ABSTRACT
OBJECTIVE: To determine whether a nonplatinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma. METHODS: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS. RESULTS: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones. CONCLUSIONS: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.
Subject(s)
Paclitaxel , Topotecan , Uterine Cervical Neoplasms , Survival Analysis , Topotecan/therapeutic use , Paclitaxel/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/mortality , Humans , Female , Cisplatin/therapeutic use , Bevacizumab/therapeutic use , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.
Subject(s)
Ovarian Neoplasms , Viral Vaccines , Humans , Female , Bevacizumab , Prospective Studies , Carcinoma, Ovarian Epithelial , Platinum , Ovarian Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. METHODS: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. RESULTS: Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. CONCLUSIONS: These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzimidazoles/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Hereditary Breast and Ovarian Cancer Syndrome/drug therapy , Ovarian Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Recombinational DNA Repair/genetics , Adult , Aged , Aged, 80 and over , Allelic Imbalance/genetics , CA-125 Antigen/metabolism , Carboplatin/administration & dosage , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/metabolism , Carcinoma, Ovarian Epithelial/pathology , Cytoreduction Surgical Procedures , Female , Genes, BRCA1 , Genes, BRCA2 , Genomic Instability/genetics , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Hereditary Breast and Ovarian Cancer Syndrome/metabolism , Hereditary Breast and Ovarian Cancer Syndrome/pathology , Humans , Induction Chemotherapy , Loss of Heterozygosity/genetics , Maintenance Chemotherapy , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Paclitaxel/administration & dosage , Progression-Free Survival , Proportional Hazards Models , Young AdultABSTRACT
BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.
Subject(s)
Bevacizumab/adverse effects , Bevacizumab/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/mortality , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Topotecan/administration & dosage , Topotecan/adverse effectsABSTRACT
BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Angiogenesis Inhibitors/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Cisplatin/administration & dosage , Female , Humans , Neoplasm Metastasis/drug therapy , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/administration & dosage , Quality of Life , Survival Analysis , Topotecan/administration & dosage , Uterine Cervical Neoplasms/mortalityABSTRACT
BACKGROUND: GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. METHODS: Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m(2) intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m(2) intravenously over 24 h or 175 mg/m(2) intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m(2) over 3 h on day 1) and topotecan (0·75 mg/m(2) for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30). INTERPRETATION: Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit. FUNDING: National Institutes of Health.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/blood supply , Carcinoma/drug therapy , Uterine Cervical Neoplasms/blood supply , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carcinoma/mortality , Carcinoma/pathology , Cisplatin/administration & dosage , Disease-Free Survival , Drug Administration Schedule , Europe , Female , Humans , Infusions, Intravenous , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Paclitaxel/administration & dosage , Proportional Hazards Models , Quality of Life , Risk Factors , Surveys and Questionnaires , Time Factors , Topotecan/administration & dosage , Treatment Outcome , United States , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND: Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. DISCUSSION: Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient's own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. SUMMARY: Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.
Subject(s)
Early Detection of Cancer , Neoplasms/diagnosis , Neoplasms/therapy , Precision Medicine , Antineoplastic Protocols , Combined Modality Therapy , Early Detection of Cancer/methods , Early Detection of Cancer/trends , Humans , Neoplasms/pathology , Precision Medicine/methods , Precision Medicine/trendsABSTRACT
BACKGROUND: Hemorrhage in trauma is a significant challenge, accounting for 30% to 40% of all fatalities, second only to central nervous system injury as a cause of death. However, hemorrhagic death is the leading preventable cause of mortality in combat casualties and typically occurs within 6 to 24 hrs of injury. In cases of severe hemorrhage, massive transfusion may be required to replace more than the entire blood volume. Early prediction of massive transfusion requirements, using clinical and laboratory parameters, combined with aggressive management of hemorrhage by surgical and nonsurgical means, has significant potential to reduce early mortality. DISCUSSION: Although the classification of massive transfusion varies, the most frequently used definition is ten or more units of blood in 24 hrs. Transfusion of red blood cells is intended to restore blood volume, tissue perfusion, and oxygen-carrying capacity; platelets, plasma, and cryoprecipitate are intended to facilitate hemostasis through prevention or treatment of coagulopathy. Massive transfusion is uncommon in civilian trauma, occurring in only 1% to 3% of trauma admissions. As a result of a higher proportion of penetrating injury in combat casualties, it has occurred in approximately 8% of Operation Iraqi Freedom admissions and in as many as 16% during the Vietnam conflict. Despite its potential to reduce early mortality, massive transfusion is not without risk. It requires extensive blood-banking resources and is associated with high mortality. SUMMARY: This review describes the clinical problems associated with massive transfusion and surveys the nonsurgical management of hemorrhage, including transfusion of blood products, use of hemostatic bandages/agents, and treatment with hemostatic medications.
Subject(s)
Blood Transfusion/methods , Critical Care/organization & administration , Hemorrhage/therapy , Hemostatics/therapeutic use , Military Medicine/organization & administration , Wounds and Injuries/complications , Acidosis/etiology , Antifibrinolytic Agents/therapeutic use , Bandages , Blood Coagulation Disorders/etiology , Cause of Death , Deamino Arginine Vasopressin/therapeutic use , Factor VIII/therapeutic use , Factor VIIa/therapeutic use , Fibrinogen/therapeutic use , Hemorrhage/etiology , Hemorrhage/mortality , Hemostatics/adverse effects , Humans , Hyperkalemia/etiology , Hypocalcemia/etiology , Hypothermia/etiology , Recombinant Proteins/therapeutic use , Resuscitation/adverse effects , Resuscitation/methods , Risk Factors , Transfusion Reaction , United States/epidemiology , Zeolites/therapeutic useSubject(s)
5-Aminolevulinate Synthetase/genetics , Amino Acid Substitution , Anemia, Sideroblastic/genetics , Iron Overload/genetics , Adult , Black or African American , Anemia, Sideroblastic/ethnology , Child , Genetic Association Studies , Genetic Diseases, X-Linked , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Severity of Illness Index , United StatesABSTRACT
PURPOSE: In the randomized phase III trial, Gynecologic Oncology Group (GOG) protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria. EXPERIMENTAL DESIGN: Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval <365 days. Risk categories included low-risk (0-1 factor), mid-risk (2-3 factors), and high-risk (4-5 factors). Each test of association was conducted at the 5% level of significance. Logistic regression and survival analysis was used to determine whether factors were prognostic or could be used to guide therapy. RESULTS: For the entire population (n = 452), high-risk patients had significantly worse OS (P < 0.0001). The HRs of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 [95% confidence interval (CI), 0.63-2.24], 1.11 (95% CI, 0.82-1.5), and 0.84 (95% CI, 0.50-1.42), respectively. The HRs of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI, 0.51-1.83; P = 0.9087), 0.673 (95% CI, 0.5-0.91; P = 0.0094), and 0.536 (95% CI, 0.32-0.905; P = 0.0196), respectively. CONCLUSIONS: This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real-world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8-month increase in median OS). Clin Cancer Res; 21(24); 5480-7. ©2015 AACR.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Bevacizumab/administration & dosage , Cisplatin/administration & dosage , Female , Humans , Kaplan-Meier Estimate , Neoplasm Staging , Odds Ratio , Paclitaxel/administration & dosage , Prognosis , Survival Analysis , Topotecan/administration & dosage , Treatment Outcome , Uterine Cervical Neoplasms/mortalityABSTRACT
Constitutive activation of Janus kinases (JAKs) is frequently detected in various human cancers. The activation of JAKs results in the phosphorylation and activation of signal transducers and activators of transcription (STATs). The constitutive activation of JAK/STAT pathway may play an important role in growth and survival of human cancer cells. In this study, we examined whether a chemotherapeutic agent cisplatin could inhibit the JAK/STAT pathway. In ovarian cancer and sarcoma cells that express constitutively active JAK2, cisplatin significantly inhibited tyrosine phosphorylation and kinase activity of JAK2 in a dose- and time-dependent manner. Meanwhile, cisplatin also inhibited Stat3 tyrosine phosphorylation and down-regulated BcL-XL anti-apoptotic protein in the cancer cells tested. In leukemia cells expressing high level of TEL-JAK2 fusion protein, cisplatin dramatically inhibited tyrosine phosphorylation of TEL-JAK2 as well. Furthermore, our results have shown that down-regulation of JAK2 by cisplatin might be through modulation of a tyrosine phosphatase SHP-1 but not SOCS family members. Taken together, our observations demonstrated that cisplatin down-regulated the JAK/STAT pathway through de-phosphorylation of JAK/STAT in cancer cells.
Subject(s)
Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Intracellular Signaling Peptides and Proteins , Ovarian Neoplasms/drug therapy , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins , Sarcoma/drug therapy , Apoptosis/drug effects , Carrier Proteins/metabolism , DNA-Binding Proteins/metabolism , Female , Humans , Janus Kinase 2 , Oncogene Proteins, Fusion/metabolism , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Protein Tyrosine Phosphatases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Repressor Proteins/metabolism , STAT3 Transcription Factor , Sarcoma/enzymology , Sarcoma/pathology , Signal Transduction , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins , Trans-Activators/metabolism , Tumor Cells, Cultured , Tyrosine/metabolism , bcl-X ProteinABSTRACT
Resuscitation with hypertonic saline (HS) appears to aggravate bleeding in a model of uncontrolled hemorrhage [J. Trauma 28 (1988) 751; J. Trauma 29 (1989) 79; Arch. Surg. 127 (1992) 93]. This property may be related to the anticoagulant effects of HS on plasma clotting factors and platelets [J. Trauma 31 (1991) 8]. The hypothesis in this study is that a hypertonic solution can be developed that would not disturb the blood coagulation mechanism and could be used as an alternative to hypertonic saline.HS and four different 2400 mosM solutions containing monosaccharides and/or glycine were screened for their in vitro effects on plasma clotting times and platelets. Significant prolongations falling outside the normal range were detected in prothrombin time (PT) and thrombin rime (TT) when only 5% of the volume of normal plasma is HS. Platelet function as measured by extent of shape change (ESC) induced by ADP and aggregation induced by thrombin were also critically impaired by HS at a 5% dilution. All alternative solutions-hypertonic glucose, sorbitol, glycine, glucose/glycine, glucose/mannitol/glycine, sorbitol/glycine-caused a significantly reduced impairment in platelet function and the plasma coagulation system. Hypertonic glycine showed a unique ability to fully preserve the function and integrity of the plasma coagulation system. Considering the pre-deposition of the trauma patient to coagulopathy, administration of HS which clearly is a potent anticoagulant and anti-platelet risks further aggravating the coagulopathy. In contrast, hypertonic glycine preserves the blood coagulation mechanism and exhibits the potential for numerous therapeutic applications. Therefore, prompt evaluation of hypertonic glycine as a resuscitative fluid is highly desirable.
Subject(s)
Blood Coagulation/drug effects , Hypertonic Solutions/adverse effects , Blood Coagulation Tests , Blood Platelets/drug effects , Drug Evaluation , Glycine/pharmacology , Humans , Hypertonic Solutions/chemistry , Hypertonic Solutions/standards , Hypertonic Solutions/therapeutic use , Monosaccharides/pharmacology , Plasma/drug effects , Platelet Activation/drug effects , Platelet Function TestsABSTRACT
epsilon -Amino caproic acid (EACA), a lysine analog that inhibits the activity of plasmin, was added to Nycomed (TC-S) fibrin bandages, and the bandages were tested for hemostatic efficacy in a swine femoral artery bleeding model. The blood loss using the bandage with EACA (TC-S+EACA; 728.8+/-132 g, n=5) was much greater as compared to the TC-S bandage alone (TC-S; 237.8+/-47.9 g, n=6, p=.02). The time to "cessation of bleeding" (T(b)) was also increased for animals treated with TC-S+EACA bandages compared to the TC-S controls (33.6+/-10.8 min vs. 9.2+/-2.2 min; p=.05). Although plasma fibrinogen concentration decreased in animals treated with the TC-S+EACA bandage, activated partial thromboplastin times (aPTT) and thrombin times (TT) were decreased. Animals treated with the TC-S control bandage exhibited no changes in fibrinogen, aPTT or TT. Prothrombin times (PT) were unchanged in either group. In conclusion, addition of EACA to the Nycomed product decreased fibrin bandage efficiency.
Subject(s)
Aminocaproic Acid/pharmacology , Fibrin Tissue Adhesive/chemistry , Hemorrhage/therapy , Hemostatic Techniques/standards , Occlusive Dressings/standards , Animals , Arteries/injuries , Blood Coagulation/drug effects , Blood Coagulation Tests , Blood Loss, Surgical/prevention & control , Disease Models, Animal , Fibrin Tissue Adhesive/standards , Hemorrhage/prevention & control , Hemostasis/drug effects , Hemostatics/pharmacology , Male , Swine , Wound Healing/drug effectsABSTRACT
Fibrin bandages manufactured by Nycomed Austria (TC-S) were modified by the addition of Hemostyptin (HS), a proprietary platelet-activating reagent containing propyl gallate. HS was added as an additional layer to TC-S fibrin bandages and the bandages were tested for hemostatic efficacy in a swine femoral artery bleeding model. Injuries were treated with a TC-S+HS bandage preparation using HS lyophilized onto a bandage surface that was then attached to the fibrin dressing. This preparation qualitatively and quantitatively exhibited more robust blood clotting at the surgical site than the control bandages. TC-S+HS bandages were more effective than control bandages with a difference in blood loss of 251.8+/-66.5 g for TC-S bandage alone, n=12 vs. 121+/-40.7 g, n=13 for the TC-S+HS bandage, P=0.05. Bleeding times were shortened for animals treated with the HS fortified bandages and residual platelets counts in these animals were higher.
Subject(s)
Fibrin Tissue Adhesive/chemistry , Hemostatic Techniques/standards , Hemostatics/pharmacology , Occlusive Dressings/standards , Propyl Gallate/pharmacology , Animals , Blood Coagulation/drug effects , Blood Loss, Surgical/prevention & control , Disease Models, Animal , Femoral Artery/injuries , Fibrin Tissue Adhesive/standards , Hemorrhage/therapy , Hemostasis/drug effects , Male , Swine , Wound Healing/drug effectsABSTRACT
INTRODUCTION: Heparin induced thrombocytopenia is a clinicopathologic syndrome that may result in severe thrombotic sequelae without prompt diagnosis and treatment. A clinical scoring system to assess the pre-test probability of heparin-induced thrombocytopenia, the 4 T's, has been reported to correlate with the serotonin release assay. MATERIALS AND METHODS: We performed a single-center, retrospective study correlating the 4 T's score with the commercial heparin-PF4 ELISA. RESULTS: One hundred forty four cases were identified. The pre-test probability scores were: low probability 45.8%, moderate probability 41.0% and high probability 13.2%. The median optical density was 0.148, 0.223 and 0.470 for low probability, moderate probability and high probability, respectively (P < 0.0005). The frequencies of obtaining an optical density>1.00 for these probability scores were 1.5%, 6.8%, and 36.8%, respectively (P < 0.0005). CONCLUSIONS: Heparin-PF4 ELISA optical density values increase with increasing probability of heparin induced thrombocytopenia.
Subject(s)
Heparin/adverse effects , Platelet Factor 4/blood , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Enzyme-Linked Immunosorbent Assay , Humans , Predictive Value of Tests , Retrospective StudiesABSTRACT
BACKGROUND: Recently, a wide variety of bandages have been formulated to attempt to improve the effectiveness of emergency intervention in situations of uncontrolled bleeding. The best of these dressings contain a mixture of human thrombin and fibrinogen. The presence of human components in these bandages, although effective, increases the cost of the dressing and raises questions of availability of raw materials and transmission of pathogens. The purpose of this study was to investigate the efficacy of dressings composed of salmon thrombin and fibrinogen in a swine aortotomy model. METHODS: A 4.4-mm aortotomy was produced in the abdominal aorta of 19 anesthetized, splenectomized swine. The United States Army standard field gauze was applied to 8 animals, and the salmon thrombin-fibrin dressing (SFD) was applied to 11 animals. Survival, blood loss, and other parameters were measured over a 60-minute period. RESULTS: All 11 animals that received the SFD survived the aortotomy injury, and bleeding stopped within 7.5 +/- 1.5 min. Seven of 8 animals in the control group were killed when bleeding continued and blood pressures decreased to the cutoff values as outlined in the animal protocol. Bleeding was significantly less in the SFD group compared with the gauze group (241 +/- 65.3 vs. 932.7 +/- 142.4 mL). CONCLUSION: Fibrin dressing using salmon-derived thrombin and fibrinogen is effective in controlling severe, uncontrolled bleeding. This dressing may offer an alternative to dressings composed of human coagulation proteins.
Subject(s)
Aorta, Abdominal/injuries , Bandages , Fibrin/pharmacology , Hemorrhage/therapy , Hemostatics/pharmacology , Thrombin/pharmacology , Animals , Hemodynamics , Salmon , SwineABSTRACT
A variety of agents are available to improve hemostasis and reduce blood loss in multiple clinical settings. These agents are most commonly used to reduce bleeding when an underlying hemostatic defect is present. Some new agents offer the potential to decrease blood loss even in the absence of an obvious underlying hemostatic defect. The authors discuss the use of a variety of products to reduce bleeding and minimize transfusion of blood products in the setting of clotting factor deficiency or inhibition, platelet deficiency and/or dysfunction, increased fibrinolysis, therapeutic anticoagulation, and coagulopathies caused by dilution and consumption in the setting of trauma and surgery. The authors primarily focus on the available pharmaceuticals.
Subject(s)
Hemostasis/drug effects , Antifibrinolytic Agents/therapeutic use , Bandages , Blood Transfusion , Coagulants/therapeutic use , Contraindications , Hematopoietic Cell Growth Factors/therapeutic use , Hemorrhage/prevention & control , HumansABSTRACT
A variety of agents can improve hemostasis and reduce blood loss caused or exacerbated by congenital or acquired defects in platelet number of function. This review discusses several available approaches for the practicing clinician to reduce bleeding (diffuse or localized) in this clinical setting.
Subject(s)
Hemostatics/therapeutic use , Thrombocytopenia/drug therapy , Antifibrinolytic Agents/therapeutic use , Blood Platelets/drug effects , Disease Management , Humans , Thrombocytopenia/blood , Thrombocytopenia/therapy , Tissue AdhesivesABSTRACT
BACKGROUND: There is a universal need, in both civilian and military settings, for a lightweight container capable of maintaining RBCs at 1 to 10 degrees C in remote areas, during extended transit times, and under austere environments. The use of ice in insulated containers or small commercial coolers for these purposes often results in loss of RBCs due to failure to maintain temperatures within the requisite range. A lightweight and thermally efficient container capable of carrying 4 to 6 units of RBCs at 1 to 10 degrees C for over 72 hours under extreme conditions would help resolve current problems in RBC transportation. STUDY DESIGN AND METHODS: Six different prototype containers incorporating phase-change materials (PCMs) in their designs were evaluated for their ability to maintain RBCs between 1 and 10 degrees C while exposed to external temperatures of -24 degrees C and 40 degrees C. In separate experiments, a container was opened and a RBC unit removed. RESULTS: One container weighing 10 pounds with four units of RBCs was capable of maintaining the temperature of the units between 1 and 10 degrees C for over 78 hours, 96 hours, and 120 hours at 40 degrees C, -24 degrees C, and 23 degrees C, respectively. Opening the container decreased these times by 2 to 3 hours. CONCLUSIONS: An energy-efficient and lightweight container that maintains RBCs at 1 to 10 degrees C under austere environments for over 78 hours is now available. This container, known as the Golden Hour container (GHC), will facilitate transport of RBCs. The GHC will have additional applications (transport and/or storage of vaccines, other biologics, organs, reagents, etc).
Subject(s)
Blood Preservation/instrumentation , Erythrocytes , Transportation , Humans , TemperatureABSTRACT
The main phase transition (Tm) of 100 nm large unilamellar vesicles (LUVs) of 1,2-dipalmitoylphosphatidylcholine (DPPC) was investigated using 1H NMR (proton magnetic resonance) in deuterium oxide, and both DSC (differential scanning calorimetry) and IR (infrared) spectroscopy in water and deuterium oxide. The ability of 1H NMR to determine Tm was demonstrated and the values obtained were in general agreement with those observed with DSC and IR. However, the temperature range of the transition observed by NMR was significantly broader than that observed with either DSC or IR. The effect of deuterium oxide on Tm was studied by comparing results obtained in water and deuterium oxide with DSC and IR. The results showed no significant difference in Tm or temperature range of transition determined in these solvents.