ABSTRACT
Archaeologists increasingly use large radiocarbon databases to model prehistoric human demography (also termed paleo-demography). Numerous independent projects, funded over the past decade, have assembled such databases from multiple regions of the world. These data provide unprecedented potential for comparative research on human population ecology and the evolution of social-ecological systems across the Earth. However, these databases have been developed using different sample selection criteria, which has resulted in interoperability issues for global-scale, comparative paleo-demographic research and integration with paleoclimate and paleoenvironmental data. We present a synthetic, global-scale archaeological radiocarbon database composed of 180,070 radiocarbon dates that have been cleaned according to a standardized sample selection criteria. This database increases the reusability of archaeological radiocarbon data and streamlines quality control assessments for various types of paleo-demographic research. As part of an assessment of data quality, we conduct two analyses of sampling bias in the global database at multiple scales. This database is ideal for paleo-demographic research focused on dates-as-data, bayesian modeling, or summed probability distribution methodologies.
ABSTRACT
In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives.
Subject(s)
Archaeology , Natural Resources , Arabia , Biodiversity , Climate , Conservation of Natural Resources , Data Management , Earth, Planet , Ecosystem , History, Ancient , Humans , MesopotamiaABSTRACT
Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth's transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
ABSTRACT
The aim of this study is to investigate livestock husbandry and its relationship to the mobilization of domestic animals for slaughter at large communal feasting events, in Late Neolithic Makriyalos, northern Greece. A multi-isotope approach is built that integrates analysis of: δ13C and δ15N values of human and animal bone collagen for understanding long-term dietary behavior,Incremental δ13C and δ18O values of domestic animal tooth enamel carbonate for assessing seasonal patterns in grazing habits and mobility, and87Sr/86Sr ratios of cattle tooth enamel for examining the possibility that some of the animals consumed at the site were born outside the local environment. The findings indicate that cattle had isotopically more variable diets than sheep, which may reflect grazing over a wider catchment area in the local landscape. Cattle products did not make a significant contribution to the long-term dietary protein intake of the humans, which may indicate that they were primarily consumed during episodic feasting events. There is no indication that pasturing of livestock was pre-determined by their eventual context of slaughter (i.e. large-scale feasting vs. more routine consumption events). Two non-local cattle identified among those deposited in a feasting context may have been brought to the site as contributions to these feasts. The evidence presented provides a more detailed insight into local land use and into the role of livestock and feasting in forging social relationships within the regional human population.
Subject(s)
Animal Feed , Animal Husbandry , Carbon Isotopes , Livestock , Nitrogen Isotopes , Sheep , Strontium Isotopes , Animals , Cattle , HumansABSTRACT
BACKGROUND: The assessment of the severity of chronic obstructive pulmonary disease (COPD) should involve a multidimensional approach that is now clearly shown to be better than using spirometric impairment alone. The aim of this study is to validate and compare novel tools without an exercise test and to extend prognostic value to patients with less severe impairment of Forced expiratory volume 1 s. METHODS: A prospective, observational, primary care cohort study identified 458 eligible patients recruited from the primary care clinics in the northeast of England in 1999-2002. A new prognostic indicator - body mass index, airflow obstruction and dyspnea (BOD) together with the conventional prognostic indices age, dyspnea and airflow obstruction (ADO), global initiative for chronic obstructive lung disease (GOLD) and new GOLD matrix were studied. We also sought to improve prognostication of BOD by adding age (A) and smoking history as pack years (S) to validate BODS (BOD with smoking history) and BODAS (BOD with smoking history and age) as prognostic tools and the predictive power of each was analyzed. RESULTS: The survival of the 458 patients was assessed after a median of 10 years when the mortality was found to be 33.6%. The novel indices BOD, BODS, and BODAS were significantly predictive for all-cause mortality in our cohort. Furthermore with ROC analysis the C statistics for BOD, BODS, and BODAS were 0.62, 0.66, and 0.72, respectively (P < 0.001 for each), whereas ADO and GOLD stages had a C statistic of 0.70 (P < 0.001) and 0.56 (P < 0.02), respectively. GOLD Matrix was not significant in this cohort. CONCLUSION: BOD, BODS, and BODAS scores are validated predictors of all-cause mortality in a primary care cohort with COPD.
ABSTRACT
PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSION: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Breast Neoplasms/drug therapy , Quinolones/therapeutic use , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Adult , Aged , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Benzimidazoles/adverse effects , Benzimidazoles/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Fibroblast Growth Factor 3/genetics , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/blood , Gene Amplification , Humans , Mice , Middle Aged , Neoplasm Staging , Quinolones/adverse effects , Quinolones/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Signal Transduction/drug effects , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.
Subject(s)
Benzimidazoles/administration & dosage , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Quinolones/administration & dosage , Benzimidazoles/blood , Benzimidazoles/pharmacokinetics , Drug Administration Schedule , Female , Humans , Male , Models, Biological , Neoplasms/metabolism , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Quinolones/blood , Quinolones/pharmacokinetics , Vascular Endothelial Growth Factor A/bloodABSTRACT
PURPOSE: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. EXPERIMENTAL DESIGN: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). RESULTS: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. CONCLUSIONS: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.
Subject(s)
Adenocarcinoma/drug therapy , Benzimidazoles/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Quinolones/therapeutic use , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles/pharmacokinetics , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Drug Evaluation, Preclinical , Female , Follow-Up Studies , Humans , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Maximum Tolerated Dose , Mice , Mice, Nude , Middle Aged , Neoplasm Staging , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Prognosis , Protein Kinase Inhibitors/therapeutic use , Quinolones/pharmacokinetics , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Sorafenib , Survival Rate , Tissue Distribution , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
BACKGROUND: Measured reductions in lung function, as a result of COPD, use a measured current value and make comparisons to a determined 'normal' value arrived at using a regression equation based upon a patients height. Osteoporosis is a recognised co-morbidity in patients with chronic obstructive pulmonary disease (COPD) and may cause excessive height loss resulting in the 'normal' values and disease progression being under-estimated. PURPOSE: The aim of the study was to examine the height variation in a cohort of COPD patients and controls over a 7-8 years period and evaluate its impact on estimates of lung function and hence COPD progression. METHODS: In 1999-2002 we studied a cohort of primary care patients in Sunderland, UK with and without COPD and reexamined 104 (56 male) during 2007-2009. We calculated FEV(1)% predicted for actual and estimated height (armspan/1.03 and armspan/1.01 in males and females respectively). RESULTS: In 1999-2002 the subjects were aged 62.6 ± 9.4 years, BMI was 26.4± 4.7 kg/m2, predicted FEV(1) was 59.0 ±16.0, and mean actual height was 167.3±8.9cm. The actual height changed significantly (p<0.001) by 2cms over time in both genders. Whilst the overall classifications of the cohort did not change significantly when armspan was used to determine height and hence normal lung volume, individual cases did move to a classification of higher severity. CONCLUSIONS: The study suggests that current measured height may underestimate the degree of impairment of FEV(1) and hence progression of COPD. The use of height, derived from armspan, may give a more accurate measure of 'normal' lung volumes and hence the degree of impairment.
ABSTRACT
PURPOSE: A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes. METHODS: Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo. The Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 were administered before randomization and on day 1 of each cycle. The FKSI-DRS and the EORTC QLQ-C30 Physical Functioning and Global Quality of Life scores were the primary endpoints examined. Longitudinal models were used to compare treatment arms. Sensitivity analyses were conducted to explore the impact of missing data assumptions. RESULTS: Longitudinal trends for FKSI-DRS scores did not differ by treatment arm. Taking nonignorable missing data into account, there were significant differences between treatment arms in the trend over time for physical functioning and global quality of life, with the everolimus arm exhibiting greater decreases. All three of these measures of health-related quality of life were significantly related to progression-free survival. CONCLUSIONS: There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/secondary , Disease-Free Survival , Double-Blind Method , Everolimus , Female , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Placebos , Protein-Tyrosine Kinases/antagonists & inhibitors , Quality of Life , Sirolimus/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported. METHODS: Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus. RESULTS: The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥ 5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01). CONCLUSIONS: These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Double-Blind Method , Everolimus , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Middle Aged , Neoplasm Metastasis , Placebos , Prognosis , Retreatment , Sirolimus/therapeutic useABSTRACT
RATIONALE: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. OBJECTIVES: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. METHODS: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. MEASUREMENTS AND MAIN RESULTS: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). CONCLUSIONS: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).
Subject(s)
Carcinoma, Renal Cell/drug therapy , Immunosuppressive Agents/adverse effects , Kidney Neoplasms/drug therapy , Pneumonia/chemically induced , Sirolimus/analogs & derivatives , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Everolimus , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Pneumonia/diagnostic imaging , Pneumonia/drug therapy , Respiratory Function Tests , Severity of Illness Index , Sirolimus/administration & dosage , Sirolimus/adverse effects , Tomography, X-Ray ComputedABSTRACT
The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
Subject(s)
Antineoplastic Agents/administration & dosage , Cell Transformation, Neoplastic/drug effects , Drug Delivery Systems/methods , Drug Discovery , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Cell Transformation, Neoplastic/pathology , Drug Discovery/methods , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/physiology , Models, Biological , Neoplasms/etiology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/physiology , TOR Serine-Threonine KinasesABSTRACT
In clinical trials of oncology drugs, overall survival (OS) is a direct measure of clinical efficacy and is considered the gold standard primary efficacy end point. The purpose of this study was to discuss the difficulties in using OS as a primary efficacy end point in the setting of evolving cancer therapies. We suggest that progression-free survival is an appropriate efficacy end point in many types of cancer, specifically those for which OS is expected to be prolonged and for which subsequent treatments are expected to affect OS.
Subject(s)
Antineoplastic Agents/standards , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Clinical Trials as Topic , Disease Progression , Disease-Free Survival , Drug Approval , Humans , Neoplasms/pathology , United States , United States Food and Drug AdministrationABSTRACT
BACKGROUND: Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. METHODS: Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124. FINDINGS: All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity. INTERPRETATION: Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Immunosuppressive Agents/therapeutic use , Kidney Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/pathology , Disease-Free Survival , Double-Blind Method , Everolimus , Female , Humans , Immunosuppressive Agents/adverse effects , Karnofsky Performance Status , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Sirolimus/adverse effects , Sirolimus/therapeutic useABSTRACT
PURPOSE: PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. PATIENTS AND METHODS: Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. RESULTS: At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease. CONCLUSION: The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Phthalazines/pharmacology , Phthalazines/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/pharmacology , Pyridines/pharmacokinetics , Administration, Oral , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Area Under Curve , Chi-Square Distribution , Chromatography, High Pressure Liquid , Disease Progression , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Phthalazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyridines/administration & dosage , Statistics, Nonparametric , Treatment OutcomeABSTRACT
PURPOSE Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. PATIENTS AND METHODS In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. Results Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. CONCLUSION This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Quality of Life , Quinazolines/therapeutic use , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Endpoint Determination , Female , Gefitinib , Health Status , Humans , Male , Middle Aged , Quinazolines/adverse effects , Sensitivity and Specificity , Survival AnalysisABSTRACT
CONTEXT: More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. OBJECTIVE: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. INTERVENTION: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). MAIN OUTCOME MEASURES: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). RESULTS: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). CONCLUSIONS: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.