Analysing the attributes of Comprehensive Cancer Centres and Cancer Centres across Europe to identify key hallmarks.

There is a persistent variation in cancer outcomes among and within European countries suggesting (among other causes) inequalities in access to or delivery of high-quality cancer care. European policy (EU Cancer Mission and Europe's Beating Cancer Plan) is currently moving towards a mission-oriented approach addressing these inequalities. In this study, we used the quantitative and qualitative data of the Organisation of European Cancer Institutes' Accreditation and Designation Programme, relating to 40 large European cancer centres, to describe their current compliance with quality standards, to identify the hallmarks common to all centres and to show the distinctive features of Comprehensive Cancer Centres. All Comprehensive Cancer Centres and Cancer Centres accredited by the Organisation of European Cancer Institutes show good compliance with quality standards related to care, multidisciplinarity and patient centredness. However, Comprehensive Cancer Centres on average showed significantly better scores on indicators related to the volume, quality and integration of translational research, such as high-impact publications, clinical trial activity (especially in phase I and phase IIa trials) and filing more patents as early indicators of innovation. However, irrespective of their size, centres show significant variability regarding effective governance when functioning as entities within larger hospitals.

Improvement of European translational cancer research. Collaboration between comprehensive cancer centers.

Even though the increasing incidence of cancer is mainly a consequence of a population with a longer life span, part of this augmentation is related to the increasing prevalence of patients living with a chronic cancer disease. To fight the problem, improved preventive strategies are mandatory in combination with an innovative health care provision that is driven by research. To overcome the weakness of translational research the OECI is proposing a practical approach as part of a strategy foreseen by the EUROCAN+PLUS feasibility study, which was launched by the EC in order to identify mechanisms for the coordination of cancer research in Europe.

Towards quality, comprehensiveness and excellence. The accreditation project of the Organisation of European Cancer Institutes (OECI).

There are important gaps in the health status of citizens across Europe, as measured by life expectancy, mortality or morbidity data (Report for the European Commission on the health status of the European Union, 2003). Among the main determinants of the major causes of mortality and morbidity, stated in this report, stands recurrently access to quality healthcare. There is a fundamental need to define quality indicators and set minimal levels of performance quality criteria for healthcare. There is a need to integrate research into healthcare and to provide patients with equity of access to such high quality care. Oncology is a specialty particularly suited to experimenting a first application of accreditation at European level. The Organisation of European Cancer Institutes is a growing network of cancer Centres in Europe. The focus of the OECI is to work with professionals and organisations with regard to prevention, care, research, development, patient's role and education. In order to fulfil its mission, the OECI initiated in 2002 an accreditation project with three objectives: * to develop a comprehensive accreditation system for oncology care, taking into account prevention, care, research, education and networking. * to set an updated database of cancer centres in Europe, with exhaustive information on their resources and activities (in care, research, education and management) * to develop a global labelling tool dedicated to comprehensive cancer centres in Europe, designating the various types of cancer structures, and the comprehensive cancer centres of reference and Excellence. An accreditation tool has been established, defining standards and criteria for prevention, care, research, education and follow-up activities. A quantitative database of cancer centres is integrated in the tool, with a questionnaire, that provides an overall view of the oncological landscape in OECI cancer centres in Europe. Data on infrastructures, resources and activities have been collected. This OECI accreditation tool will be launched in autumn 2008 for all cancer centres in Europe. It serves as a basis for the development of the labelling tool for cancer structures in Europe, with a focus on Comprehensiveness and Excellence labels. Quality assessment and improvement is a critical need in Europe and is addressed by the OECI for cancer care in Europe. Accreditation is a well accepted process and is feasible. Standards and criteria as well as an accreditation tool have been developed. The OECI questionnaire gives an accurate vision of cancer institutions throughout Europe, helping assessing the needs and providing standards. The accreditation project is a long-term complete and voluntary process with external and internal added value, an active process of sharing information and experience that should help the whole cancer community reach comprehensiveness and excellence.

Results of the Belgian expanded access program of eribulin in the treatment of metastatic breast cancer closely mirror those of the pivotal phase III trial.

BACKGROUND: Eribulin is a non-taxane microtubule dynamics inhibitor that showed a survival benefit versus treatment of physician's choice in a phase III trial enrolling patients with metastatic breast cancer (MBC). METHODS: The E7389-G000-398 trial was designed to provide eribulin to MBC patients pre-treated with anthracylines, taxanes and capecitabine. Patient characteristics, efficacy and safety data were collected prospectively. Efficacy and survival analyses were performed using retrospectively collected data of patients treated at a single institution. RESULTS: One hundred fifty-four patients were enrolled and the median number of previous lines of chemotherapy was 4. The most frequent adverse events were fatigue/asthenia (74%), alopecia (55%), peripheral neuropathy (46%) and neutropenia (43%). Objective response rate (ORR) was 24% in the evaluable population and 14% in patients pre-treated with both taxanes and vinorelbine. In patients with oestrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- MBC, response rate was 29% and 21% with triple-negative disease. Activity was minimal in HER2+ MBC treated with eribulin monotherapy (14% ORR). Median progression-free survival was 3.2 months. Median overall survival was 11.3 months; 77% of patients were alive at 6 months and 43% at 12 months. CONCLUSION: Eribulin was active in MBC patients with a high tumour burden and predominant visceral disease. Safety profile was similar to what was reported in the phase III trials. Prophylactic granulocyte colony-stimulating factor administration allowed optimal dose intensity and could have contributed to the recorded response rate. Activity is sustained after treatment with taxanes and vinorelbine. The recently investigated combination of eribulin and trastuzumab should lead to higher activity in HER2-positive MBC.

Influence of amifostine on the toxicity and pharmacokinetics of docetaxel in metastatic breast cancer patients: a pilot study.

Preclinical studies suggest that amifostine could protect against toxicities induced by taxoids. We conducted a clinical and pharmacokinetic pilot study to assess the feasibility and toxicity of the docetaxel plus amifostine combination and the absence of influence of amifostine on docetaxel pharmacokinetics. We included 18 previously treated women with metastatic breast cancer (median age, 58.5 years; range, 34-74) in this single-center study. They were to receive a first course of docetaxel at 100 mg/m(2) i.v. as a 1-h infusion, then subsequent courses of docetaxel at 100 mg/m(2) preceded by amifostine at 910 mg/m(2) given as a 15-min i.v. infusion. Treatment was given every 3 weeks until disease progression or occurrence of unacceptable toxicity. We focused on neutrophils nadir (NN), time to nadir occurrence, and time to recovery of a neutrophil count >2 x 10(9)/liter, means of which were compared between cycle 1 and each of the other cycles by paired Student's t test. The total number of administered cycles was 84 (median number/patient, 4; range, 1-8). One patient received only the first course of docetaxel and was therefore not evaluable for amifostine effect. Neutropenia grade >2 occurred in 16 patients and was febrile in only 1. Other hematological and nonhematological toxicities were mild and manageable. Amifostine had no obvious influence on docetaxel-induced myelotoxicity as expressed by NN, time to nadir occurrence, and time to recovery. The mean NN (1 x 10(6)/liter) was 345 (18 patients) for cycle 1, then 318 (17 patients), 330 (13 patients), 340 (11 patients), 470 (8 patients), 200 (8 patients), 680 (5 patients), and 545 (4 patients) for cycles 2, 3, 4, 5, 6, 7, and 8, respectively (P >0.2). Individual pharmacokinetic (PK) parameters of docetaxel estimated in 11 patients undergoing blood sampling showed no influence of amifostine on the PK profile of docetaxel. Mean clearances (liter/h/m(2)) and peak concentration (C(peak); ng/ml) were 29.9 at cycle 1 versus 32.8 at cycle 2 (not significant) and 2849.9 at cycle 1 versus 2542.5 at cycle 2 (not significant), respectively. The population analysis including those 11 patients and 49 additional patients receiving docetaxel in other studies confirmed those findings. This study does not support evidence for amifostine cytoprotection against docetaxel-induced myelosuppression and shows that there is no major influence of amifostine on docetaxel PK parameters. For the other toxicities, which are usually cumulative, the present study has design limitations and further comparative trials are warranted.

Participation of Italian Cancer Centres of the Alleanza Contro Il Cancro (ACC) in the Organisation of European Cancer Institutes (OECI) Accreditation and Designation program: a successful first national initiative.

The Organisation of European Cancer Institutes (OECI) launched a program for accreditation and designation (A&D) of cancer centers in Europe based on voluntary participation in 2008. In 2012, the Italian Ministry of Health decided to fund cancer centers in Italy, members of the Alleanza Contro il Cancro (ACC), to go through the OECI accreditation program. Ten centers participated in the program and 10 completed the full cycle of the OECI A&D process in consecutive series over a 2-year period. The process was successfully completed within the planned timeline and the overall findings were presented to the Italian Ministry of Health and representatives of all the participating centers in November 2015. The program had a considerable team-building effect, which will likely continue as the improvement plans are implemented. Centers fed back to OECI that the A&D program had led to better formal organization of multidisciplinary teams (MDTs) and cancer care pathways, and had helped them to harmonize the integration of research into clinical practice. Centers also concluded that they benefited from recognition through an international accreditation system, and that it had led to them developing better patient information and involvement. The importance of the improvement plans that each center had to produce following the audit reviews cannot be underestimated. The OECI concludes that implementation of the A&D program at the national level is feasible despite national peculiarities related to health planning and organization in each member state. This is a good example of an EU project working well, with member states helping each other and learning from best practice, to improve the overall quality of cancer care and research and to establish consistency. The initial accreditation is the first part of an ongoing process of improving comprehensive cancer care, integrating bench to bedside.

Pioneering quality assessment in European cancer centers: a data analysis of the organization for European cancer institutes accreditation and designation program.

PURPOSE: In order to improve the quality of care in Cancer Centers (CC) and designate Comprehensive Cancer Centers (CCCs), the Organization for European Cancer Institutes (OECI) launched an Accreditation and Designation (A&D) program. The program facilitates the collection of defined data and the assessment of cancer center quality. This study analyzes the results of the first 10 European centers that entered the program. METHODS: The assessment included 927 items divided across qualitative and quantitative questionnaires. Data collected during self-assessment and peer-review from the 10 first participating centers were combined in a database for comparative analysis using simple statistics. Quantitative and qualitative results were validated by auditors during the peer review visits. RESULTS: Volumes of various functions and activities dedicated to care, research, and education varied widely among centers. There were no significant differences in resources for radiology, radiotherapy, pathologic diagnostic, and surgery. Differences were observed in the use of clinical pathways but not for the practices of holding multidisciplinary team meetings and conforming to guidelines. Regarding human resources, main differences were in the composition and number of supportive care and research staff. All 10 centers applied as CCCs; five obtained the label, and five were designated as CCs. CONCLUSION: The OECI A&D program allows comparisons between centers with regard to management, research, care, education, and designation as CCs or CCCs. Through the peer review system, recommendations for improvements are given. Assessing the added value of the program, as well as research and patient treatment outcomes, is the next step.

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours.

AIM: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial. METHODS: Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles. RESULTS: Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration-time curve (AUC)(0-24) increased by 5% (cohort 1), 54% (cohort 2), 36% (Cohort 3) and 80% (cohort 4) with docetaxel plus sorafenib, while C(max) increased by 16-32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. CONCLUSION: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for phase II.

A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies.

PURPOSE: This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300 mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21-day cycles; intravenous (i.v.) docetaxel was administered on day 1 of each cycle at 60, 75, or 85 mg/m2. RESULTS: A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300 mg BID for 14 days with 60 mg/m2 docetaxel; tipifarnib: 200 mg BID for 14 days with 75 mg/m2 docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (Cmax) and the area under the serum concentration-time curve (AUC) values of both tipifarnib and docetaxel were similar (p > or = 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six > or = 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease > or = 24 weeks) was 42%. CONCLUSIONS: Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.

Pharmacokinetics, metabolism, and routes of excretion of intravenous irofulven in patients with advanced solid tumors.

Irofulven is currently in Phase 2 clinical trials against a wide variety of solid tumors and has demonstrated activity in ovarian, prostate, gastrointestinal, and non-small cell lung cancer. The objectives of this study were to determine its pharmacokinetics and route of excretion and to characterize its metabolites in human plasma and urine samples after a 30-min i.v. infusion at a dose of 0.55 mg/kg in patients with advanced solid tumors. Three patients were administered i.v. 100 microCi of [14C]irofulven over a 30-min infusion on day 1 of cycle 1. Serial blood and plasma samples were drawn at 0 (before irofulven infusion) and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 144 h after the start of infusion. The mean urinary and fecal excretion of radioactivity up to 144 h were 71.2 and 2.9%, respectively, indicating renal excretion was the major route of elimination of [14C]irofulven. The C(max), AUC(0-infinity), and terminal half-life values for total radioactivity were 1130 ng-Eq/ml, 24,400 ng-Eq . h/ml, and 116.5 h, respectively, and the corresponding values for irofulven were 82.7 ng/ml, 65.5 ng . h/ml, and 0.3 h, respectively, suggesting that the total radioactivity in human plasma was a result of the metabolites. Twelve metabolites of irofulven were detected in human urine and plasma by electrospray ionization/tandem mass spectrometry. Among these metabolites, the cyclopropane ring-opened metabolite (M2) of irofulven was found, and seven others were proposed as glucuronide and glutathione conjugates.