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Blumenschein G.R.,University of Texas M. D. Anderson Cancer Center | Ciuleanu T.,Oncological Institute Ion Chiricuta | Robert F.,Central European Cooperative Oncology Group CECOG | Groen H.J.M.,University of Alabama at Birmingham | And 6 more authors.
Journal of Thoracic Oncology | Year: 2012

BACKGROUND:: This randomized, double-blind, multicenter study evaluated sunitinib plus erlotinib versus placebo plus erlotinib. Subjects with advanced non-small-cell lung cancer had received prior treatment with a platinum-based regimen. Here, we report safety, pharmacokinetics, and antitumor activity of the combination of sunitinib and erlotinib. METHODS:: Lead-in subjects in this phase II study received sunitinib 37.5 mg/d and erlotinib 150 mg/d. Safety, including dose-limiting toxicities (DLTs, cohort 1 only), pharmacokinetic profiles, and antitumor activity were investigated (cohorts 1 and 2). RESULTS:: Thirty patients were evaluated. The combination of sunitinib and erlotinib was tolerable. Diarrhea (76.9%), fatigue (61.5%), and decreased appetite (53.8%) were the most frequent adverse events in cohort 1; and diarrhea (52.9%) and rash (41.2%) were the most frequent adverse events in cohort 2. DLTs were observed (fatigue, n = 2 and paronychial inflammation, n = 1) in three of 13 patients evaluated for DLTs. Geometric mean ratios for the maximum plasma concentration (Cmax) and area under plasma concentration-time profile from time 0 to 24 hours of erlotinib with and without sunitinib were 1.05 and 1.03, respectively. Corresponding values for sunitinib with and without erlotinib were 0.62 and 0.62 for sunitinib, 2.13 and 2.07 for SU12662; and 0.81 and 0.79 for total drug. Three patients experienced partial response as per response evaluation criteria in solid tumor. CONCLUSION:: A dosage of sunitinib 37.5 mg/d concurrently with erlotinib 150 mg/d was tolerable and established the recommended combinatorial dose in subjects with platinum-refractory non-small-cell lung cancer. Coadministration of sunitinib with erlotinib does not affect the pharmacokinetics of erlotinib, but may result in decreased exposure to sunitinib. Copyright © 2012 by the International Association for the Study of Lung Cancer.


Ramalingam S.S.,Emory University | Goss G.,University of Ottawa | Rosell R.,Catalan Institute of Nanoscience and Nanotechnology | Schmid-Bindert G.,University of Mannheim | And 18 more authors.
Annals of Oncology | Year: 2015

Background: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients and methods: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m2 on day 1) was administered alone or with ganetespib (150 mg/m2 on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Results: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Conclusion: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | McGill University, Oncological Institute Ion Chiricuta, University of Barcelona, University of Ottawa and 15 more.
Type: Clinical Trial, Phase II | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination.Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade 3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the studys primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.


PubMed | National Oncology Hospital, Institute of Public Health of Serbia, Oncological Institute Ion Chiricuta, Institute of Oncology and 15 more.
Type: | Journal: Hematological oncology | Year: 2016

Childhood (0-14years) lymphomas, nowadays, present a highly curable malignancy compared with other types of cancer. We used readily available cancer registration data to assess mortality and survival disparities among children residing in Southern-Eastern European (SEE) countries and those in the United States. Average age-standardized mortality rates and time trends of Hodgkin (HL) and non-Hodgkin (NHL; including Burkitt [BL]) lymphomas in 14 SEE cancer registries (1990-2014) and the Surveillance, Epidemiology, and End Results Program (SEER, United States; 1990-2012) were calculated. Survival patterns in a total of 8918 cases distinguishing also BL were assessed through Kaplan-Meier curves and multivariate Cox regression models. Variable, rather decreasing, mortality trends were noted among SEE. Rates were overall higher than that in SEER (1.02/10


PubMed | Institute of Public Health of Serbia, Institute of Oncology, G Gennimatas General Hospital, National and Kapodistrian University of Athens and 19 more.
Type: Journal Article | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2015

Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region.Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants.Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4).Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.


PubMed | National Oncology Hospital, Hygeia Hospital, Oncological Institute Ion Chiricuta, Institute of Oncology and 15 more.
Type: | Journal: Journal of neuro-oncology | Year: 2016

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N=552; 1983-2014) and SEER (N=2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/10


PubMed | National Oncology Hospital, Institute of Public Health of Serbia, Oncological Institute Ion Chiricuta, Institute of Oncology and 16 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

To assess trends in survival and geographic disparities among children (0-14 years) with chronic myeloid leukaemia (CML) before and after the introduction of molecular therapy, namely tyrosine kinase inhibitors (TKIs) in Southern-Eastern European (SEE) countries and the USA.We calculated survival among children with CML, acute lymphoblastic (ALL) and acute myeloidleukaemia (AML) in 14 SEE (1990-2014) cancer registries and the U.S.Surveillance, Epidemiology and End Results Program (SEER, 1990-2012). We used Kaplan-Meier curves and multivariate Cox regression models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).Among 369 CML cases, substantial improvements were noted in 2-year survival during the post-TKI (range: 81-89%) compared to pre-TKI period (49-66%; HR: 0.37, 95% CI: 0.23-0.60). Risk of death was three times higher for <5-year-old children versusthose aged 10-14 years (HR: 3.03, 95% CI: 1.85-4.94) and 56% higher for those living in SEE versusSEER (HR: 1.56, 95% CI: 1.01-2.42). Regardless of geographic area and period of TKI administration, however, age seems to be a significant determinant of CML prognosis (pre-TKI period, HRRegistry data show that introduction of molecular therapies coincides with revolutionised therapeutic outcomes in childhood CML entailing dramatically improved survival which is now similar to that in ALL. Given that age disparities in survival remain substantial, offering optimal therapy to entire populations is an urgent priority.


PubMed | Piedmont Cancer Registry, Oncological Institute Ion Chiricuta, IKZ Integraal Kankercentrum Zuid, Ferrara Cancer Registry and 10 more.
Type: Journal Article | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2015

Cancer registries must provide complete and reliable incidence information with the shortest possible delay for use in studies such as comparability, clustering, cancer in the elderly and adequacy of cancer surveillance. Methods of varying complexity are available to registries for monitoring completeness and timeliness. We wished to know which methods are currently in use among cancer registries, and to compare the results of our findings to those of a survey carried out in 2006.In the framework of the EUROCOURSE project, and to prepare cancer registries for participation in the ERA-net scheme, we launched a survey on the methods used to assess completeness, and also on the timeliness and methods of dissemination of results by registries. We sent the questionnaire to all general registries (GCRs) and specialised registries (SCRs) active in Europe and within the European Network of Cancer Registries (ENCR).With a response rate of 66% among GCRs and 59% among SCRs, we obtained data for analysis from 116 registries with a population coverage of 280 million. The most common methods used were comparison of trends (79%) and mortality/incidence ratios (more than 60%). More complex methods were used less commonly: capture-recapture by 30%, flow method by 18% and death certificate notification (DCN) methods with the Ajiki formula by 9%. The median latency for completion of ascertainment of incidence was 18 months. Additional time required for dissemination was of the order of 3-6 months, depending on the method: print or electronic. One fifth (21%) did not publish results for their own registry but only as a contribution to larger national or international data repositories and publications; this introduced a further delay in the availability of data.Cancer registries should improve the practice of measuring their completeness regularly and should move from traditional to more quantitative methods. This could also have implications in the timeliness of data publication.


Golfinopoulos V.,University of Ioannina | Golfinopoulos V.,Hellenic Cooperative Oncology Group HeCOG | Pentheroudakis G.,University of Ioannina | Pentheroudakis G.,Hellenic Cooperative Oncology Group HeCOG | And 14 more authors.
Annals of Oncology | Year: 2012

Background: Hypothesising that cancer of unknown primary (CUP) may harbour unique characteristics, we present a translational study of the immunohistochemical expression and clinical correlation of key PTEN/AKT pathway molecules. Patients and methods: We collected 100 paraffin-embedded CUP tissue blocks. We studied using tissue microarrays the expression of PTEN, phospho-AKT, Cyclin D1, p21, phospho-RPS6. From the percentage of staining tumour cells and the literature, we selected cut-offs to classify the expression of each biomolecule. We correlated IHC expression with clinical data. Results: PTEN, pAKT, and pRPS6 showed frequent expression. At univariate analysis, high IHC expression of pAKT and pRPS6 displayed statistically significant association with worse survival. Prognosis was worse upon concurrent high IHC expression of pMAPK and pAKT {median overall survival = 8 months [95% confidence interval (CI) 5.3-10.7] versus 17 months [95% CI 13.1-20.9]}. In multivariate analysis, high p21 was associated with better survival (risk ratio [RR] = 0.34 [95% CI 0.16-0.73], P = 0.005). High expression of pAKT (RR = 2.39 [95% CI 1.23-4.66], P = 0.01) or pRPS6 (RR = 2.76 [95% CI 1.31-5.84], P = 0.008) was associated with worse survival. Conclusions: p21 expression conferred favourable prognosis, while high pAKT or pRPS6 expression predicted worse prognosis. Concurrent MAPK and pAKT expression had a marked adverse impact on survival. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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