A Factorial Survey on Safety Behavior Providing Opportunities to Improve Safety.

OBJECTIVES: To realize safe, high-quality treatment, employees should behave according to patient safety standards. Periodic measurement of safety behavior could provide management-relevant information to adjust the implementation of interventions and maximize improvement. Therefore, we constructed a factorial survey measuring safety awareness and intentions for behavior. METHODS: Cross-sectional results of the factorial survey were compared with results from the Hospital Survey on Patient Safety Culture, distributed in MAASTRO radiotherapy in 2010 to 2011. Respondents were presented 20 scenarios about incidents, randomly varying on work pressure, person causing incident, whether patient level was reached, severity of harm, notification by patient, and management support. After each scenario, questions were asked about safety awareness and behavior. χ and multilevel regression analyses were used. RESULTS: Response rates were 64% (n = 54) for the culture survey and 62% (n = 52) for the factorial survey on intentions. The culture survey reflected positive opinions regarding nonpunitive response and incident reporting, in accordance with high scores (factorial survey) on safety awareness (9.0; scale, 1-10) and reporting intentions (8.7). Whether an incident reached the patient level predicted safety awareness and intentions for safety behavior (ß = -1.3/-3.08) most strongly. Severity of harm showed minimal additional effects (ß = -0.24/-0.42). CONCLUSIONS: The factorial survey presented practical information on safety awareness and intentions for behavior. Therefore, it created additional opportunities for improving safety interventions. Because behavior is expected to change before values, one could hypothesize that factorial surveys would be more sensitive to change than culture surveys. Longitudinal research should further study the surveys' sensitivity to measure changes.

Safer radiation therapy treatment resulting from an equipment transition: A mixed-methods study.

PURPOSE: To realize individualized safe radiation therapy, reliable treatment equipment is essential in combination with a system-level improvement approach. We hypothesized that implementation of a system that integrated all required treatment equipment would result in improved safety and stability of the irradiation treatment process. METHODS AND MATERIALS: Seven accelerators, portal imaging, and the treatment planning software were replaced by an integrated system that included 6 accelerators. The number of reported safety incidents and root causes were recorded between 2010 and 2014. Time series analysis was performed, and quantitative results were explored by structured interviews. Additionally, downtime was recorded. RESULTS: From January 2010 to July 2014, 5085 incidents were reported. Reports related to the accelerators decreased from 33% (2010) to 20% (2013-2014) of total reports, whereas the number of delivered fractions per accelerator increased by 20% (2010: 643 per month; 2013: 795 per month). Reports related to portal imaging decreased from 16.5 reports per month (2010) to 3.1 (2013-2014). Of these portal imaging reports, 316 had at least 1 technical cause in 2010, which decreased to 13 in 2013-2014. Interviewees attributed the decreased reporting to the equipment transition, not to decreased safety awareness. Downtime decreased by 46%, from 5.4% in 2010 to 2.9% in 2013. CONCLUSIONS: The number of reported accelerator- and portal imaging-related incidents decreased significantly, whereas safety awareness remained stable. In addition, accelerator downtime decreased, possibly resulting in less rescheduling of patients and fewer disruptions of work processes. Therefore, we conclude that the risk for serious safety incidents and patient harm decreased after implementation of the new integrated system.

Workshops as a useful tool to better understand care professionals' views of a lean change program.

PURPOSE: For change programs to succeed, it is vital to have a detailed understanding of employees' views regarding the program, especially when the proposed changes are potentially contested. Gaining insight into employee perceptions helps managers to decide how to proceed. The authors conducted two workshops in a radiotherapy institute to assess the benefits and drawbacks, as well as their underlying causes, of a proposed Lean change program. Managers' views on the workshops' usefulness were charted. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: Two workshops were organized in which employees predicted positive and negative effects of a Lean program. The workshops combined a structured brainstorm (KJ-technique) and an evaluation of the expected effects. Eight top managers judged the workshops' value on supporting decision making. FINDINGS: In total, 15 employees participated in the workshops. Participants from workshop 2 reported more expected effects (27 effects; 18 positive) than from workshop 1 (14 effects; six positive). However, when effects were categorized, similar results were shown. Three from eight managers scored the results relevant for decision making and four neutral. Seven managers recommended future use of the instrument. Increased employee involvement and bottom-up thinking combined with relatively low costs were appreciated most. PRACTICAL IMPLICATIONS: The workshop could serve as a simple instrument to improve decision making and enhance successful implementation of change programs, as it was expected to enhance employees' involvement and was relatively easy to conduct and cheap. ORIGINALITY/VALUE: The workshop increased insight into employee views, facilitating adaptive actions by healthcare organization managers.

Cost-Effectiveness of Reduced Waiting Time for Head and Neck Cancer Patients due to a Lean Process Redesign.

BACKGROUND: Compared with new technologies, the redesign of care processes is generally considered less attractive to improve patient outcomes. Nevertheless, it might result in better patient outcomes, without further increasing costs. Because early initiation of treatment is of vital importance for patients with head and neck cancer (HNC), these care processes were redesigned. OBJECTIVES: This study aimed to assess patient outcomes and cost-effectiveness of this redesign. METHODS: An economic (Markov) model was constructed to evaluate the biopsy process of suspicious lesion under local instead of general anesthesia, and combining computed tomography and positron emission tomography for diagnostics and radiotherapy planning. Patients treated for HNC were included in the model stratified by disease location (larynx, oropharynx, hypopharynx, and oral cavity) and stage (I-II and III-IV). Probabilistic sensitivity analyses were performed. RESULTS: Waiting time before treatment start reduced from 5 to 22 days for the included patient groups, resulting in 0.13 to 0.66 additional quality-adjusted life-years. The new workflow was cost-effective for all the included patient groups, using a ceiling ratio of €80,000 or €20,000. For patients treated for tumors located at the larynx and oral cavity, the new workflow resulted in additional quality-adjusted life-years, and costs decreased compared with the regular workflow. The health care payer benefited €14.1 million and €91.5 million, respectively, when individual net monetary benefits were extrapolated to an organizational level and a national level. CONCLUSIONS: The redesigned care process reduced the waiting time for the treatment of patients with HNC and proved cost-effective. Because care improved, implementation on a wider scale should be considered.

Spacers in radiotherapy treatment of prostate cancer: is reduction of toxicity cost-effective?

BACKGROUND AND PURPOSE: To compare the cost-effectiveness of treating prostate cancer patients with intensity-modulated radiation therapy and a spacer (IMRT+S) versus IMRT-only without a spacer (IMRT-O). MATERIALS AND METHODS: A decision-analytic Markov model was constructed to examine the effect of late rectal toxicity and compare the costs and quality-adjusted Life Years (QALYs) of IMRT-O and IMRT+S. The main assumption of this modeling study was that disease progression, genito-urinary toxicity and survival were equal for both comparators. RESULTS: For all patients, IMRT+S revealed a lower toxicity than IMRT-O. Treatment follow-up and toxicity costs for IMRT-O and IMRT+S amounted to €1604 and €1444, respectively, thus saving €160 on the complication costs at an extra charge of €1700 for the spacer in IMRT+S. The QALYs yielded for IMRT-O and IMRT+S were 3.542 and 3.570, respectively. This results in an incremental cost-effectiveness ratio (ICER) of €55,880 per QALY gained. For a ceiling ratio of €80,000, IMRT+S had a 77% probability of being cost-effective. CONCLUSION: IMRT+S is cost-effective compared to IMRT-O based on its potential to reduce radiotherapy-related toxicity.

Does lean management improve patient safety culture? An extensive evaluation of safety culture in a radiotherapy institute.

PURPOSE: The importance of a safety culture to maximize safety is no longer questioned. However, achieving sustainable culture improvements are less evident. Evidence is growing for a multifaceted approach, where multiple safety interventions are combined. Lean management is such an integral approach to improve safety, quality and efficiency and therefore, could be expected to improve the safety culture. This paper presents the effects of lean management activities on the patient safety culture in a radiotherapy institute. METHODS: Patient safety culture was evaluated over a three year period using triangulation of methodologies. Two surveys were distributed three times, workshops were performed twice, data from an incident reporting system (IRS) was monitored and results were explored using structured interviews with professionals. Averages, chi-square, logistical and multi-level regression were used for analysis. RESULTS: The workshops showed no changes in safety culture, whereas the surveys showed improvements on six out of twelve dimensions of safety climate. The intention to report incidents not reaching patient-level decreased in accordance with the decreasing number of reports in the IRS. However, the intention to take action in order to prevent future incidents improved (factorial survey presented ß: 1.19 with p: 0.01). CONCLUSIONS: Due to increased problem solving and improvements in equipment, the number of incidents decreased. Although the intention to report incidents not reaching patient-level decreased, employees experienced sustained safety awareness and an increased intention to structurally improve. The patient safety culture improved due to the lean activities combined with an organizational restructure, and actual patient safety outcomes might have improved as well.

Does compliance to patient safety tasks improve and sustain when radiotherapy treatment processes are standardized?

PURPOSE: To realize safe radiotherapy treatment, processes must be stabilized. Standard operating procedures (SOP's) were expected to stabilize the treatment process and perceived task importance would increase sustainability in compliance. This paper presents the effects on compliance to safety related tasks of a process redesign based on lean principles. METHOD: Compliance to patient safety tasks was measured by video recording of actual radiation treatment, before (T0), directly after (T1) and 1.5 years after (T2) a process redesign. Additionally, technologists were surveyed on perceived task importance and reported incidents were collected for three half-year periods between 2007 and 2009. RESULTS: Compliance to four out of eleven tasks increased at T1, of which improvements on three sustained (T2). Perceived importance of tasks strongly correlated (0.82) to compliance rates at T2. The two tasks, perceived as least important, presented low base-line compliance, improved (T1), but relapsed at T2. The reported near misses (patient-level not reached) on accelerators increased (P < 0.001) from 144 (2007) to 535 (2009), while the reported misses (patient-level reached) remained constant. CONCLUSIONS: Compliance to specific tasks increased after introducing SOP's and improvements sustained after 1.5 years, indicating increased stability. Perceived importance of tasks correlated positively to compliance and sustainability. Raising the perception of task importance is thus crucial to increase compliance. The redesign resulted in increased willingness to report incidents, creating opportunities for patient safety improvement in radiotherapy treatment.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Health economic controversy and cost-effectiveness of proton therapy.

Owing to increasing healthcare costs, there is a need to examine whether the benefits of new technologies are worth the extra cost. In proton therapy, where the evidence in favor is limited, it is heavily debated whether the expected benefit justifies the higher capital and operating costs. The aim of this article was to explore the existing methodologies of economic evaluations (EEs) of particle therapy and recommend an approach for future data collection and analysis. We reviewed the published literature on health economics of proton therapy using accepted guidelines on performing EE. Different cost strategies were assessed and comparisons with other treatment modalities were made in terms of cost-effectiveness. Potential bias in the existing studies was identified and new methodologies proposed. The principal cause of bias in EEs of proton therapy is the lack of valid data on effects as well as costs. The introduction of proton therapy may be seriously hampered by the lack of outcome and cost data and the situation is likely to continue not only in terms of justifying the capital investment but also covering the operational costs. We identified an urgent need to collect appropriate data to allow for reimbursement of such novel technology. In the absence of level 1 evidence, well-performed modeling studies taking into account the available cost and outcome parameters, including the current uncertainties, can help to address the problem of limited outcome and health economic data. The approach of coverage with evidence development, in which evidence is collected in an ongoing manner in population-based registries along with dedicated financing, may allow technological advances with limited initial evidence of benefit and value, such as protons, to become available to patients in an early phase of their technology life cycle.

Protons in head-and-neck cancer: bridging the gap of evidence.

PURPOSE: To use Normal Tissue Complication Probability (NTCP) models and comparative planning studies to explore the (cost-)effectiveness of swallowing sparing intensity modulated proton radiotherapy (IMPT) compared with swallowing sparing intensity modulated radiotherapy with photons (IMRT) in head and neck cancer (HNC). METHODS AND MATERIALS: A Markov model was constructed to examine and compare the costs and quality-adjusted life years (QALYs) of the following strategies: (1) IMPT for all patients; (2) IMRT for all patients; and (3) IMPT if efficient. The assumption of equal survival for IMPT and IMRT in the base case analysis was relaxed in a sensitivity analysis. RESULTS: Intensity modulated proton radiation therapy and IMRT for all patients yielded 6.620 and 6.520 QALYs and cost €50,989 and €41,038, respectively. Intensity modulated proton radiation therapy if efficient yielded 6.563 QALYs and cost €43,650. The incremental cost-effectiveness ratio of IMPT if efficient versus IMRT for all patients was €60,278 per QALY gained. In the sensitivity analysis, IMRT was more effective (0.967 QALYs) and less expensive (€8218) and thus dominated IMPT for all patients. CONCLUSIONS: Cost-effectiveness analysis based on normal tissue complication probability models and planning studies proved feasible and informative and enables the analysis of individualized strategies. The increased effectiveness of IMPT does not seem to outweigh the higher costs for all head-and-neck cancer patients. However, when assuming equal survival among both modalities, there seems to be value in identifying those patients for whom IMPT is cost-effective.

Charged particles in radiotherapy: a 5-year update of a systematic review.

Although proton therapy has been used for many decades because of their superior dose distribution over photons and reduced integral dose, their clinical implementation is still controversial. We updated a systematic review of charged particle therapy. Although still no randomised trials were identified, the field is moving quickly and we therefore also formulated ways to move forward. In our view, the aim should be to build enough proton therapy facilities with interest in research to further improve the treatment and to run the needed clinical trials.

Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with photons and protons for non-small cell lung cancer.

INTRODUCTION: This multicentric in silico trial compares photon and proton radiotherapy for non-small cell lung cancer patients. The hypothesis is that proton radiotherapy decreases the dose and the volume of irradiated normal tissues even when escalating to the maximum tolerable dose of one or more of the organs at risk (OAR). METHODS: Twenty-five patients, stage IA-IIIB, were prospectively included. On 4D F18-labeled fluorodeoxyglucose-positron emission tomography-computed tomography scans, the gross tumor, clinical and planning target volumes, and OAR were delineated. Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) photon and passive scattered conformal proton therapy (PSPT) plans were created to give 70 Gy to the tumor in 35 fractions. Dose (de-)escalation was performed by rescaling to the maximum tolerable dose. RESULTS: Protons resulted in the lowest dose to the OAR, while keeping the dose to the target at 70 Gy. The integral dose (ID) was higher for 3DCRT (59%) and IMRT (43%) than for PSPT. The mean lung dose reduced from 18.9 Gy for 3DCRT and 16.4 Gy for IMRT to 13.5 Gy for PSPT. For 10 patients, escalation to 87 Gy was possible for all 3 modalities. The mean lung dose and ID were 40 and 65% higher for photons than for protons, respectively. CONCLUSIONS: The treatment planning results of the Radiation Oncology Collaborative Comparison trial show a reduction of ID and the dose to the OAR when treating with protons instead of photons, even with dose escalation. This shows that PSPT is able to give a high tumor dose, while keeping the OAR dose lower than with the photon modalities.

When to wait for more evidence? Real options analysis in proton therapy.

PURPOSE: Trends suggest that cancer spending growth will accelerate. One method for controlling costs is to examine whether the benefits of new technologies are worth the extra costs. However, especially new and emerging technologies are often more costly, while limited clinical evidence of superiority is available. In that situation it is often unclear whether to adopt the new technology now, with the risk of investing in a suboptimal therapy, or to wait for more evidence, with the risk of withholding patients their optimal treatment. This trade-off is especially difficult when it is costly to reverse the decision to adopt a technology, as is the case for proton therapy. Real options analysis, a technique originating from financial economics, assists in making this trade-off. METHODS: We examined whether to adopt proton therapy, as compared to stereotactic body radiotherapy, in the treatment of inoperable stage I non-small cell lung cancer. Three options are available: adopt without further research; adopt and undertake a trial; or delay adoption and undertake a trial. The decision depends on the expected net gain of each option, calculated by subtracting its total costs from its expected benefits. RESULTS: In The Netherlands, adopt and trial was found to be the preferred option, with an optimal sample size of 200 patients. Increase of treatment costs abroad and costs of reversal altered the preferred option. CONCLUSION: We have shown that real options analysis provides a transparent method of weighing the costs and benefits of adopting and/or further researching new and expensive technologies.

The impact of late treatment-toxicity on generic health-related quality of life in head and neck cancer patients after radiotherapy.

To examine the impact of late treatment-related xerostomia and dysphagia on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients after radiotherapy. A multi-center cross-sectional survey was performed. Patients with a follow-up of at least 6months after curative radiotherapy, without evidence of recurrent disease were eligible for inclusion. The Euroqol-5D questionnaire (EQ-5D) was filled out and toxicity was scored and converted to the RTOG scale. The EQ-5D measures generic HRQOL in terms of utility and visual analogue scale (VAS) scores. Missing data on the EQ-5D were imputed using multiple imputation. HRQOL was compared between subgroups of patients with and without toxicity. Subsequently, the impact of xerostomia and dysphagia on HRQOL was analyzed using multivariate regression analyses. Both analyses were performed separately for utility scores and VAS scores. The study population was composed of 396 HNC patients. The average utility and VAS scores were 0.85 (scale 0-1) and 75 (scale 0-100). Subgroups of patients with xerostomia and/or dysphagia showed statistically significantly lower utility and VAS scores (P=0.000-0.022). The multivariate regression model showed that xerostomia and dysphagia were negative predictors of both utility and VAS scores. Other factors which influenced HRQOL in at least one of the two regression models were: sex, tumor location and the addition of surgery to radiotherapy. Xerostomia and dysphagia diminish generic HRQOL. Moreover dysphagia affects patients' HRQOL stronger than xerostomia.

The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature.

PURPOSE: Clinical studies concerning head and neck cancer patients treated with protons reporting on radiation-induced side effects are scarce. Therefore, we reviewed the literature regarding the potential benefits of protons compared with the currently used photons in terms of lower doses to normal tissue and the potential for fewer subsequent radiation-induced side effects, with the main focus on in silico planning comparative (ISPC) studies. MATERIALS AND METHODS: A literature search was performed by two independent researchers on ISPC studies that included proton-based and photon-based irradiation techniques. RESULTS: Initially, 877 papers were retrieved and 14 relevant and eligible ISPC studies were identified and included in this review. Four studies included paranasal sinus cancer cases, three included nasopharyngeal cancer cases, and seven included oropharyngeal, hypopharyngeal, and/or laryngeal cancer cases. Seven studies compared the most sophisticated photon and proton techniques: intensity-modulated photon therapy versus intensity-modulated proton therapy (IMPT). Four studies compared different proton techniques. All studies showed that protons had a lower normal tissue dose, while keeping similar or better target coverage. Two studies found that these lower doses theoretically translated into a significantly lower incidence of salivary dysfunction. CONCLUSION: The results of ISPC studies indicate that protons have the potential for a significantly lower normal tissue dose, while keeping similar or better target coverage. Scanned IMPT probably offers the most advantage and will allow for a substantially lower probability of radiation-induced side effects. The results of these ISPC studies should be confirmed in properly designed clinical trials.

Information for decision making by patients with early-stage prostate cancer: a comparison across 9 countries.

PURPOSE: To describe decisional roles of patients with early-stage prostate cancer in 9 countries and to compare the information they rated important for decision making (DM). METHOD: A survey of recently treated patients was conducted in Canada, Italy, England, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Participants indicated their decisional role in their actual decision and the role they would prefer now. Each participant also rated (essential/desired/no opinion/avoid) the importance of obtaining answers, between diagnosis and treatment decision, to each of 92 questions. For each essential/desired question, participants specified all purposes for that information (to help them: understand/decide/plan/not sure/other). RESULTS: A total of 659 patients participated with country-specific response rates between 58%-77%. Between 83%-96% of each country's participants recalled actually taking an active decisional role and, in most countries, that increased slightly if they were to make the decision today; there were no significant differences among countries. There was a small reliable difference in the mean number of questions rated essential for DM across countries. More striking, however, was the wide variability within each country: no question was rated essential for DM by even 50% of its participants but almost every question was rated essential by some. CONCLUSIONS: Almost all participants from each country want to participate in their treatment decisions. Although there are country-specific differences in the amount of information required, wide variation within each country suggests that information that patients feel is essential or desired for DM should be addressed on an individual basis in all countries.

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons.

PURPOSE: To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer. METHODS: A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy. RESULTS: In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site. CONCLUSIONS: For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.

Health-related quality of life in patients surviving non-small cell lung cancer.

BACKGROUND AND AIMS: The EuroQol 5D (EQ-5D) is a standardised instrument for measuring health-related quality of life (HRQoL). It provides a utility score for health, and a self-rating of HRQoL (EQ-VAS). In this study, the EQ-5D was used to assess HRQoL in survivors of non-small cell lung cancer (NSCLC). The influence of tumour stage, adverse events, initial treatment and presence of recurrence was examined. METHODS: Patients treated for NSCLC were sent a questionnaire, consisting of the EQ-5D, EQ-VAS and questions regarding adverse events. Tumour stage, date and type of initial treatment, and presence of recurrence were derived from patient files once patients had completed the questionnaire and informed consent form. Influencing factors were examined by exploring subgroups and using multiple regression analysis. RESULTS: Of the 374 patients contacted, 260 (70%) returned a completed questionnaire. The EQ-VAS generated an average self-rated health of 69 (SD 18). The mean utility score was 0.74 (SD 0.27). Respondents with severe adverse events (dyspnoea grade ≥ 3) had statistically significantly lower utility scores than respondents without severe adverse events (median 0.52 vs 0.81; p <0.001). Subgroups based on a patient's initial treatment modality revealed statistically significantly different utility scores (p=0.010). CONCLUSION: The results of the present study provide original data on HRQoL during survival of NSCLC. Adverse events were found to have a considerable impact on HRQoL. This stresses the need to search for treatment modalities that not only improve survival, but also reduce adverse events.

Design of and technical challenges involved in a framework for multicentric radiotherapy treatment planning studies.

This report introduces a framework for comparing radiotherapy treatment planning in multicentric in silico clinical trials. Quality assurance, data incompatibility, transfer and storage issues, and uniform analysis of results are discussed. The solutions that are given provide a useful guide for the set-up of future multicentric planning studies or public repositories of high quality data.