/administration & dosage , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy
7.
J Clin Oncol ; 34(19): 2279-86, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27217446

ABSTRACT

PURPOSE: The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS: The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION: On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Fallopian Tube Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Fallopian Tube Neoplasms/mortality , Female , Humans , Middle Aged , Ovarian Neoplasms/mortality , Peritoneal Neoplasms/mortality , Stilbenes/administration & dosage , Stilbenes/adverse effects
8.
Gynecol Oncol ; 138(3): 507-12, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26186911

ABSTRACT

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.


Subject(s)
Antineoplastic Agents/therapeutic use , Endometrial Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects
9.
Gynecol Oncol ; 135(3): 441-5, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25312396

ABSTRACT

INTRODUCTION: Patients presenting with advanced, recurrent, or metastatic endometrial cancer have limited treatment options. On behalf of the Gynecologic Oncology Group, we conducted this phase II trial of nintedanib (BIBF 1120), a potent small molecule triple receptor tyrosine kinase inhibitor of PDGFR α and ß, FGFR 1/3, and VEGFR 1-3, in this population. OBJECTIVES: The primary objectives were to estimate event-free survival (EFS) at 6 months and the proportion of patients who have an objective tumor response. In addition, we sought to determine the nature and degree of toxicity. Secondary objectives were to estimate progression-free and overall survival. METHODS: This was a two-stage, single-arm phase II study. Eligible patients were treated with single-agent nintedanib at a dose of 200mg twice daily. RESULTS: Of 37 patients enrolled, 32 were eligible. There were zero complete and three partial responses for an overall response rate of 9.4% (90% 2-sided CI=2.6-22.5%). Seven patients (21.9%; 90% 2-sided CI=10.7-37.2%) were EFS at 6 months, with one patient continuing on study at the time of this writing. Serious toxicity included the following grade 3 events: gastrointestinal toxicity (5), neutropenia (1), edema (1), hypertension (1), and liver function abnormalities (5). CONCLUSIONS: Nintedanib lacked sufficient activity as a single agent to warrant enrollment to second stage. However, preclinical data indicate it may be synergistic with paclitaxel in a population of patients enriched for specific p53 mutations that result in loss of function. Subsequent studies may evaluate this agent in combination with paclitaxel.


Subject(s)
Antineoplastic Agents/administration & dosage , Endometrial Neoplasms/drug therapy , Indoles/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Disease-Free Survival , Endometrial Neoplasms/pathology , Female , Humans , Indoles/adverse effects , Middle Aged , Neoplasm Recurrence, Local/pathology
10.
Gynecol Oncol ; 129(1): 22-7, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23262204

ABSTRACT

OBJECTIVE: This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent or recurrent EMC after receiving 1-2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2. Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. RESULTS: Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months, respectively. CONCLUSION: Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Disease-Free Survival , Endometrial Neoplasms/mortality , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/mortality , Sirolimus/administration & dosage , Sirolimus/adverse effects
11.
Gynecol Oncol ; 127(3): 564-8, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22940492

ABSTRACT

OBJECTIVES: There is a lack of knowledge about the health care events experienced by individual patients that lead to a definitive diagnosis of ovarian cancer (OC). The goal of this study was to describe the various pathways and to identify an optimal path to accurate diagnosis. METHODS: Women who were referred to gynecologic oncology for a suspected OC were enrolled to this study. Medical records (MRs) from all health care providers were obtained from the time the patient recalled first suspecting a health issue through the time of diagnosis to build a decision tree model. A Monte Carlo simulation was conducted of 83,000 patients to identify the optimal pathway to reach diagnosis. RESULTS: In the Monte Carlo simulation, gynecologic oncologists and gynecologists accounted for the most efficient diagnosis in over 37.9% and 29.2% of suspected OC cases, respectively, in terms of the least amount of time to reach diagnosis. Gynecologic oncologists were further associated with the fewest health care visits needed to reach diagnosis in 37% of the simulation cases; however, 23% of trials were indifferent to any specific provider. CONCLUSIONS: The decision tree provides a more comprehensive view of the complexity in reaching an accurate diagnosis of OC. This analysis was able to identify the health care utilization patterns that underlie the events that occur to reach an accurate diagnosis in the setting of a suspected OC, and was able to identify the most efficient pathways that utilize the fewest health care resources in the least amount of time.


Subject(s)
Early Detection of Cancer , Ovarian Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , CA-125 Antigen/blood , Female , Humans , Middle Aged , Monte Carlo Method
12.
Gynecol Oncol ; 127(1): 94-7, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22776722

ABSTRACT

OBJECTIVE: To determine whether clinicians at various levels of training can reproduce and apply the Morphology Index when compared to Ueland's Morphology Index data, and to determine intra-observer variability when applied by observers at various levels of training. METHODS: One hundred four transvaginal ultrasound images of adnexal masses obtained at Indiana University between 1991 and 2003 were identified which had correlating surgical pathology. The images were scored by four investigators at four different levels of training. Scoring was based upon the revised University of Kentucky Morphology Index by Ueland. Each mass received 0-5 points for its structure, and 0-5 points for tumor volume. Each total score was then correlated with the surgical pathology. Sensitivity, specificity, positive predictive value and negative predictive value for each investigator were determined. All images were reviewed independently by each investigator; each was blinded to scores given by the other investigators and to final pathology. RESULTS: Nine malignant and 95 benign masses were noted on final pathology. Ranges for statistical values were: positive predictive value (PPV) 15-18%, negative predictive value (NPV) 93-98%, sensitivity 44-89%, and specificity 52-76%. CONCLUSION: The Morphology Index is a consistent and reliable tool for predicting benign disease demonstrating a high negative predictive value with little intra-observer variability. However, when predicting malignancy, the results showed more intra-observer variability and a positive predictive value half of that previously reported. This study confirms the clinical utility of the Morphology Index when utilized for its NPV and demonstrates its widespread application even among clinicians with minimal ultrasound training.


Subject(s)
Adnexal Diseases/diagnostic imaging , Ovarian Neoplasms/diagnostic imaging , Adnexal Diseases/diagnosis , Adnexal Diseases/pathology , Diagnosis, Differential , Female , Humans , Observer Variation , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Physicians , Predictive Value of Tests , Retrospective Studies , Ultrasonography/standards
13.
FASEB J ; 26(8): 3306-20, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22767227

ABSTRACT

Ascites in epithelial ovarian cancer (EOC) promotes tumor development by mechanisms that are incompletely understood. Lysophosphatidic acid (LPA), a major tumor-promoting factor in EOC ascites, is an enzymatic product of autotaxin (ATX) and phospholipase A(2) (PLA(2))enzymes. The contribution of PLA(2) activities to ovarian tumorigenesis was investigated. The quantitative measurement of PLA(2) activities in ascites and tissues, as well as assay conditions selective for PLA(2) subtypes, were optimized and validated. PLA(2) activities correlated with tumor-promoting activates in cell-based and in vivo assays. High activities consistent with both cytosolic and calcium-independent PLA(2) were found in human EOC ascites for the first time. Elevated PLA(2) and ATX activities were also observed in EOC compared to benign tumors and normal tissues. Cell-free and vesicle-free (S4) human EOC ascites potently promoted proliferation, migration, and invasion of human EOC cells in a PLA(2)-dependent manner. LPA mediated a significant part of the cell-stimulating effects of ascites. S4 ascites stimulated tumorigenesis/metastasis in vivo, and methyl arachidonyl fluorophosphonate was highly effective in inhibiting EOC metastasis in mouse xenograft models. PLA(2) activity was found in conditioned media from both EOC cells and macrophages. Collectively, our work implies that PLA(2) activity is a potential marker and therapeutic target in EOC.


Subject(s)
Neoplasms, Glandular and Epithelial/physiopathology , Ovarian Neoplasms/physiopathology , Animals , Arachidonic Acids/therapeutic use , Ascites/pathology , Ascites/physiopathology , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Female , Humans , Lysophospholipids , Mice , Neoplasm Transplantation , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/pathology , Organophosphonates/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phospholipases A2, Secretory , Phosphoric Diester Hydrolases/metabolism , Transplantation, Heterologous
14.
Cancer Res ; 72(9): 2197-205, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22549947

ABSTRACT

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine-cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA Methylation/drug effects , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/analogs & derivatives , Carboplatin/administration & dosage , Carboplatin/adverse effects , Decitabine , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/genetics
15.
Gynecol Oncol ; 120(2): 224-8, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21075438

ABSTRACT

OBJECTIVES: The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers. PATIENTS AND METHODS: Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m(2)) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks. RESULTS: Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25mg/m(2), grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m(2), grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20mg/m(2) was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7-61%). CONCLUSIONS: Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m(2) was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.


Subject(s)
Antineoplastic Agents/adverse effects , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/radiotherapy , Taxoids/adverse effects , Adult , Aged , Antineoplastic Agents/administration & dosage , Carcinoma, Ovarian Epithelial , Combined Modality Therapy , Disease-Free Survival , Docetaxel , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Administration Schedule , Female , Humans , Middle Aged , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/radiotherapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/radiotherapy , Taxoids/administration & dosage , Treatment Outcome
16.
Cancer ; 116(17): 4043-53, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20564122

ABSTRACT

BACKGROUND: Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low-dose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. METHODS: Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m(2) (7 patients) or 20 mg/m(2) (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. RESULTS: Dose-limiting toxicity (DLT) at the 20-mg/m(2) dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m(2). The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for >/=6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. CONCLUSIONS: Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. (c) 2010 American Cancer Society.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/analogs & derivatives , Carboplatin/administration & dosage , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Platinum Compounds/therapeutic use , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/pharmacology , DNA Methylation , Decitabine , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Middle Aged
17.
J Am Coll Radiol ; 6(11): 800-3, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19878888

ABSTRACT

PURPOSE: Low-dose-rate (LDR) brachytherapy is an integral treatment modality in radiation oncology. Clinical efficacy is based on experience with manual source loading and continuous dose delivery. With remote afterloading technology, sources may be loaded and unloaded during the treatment course to prevent radiation exposure to nursing staff members and visitors. The aim of this study was to investigate treatment interruptions in terms of frequency and duration as well as extension of the overall treatment time period. The potential clinical impact of treatment interruptions was also considered. MATERIALS AND METHODS: The treatment records of 20 patients who underwent brachytherapy in the Indiana University Department of Radiation Oncology administered with a Selectron LDR remote afterloader were reviewed. Results were tabulated and analysis performed with respect to 1) the number of interruptions, 2) delay time, 3) delay time (T(d)) as a function of total implant time (T), 4) the time of day that each interruption occurred, and 5) the time in minutes of each individual interruption. RESULTS: The mean number of interruptions was 44.9 per patient, (range, 24-76), with a mean prescription implantation duration of 45.7 hours and a mean actual treatment time of 51.2 hours resulting in a mean interruption time of 6.4 minutes per treatment hour. The number of interruptions was standardized and divided by the number of prescribed dose in grays, translating to 1.2 to 3.7 interruptions per gray delivered, with a mean of 1.6, resulting in an average T(d) of 11.21% (range, 7.35%-17.12%). CONCLUSION: Significant interruptions are frequent using remote afterloading LDR techniques, reducing the effective dose rate. Careful monitoring of such interruptions is warranted.


Subject(s)
Brachytherapy/methods , Brachytherapy/statistics & numerical data , Radiotherapy Dosage , Time Factors , Workload , Indiana , Radiation Dosage
18.
Gynecol Oncol ; 115(2): 285-9, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19726073

ABSTRACT

PURPOSE: To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. PATIENTS AND METHODS: Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m(2) on days 1, 8, and 15 every 28 days. RESULTS: Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5-8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. CONCLUSION: There were no complete or partial responders to weekly topotecan among the 25 patients in this study.


Subject(s)
Antineoplastic Agents/administration & dosage , Topotecan/administration & dosage , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Drug Administration Schedule , Female , Humans , Middle Aged , Topotecan/adverse effects
19.
Cancer Nurs ; 32(5): 378-84, 2009.
Article in English | MEDLINE | ID: mdl-19661797

ABSTRACT

No research has investigated patients' representations of the vaginal symptoms commonly experienced after cervical cancer treatment. Leventhal's Self-regulation or Common Sense Model was used to explore these representations and their relationships with quality of life after cervical cancer. Women posttreatment for cervical cancer (n = 26) from a Midwest cancer center provided information on symptom representations for their 3 most bothersome symptoms and also completed a quality-of-life scale. Women perceived vaginal symptoms as mild to moderate overall but rated approximately one-third of 11 different symptoms as severe. Symptoms identified most frequently as the most bothersome were painful intercourse (23%), decrease in sexual desire (15%), and vaginal dryness (12%). On average, symptoms were mildly distressing and acute, had a minimal effect on life, and were associated with an indeterminate degree of perceived control. Cause was attributed equally to treatment and to the cancer. Quality of life was below normed data, to a degree consistent with a minimally important difference for total well-being scores and physical, emotional, and functional well-being. Emotional and consequence representations were significantly related to quality of life. Understanding and altering symptom representations may improve quality of life for women treated for cervical cancer.


Subject(s)
Quality of Life , Uterine Cervical Neoplasms/physiopathology , Vagina/pathology , Vaginal Diseases/etiology , Cross-Sectional Studies , Female , Health Status Indicators , Health Surveys , Humans , Indiana/epidemiology , Middle Aged , Models, Psychological , Psychometrics , Survival Analysis , United States/epidemiology , Uterine Cervical Neoplasms/complications , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/mortality , Vaginal Diseases/physiopathology
20.
Gynecol Oncol ; 115(1): 90-96, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19577796

ABSTRACT

BACKGROUND: 2-Methoxyestradiol (Panzem, 2ME2) is an endogenous metabolite of estradiol that destabilizes microtubules and exerts anti-angiogenic properties. This study was conducted to determine the activity and safety of 2ME2 administered as a NanoCrystal dispersion (NCD) formulation in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). METHODS: Eligible patients had relapsed, platinum-resistant or refractory EOC with measurable or detectable disease. There was no limit on the number of prior treatment regimens. 2ME2 NCD 1000 mg orally four times daily (q.i.d.) was administered continuously during 4 week cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were assessment of toxicity, rate of clinical benefit defined as the number of patients experiencing an objective response, a CA125 response or stable disease (SD) >3 months, mean change in CA-125, progression-free survival (PFS), and pharmacokinetic analyses of 2ME2. RESULTS: Eighteen patients were enrolled. Median age was 65.5 (range 40-73). Patients had received a median of five prior treatments. The most common adverse events were fatigue (78%), nausea (78%), diarrhea (39%), neuropathy (50%), edema (39%), and dyspnea (44%), the majority being grade 1-2. There were no objective responses, but seven patients had SD as best response. Of those, two patients had SD for greater than 12 months. The rate of clinical benefit was 31.3%. Fairly stable plasma levels of 2ME2 ranging within the predicted therapeutic window were observed. CONCLUSIONS: The NCD formulation of 2ME2 is well tolerated in patients with heavily pretreated EOC. Few of these heavily pretreated patients had sustained stable disease.


Subject(s)
Antineoplastic Agents/therapeutic use , Estradiol/analogs & derivatives , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , 2-Methoxyestradiol , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , CA-125 Antigen/blood , Disease-Free Survival , Drug Resistance, Neoplasm , Estradiol/adverse effects , Estradiol/blood , Estradiol/pharmacokinetics , Estradiol/therapeutic use , Female , Humans , Hydroxyestrones/blood , Middle Aged , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/blood , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/blood , Peritoneal Neoplasms/metabolism
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