Effects of and Lessons Learned from an Internet-Based Physical Activity Support Program (with and without Physiotherapist Telephone Counselling) on Physical Activity Levels of Breast and Prostate Cancer Survivors: The PABLO Randomized Controlled Trial.

BACKGROUND: We developed an Internet-based physical activity (PA) support program (IPAS), which is embedded in a patient portal. We evaluated the effectiveness and costs of IPAS alone (online only) or IPAS combined with physiotherapist telephone counselling (blended care), compared to a control group. METHODS: Breast or prostate cancer survivors, 3-36 months after completing primary treatment, were randomized to 6-months access to online only, blended care, or a control group. At baseline and 6-month post-baseline, minutes of moderate-to-vigorous PA (MVPA) were measured by accelerometers. Secondary outcomes were self-reported PA, fatigue, mood, health-related quality of life, attitude toward PA, and costs. (Generalized) linear models were used to compare the outcomes between groups. RESULTS: We recruited 137 survivors (participation rate 11%). We did not observe any significant between-group differences in MVPA or secondary outcomes. Adherence was rather low and satisfaction scores were low to moderate, with better scores for blended care. Costs for both interventions were low. CONCLUSIONS: Recruitment to the study was challenging and the interventions were less efficacious than anticipated, which led to lessons learned for future trials. Suggestions for future research are as follows: improved accessibility of the support program, increased frequency of support, and use of activity trackers.

Validating a generic cancer consumer quality index in eight European countries, patient reported experiences and the influence of cultural differences.

BACKGROUND: Taking patient centeredness into account is important in healthcare. The European Cancer Consumer Quality Index (ECCQI) is a validated tool for international benchmarking of patient experiences and satisfaction. This study aimed to further validate the ECCQI in larger and more uniform groups of high volume tumours such as breast and prostate cancer. A second objective was the verification of the influence of cultural factors of the country to determine its possible use in international benchmarking. METHODS: Data from two survey studies in eight European countries were combined. Socio-demographic correlations were analysed with Kruskall-Wallis and Mann-Whitney tests. Cronbach's alpha was calculated to validate internal consistency. Influences of masculinity (MAS), power distance (PD) and uncertainty avoidance (UA) were determined by linear regression analysis in a general model and subgroup models. RESULTS: A total of 1322 surveys were included in the analysis (1093 breast- and 348 prostate cancer patients). Cronbach's alpha was good (α ≥ 0.7) or acceptable (0.5 ≤ α ≤ 0.7) in 8 out of 9 questionnaire categories, except in the category 'Safety' (α = 0.305). Overall ECCQI scores ranged from 22.1 to 25.1 between countries on a 1-35 scale (categories had a 1-4 scale). In certain subcategories such as 'Organisation' (range 2.2 vs 3.0) and 'Supervision & Support' (range 3.0 vs 3.8) a large difference was observed between countries. Differences in 'Overall opinion' were however small: mean scores of 3.7 vs 3.9, whereas median scores were all the maximum of 4.0. Power distance was positively associated with higher patient satisfaction scores whereas Uncertainty avoidance was negatively associated with these scores. Masculinity was only associated with patient satisfaction scores in lower educated patients. We found the highest impact of culture on overall scores in Hungary and Portugal and the lowest in Romania. CONCLUSIONS: The ECCQI shows high internal consistency in all categories except 'Safety'. Especially in separate categories and overall ECCQI scores the questionnaire showed discriminative value. This study showed a positive correlation of power distance and a negative correlation for uncertainty avoidance in some countries. When using the ECCQI for international benchmarking these two dimensions of culture should be taken into account.

Securing sustainable price levels of innovative anticancer drugs: How to move forward?

BACKGROUND: Novel cancer treatments come with high price tags that compromise access to treatment and the sustainability of healthcare systems. Innovative policies are needed to reach a system that balances innovation and reasonable prices. However, structured approaches to explore, test, and compare innovative proposals are lacking. METHODS: We surveyed experts to evaluate seven promising proposals to reduce drug prices: Transparency, Combined European purchasing, Public drug development, Public clinical trials, Two-part-pricing, Orphan drug reform, and De-linkage. Experts were asked to rank proposals, identify main risk and success factors, and to reflect on missing proposals. The survey was distributed via the networks of the European Cancer League and the Organisation of European Cancer Institutes. RESULTS: Respondents (n = 41) originated from 19 European countries and included stakeholders in health economics, law, medicine, drug discovery, and healthcare policy.Transparency (M = 2; SD = 2 1) and Combined purchasing (M = 3; SD = 1 9) were ranked as the most promising proposals, Two-part pricing (M = 5; SD = 2 3) and De-linkage (M = 6; SD = 2 4) were considered as the most controversial. Main risk categories were a negative impact on R&D (n = 47), technical feasibility (n = 38), and reduced access to medicines (n = 33). Main success categories were international collaboration (n = 34) and agreement of pricing mechanisms (n = 25). Experts considered value assessment and strengthening of the competitive market as additional proposals for further analysis. CONCLUSION: We recommend expanding on these results to further specify actionable policies that can be tested. Pilots should consider uncertainties and conducted with a focus on international collaboration, preferably in cooperation with the pharmaceutical industry.

Barriers and facilitators of patient access to medical devices in Europe: A systematic literature review.

A large number of medical devices (MDs) is available in Europe. Procedures for market approval and reimbursement have been adopted over recent years to promote accelerating patient access to innovative MDs. However, there remains uncertainty and non-transparency regarding these procedures. We provide a structured overview of market approval and reimbursement procedures and practices regarding access to MDs in the EU. Market approval procedures were found to be uniformly described. Data on reimbursement procedures and practices was both heterogeneous and incomplete. Time to MD access was mainly determined by reimbursement procedures. The influence of the patient on time to access was not reported. Prescription practices varied among device types. Barriers to and facilitators of early patient access that set the agenda for policy implications were also analyzed. Barriers were caused by unclear European legislation, complex market approval procedures, lack of data collection, inconsistency in evidence requirements between countries, regional reimbursement and provision, and factors influencing physicians' prescription including the device costs, waiting times and hospital-physician relationships. Facilitators were: available evidence that meets country-specific requirements for reimbursement, diagnosis-related groups, additional payments and research programs. Further research needs to focus on creating a complete overview of reimbursement procedures and practices by extracting further information from sources such as grey literature and interviews with professionals, and defining clear criteria to objectify time to access.

Effects and moderators of exercise on sleep in adults with cancer: Individual patient data and aggregated meta-analyses.

OBJECTIVES: To evaluate the effects of exercise interventions on sleep disturbances and sleep quality in patients with mixed cancer diagnoses, and identify demographic, clinical, and intervention-related moderators of these effects. METHODS: Individual patient data (IPD) and aggregated meta-analyses of randomized controlled trials (RCTs). Using data from the Predicting OptimaL cAncer RehabIlitation and Supportive care project, IPD of 2173 adults (mean age = 54.8) with cancer from 17 RCTs were analyzed. A complementary systematic search was conducted (until November 2018) to study the overall effects and test the representativeness of analyzed IPD. Effect sizes of exercise effects on self-reported sleep outcomes were calculated for all included RCTs. Linear mixed-effect models were used to evaluate the effects of exercise on post-intervention outcome values, adjusting for baseline values. Moderator effects were studied by testing interactions for demographic, clinical and intervention-related characteristics. RESULTS: For all 27 eligible RCTs from the updated search, exercise interventions significantly decreased sleep disturbances in adults with cancer (g = -0.09, 95% CI [-0.16; -0.02]). No significant effect was obtained for sleep quality. RCTs included in IPD analyses constituted a representative sample of the published literature. The intervention effects on sleep disturbances were not significantly moderated by any demographic, clinical, or intervention-related factor, nor by sleep disturbances. CONCLUSIONS: This meta-analysis provides some evidence that, compared to control conditions, exercise interventions may improve sleep disturbances, but not sleep quality, in cancer patients, although this effect is of a small magnitude. Among the investigated variables, none was found to significantly moderate the effect of exercise interventions on sleep disturbances.

Variation in the time to treatment for stage III and IV non-small cell lung cancer patients for hospitals in the Netherlands.

OBJECTIVES: Increased emphasis on molecular diagnostics can lead to increased variation in time to treatment (TTT) for patients with stage III and IV non-small cell lung cancer. This article presents the variation in TTT for advanced NSCLC patients observed in Dutch hospitals before the widespread use of immunotherapy. The aim of this article was to explore the variation in TTT between patients, as well as between hospitals. MATERIAL AND METHODS: Based on the Netherlands Cancer Registry, we used patient-level data (n = 4096) from all 78 hospitals that diagnosed stage III or IV NSCLC in the Netherlands in 2016. To investigate how patient characteristics and hospital-level effects are associated with TTT (from diagnosis until start treatment), we interpreted regression model results for five common patient profiles to analyze the influence of age, gender, tumor stage, performance status, histology, and referral status as well as hospital-level characteristics on the TTT. RESULTS AND CONCLUSIONS: TTT varies substantially between and within hospitals. The median TTT was 28 days with an inter-quartile range of 22 days. The hospital-level median TTT ranges from 17 to 68 days. TTT correlates significantly with tumor stage, performance status, and histology. The hospital-level effect, unrelated to hospital volume and type, affected TTT by several weeks at most. For most patients, TTT is within range as recommended in current guidelines. Variation in TTT seems higher for patients receiving either radiotherapy or targeted therapy, or for patients referred to another hospital and we hypothesize this is related to the complexity of the diagnostic pathway. With further advances in molecular diagnostics and precision oncology we expect variation in TTT to increase and this needs to be considered in designing optimal cancer care delivery.

Patient access to voice prostheses and heat and moisture exchangers: Factors influencing physician's prescription and reimbursement in eight European countries.

OBJECTIVES: Patient access to the voice prosthesis and heat and moisture exchanger (HME) is not always guaranteed in Europe. Therefore, the aim of this qualitative study is to evaluate factors influencing physician's prescription and reimbursement of these devices in eight European countries, and to identify barriers of and facilitators to effective patient access. MATERIALS AND METHODS: In this mixed methods study, we conducted a survey among stakeholders evaluating prescription (Part 1 of the survey), reimbursement (Part 2), and barriers of and facilitators to effective patient access (Part 3). Part 1 was completed by head and neck surgeons employed in France, Germany, the United Kingdom, Italy, Spain, Belgium, the Netherlands and Poland. Part 2 and 3 were completed by medical device company representatives in respective countries, followed by semi-structured interviews. RESULTS: Based on the survey, filled in by 36 surgeons, all prescribed the voice prosthesis. Four surgeons didn't prescribe the HME in Italy and Poland due to lack of both reimbursement and experience/training, and feeling uncomfortable with device use. Most restrictive factors (e.g. increased workload, insufficient staff) occurred in countries with decentralized healthcare systems including Spain and Italy. CONCLUSION: Non-HME-usage was influenced by economical and physician-related factors. Restrictive factors were related to limited regional device reimbursement and provision. Nationwide reimbursement, guideline implementation, support for physicians by training/education and providing a rehabilitation team will increase device use.

(Cost-)effectiveness of an internet-based physical activity support program (with and without physiotherapy counselling) on physical activity levels of breast and prostate cancer survivors: design of the PABLO trial.

BACKGROUND: Higher levels of physical activity (PA) after treatment are associated with beneficial effects on physical and psychosocial functioning of cancer survivors. However, survivors often do not meet the recommended levels of PA. In order to promote PA, we developed a closed internet-based program. The aim of the study is to evaluate the (cost-)effectiveness of an internet-based PA-promotion program, alone or combined with physiotherapy counselling, compared to usual care, on PA-levels of breast or prostate cancer survivors. In this multicenter randomised controlled trial (RCT), breast or prostate cancer survivors who completed their primary treatment 3-12 months earlier, will be randomised to either 6-months access to a fully-automated internet-based intervention alone, an internet-based intervention plus remote support by a physiotherapist, or a control group. The intervention is based on the Transtheoretical Model and includes personalized feedback, information, video's and assignments. Additionally, in a second arm, physiotherapy counselling is provided through monthly scheduled and on-demand telephone calls. The control group will receive usual care and a leaflet with PA guidelines. METHODS: At baseline, 6 and 12 months, the primary outcome (PA) will be measured during 7 consecutive days by accelerometers. Secondary outcomes are self-reported PA, fatigue, mood, health-related quality of life, and costs. The group differences for primary and secondary outcomes will be analyzed using linear mixed models. DISCUSSION: If proven to be (cost)effective, this internet-based intervention, either alone or in combination with telephone support, will be a welcome addition to previous RCT's. TRIAL REGISTRATION: Netherlands trial register (NTR6911), Date of trial registration: December 21, 2017.

Review: Effectiveness of implementation strategies to increase physical activity uptake during and after cancer treatment.

BACKGROUND: The purpose of this review was to assess the effectiveness of different strategies to implement physical activity during and after cancer treatment. DESIGN: We searched for studies containing strategies to implement physical activity in cancer care that meet the inclusion criteria of the Cochrane EPOC group. The primary outcome was physical activity uptake. We expressed the effectiveness of the strategies as the percentage of studies with improvement. RESULTS: Nine studies met the inclusion criteria. Patient groups doing physical activities via an implementation strategy had better outcomes than those receiving usual care: 83% of the studies showed improvement. Strategies showing significant improvement compared to usual care employed healthcare professionals to provide individual counselling or advice for exercise or interactive elements such as audit and feedback systems. When comparing the different strategies 1) interactive elements or 2) elements tailored to the needs of the patients had better physical activity uptake. CONCLUSIONS: Implementation strategies containing individual and interactive elements, tailored to the individual needs of patients, are more successful in improving physical activity uptake.

Implementing large scale fast track diagnostics in a comprehensive cancer center, pre- and post-measurement data.

BACKGROUND: In general, patients with a cancer suspicion visit the hospital multiple times before diagnosis is completed. Using various "operations management" techniques a few fast track diagnostic services were implemented in the Netherlands Cancer Institute (NKI) in 2006. Growing patient numbers and increasing process complexity, led to diminished service levels. To decrease the amount of patient visits and to extend these services beyond the (obvious) breast cancer services, fast track diagnostics is now implemented for all 18 cancer types that present with a frequency of minimally one per week. METHODS: The throughput time (first visit to diagnosis conversation) was measured before, and after implementation of fast track diagnostics. The process was redesigned closely involving the multidisciplinary teams. In an eclectic approach elements from lean management, theory of constraints and mathematical analysis were used to organize slots per tumor type for MRI, CT, PET and echography. A post measurement was performed after 3 and 6 months. RESULTS: In pre measurement access time was calculated to be 10 to 15 workdays, mean throughput time was 6.0 workdays. It proved possible to design the process of 18 tumors as a fast track, of which 7 as "one stop shop" (diagnosis completed in one visit). Involvement of clinical- and board leadership, massive communication efforts and commitment of physicians to reschedule their work proved decisive. After 3 and 6 months of implementation, the mean access time was 8.2 and 8.7 workdays respectively and mean throughput time was 3.4 and 3.3 workdays respectively. CONCLUSIONS: Throughput- and access time were considerably shortened after implementation of fast track diagnostics for 18 cancer types. The involvement of physicians in reorganizing their work and rapid responding to their needs during the implementation phase were a crucial success factor.

Turning teams and pathways into integrated practice units: Appearance characteristics and added value.

It has been 12 years after Porter and Teisberg published their landmark manuscript on "Redefining Health Care." Apart from stressing the need for a fundamental change from fee-for-service to value or outcome-based financing and to a focus on reducing waste, they emphasized the need to work along patient pathways and in Integrated Practice Units to overcome function based and specialist group silos and promote working in multidisciplinary patient-oriented teams. Integrated Practice Units are defined as "organized around the patient and providing the full cycle of care for a medical condition, including patient education, engagement, and follow-up and encompass inpatient, outpatient and rehabilitative care as well as supporting services." Although relatively few papers are published with empirical evidence on Integrated Practice Units development, some providers have impressively developed pathways and integrated care toward alignment with Integrated Practice Units criteria. From the field, we learn that possible advantages lay in improving patient centeredness, breaking through professional boundaries, and reducing waste in unnecessary duplications. A firm body of evidence on the added value of turning pathways into Integrated Practice Units is hard to find and this leaves room for much variation. Although intuitively attractive, this development requires staff efforts and costs and therefore cost-effectiveness and budget impact studies are much needed. Randomized controlled trials may be difficult to realize in organizational research, it is long known that turning to alternative designs such as larger case study series and before-after designs can be helpful. Thus, it can become clear what added value is achievable and how to reach that.

Benchmarking specialty hospitals, a scoping review on theory and practice.

BACKGROUND: Although benchmarking may improve hospital processes, research on this subject is limited. The aim of this study was to provide an overview of publications on benchmarking in specialty hospitals and a description of study characteristics. METHODS: We searched PubMed and EMBASE for articles published in English in the last 10 years. Eligible articles described a project stating benchmarking as its objective and involving a specialty hospital or specific patient category; or those dealing with the methodology or evaluation of benchmarking. RESULTS: Of 1,817 articles identified in total, 24 were included in the study. Articles were categorized into: pathway benchmarking, institutional benchmarking, articles on benchmark methodology or -evaluation and benchmarking using a patient registry. There was a large degree of variability:(1) study designs were mostly descriptive and retrospective; (2) not all studies generated and showed data in sufficient detail; and (3) there was variety in whether a benchmarking model was just described or if quality improvement as a consequence of the benchmark was reported upon. Most of the studies that described a benchmark model described the use of benchmarking partners from the same industry category, sometimes from all over the world. CONCLUSIONS: Benchmarking seems to be more developed in eye hospitals, emergency departments and oncology specialty hospitals. Some studies showed promising improvement effects. However, the majority of the articles lacked a structured design, and did not report on benchmark outcomes. In order to evaluate the effectiveness of benchmarking to improve quality in specialty hospitals, robust and structured designs are needed including a follow up to check whether the benchmark study has led to improvements.

Close cooperation with Health Technology Assessment expertise is crucial for implementation and ultimately reimbursement of innovations in oncology.

The Organisation of European Cancer Institutes OECI working group on Health Economics and Cost Benefit in Oncology suggests four actions that are needed to improve alignment and integration between clinicians, researchers, and Health Technology Assessment (HTA) experts and agencies: 1) HTA expertise is necessary close to or within the comprehensive cancer centres (CCC); 2) HTA expertise should be physically present throughout the translational research process; 3) Appropriate knowledge is necessary within the research staff; 4) Close cooperation between translational researchers, clinicians, and health economists guarantees clinical ownership. Fulfilling these conditions may help the translational research field in oncology to interact with agencies and efficiently move innovative technologies through the translational research stages into that of implementation and diffusion. This brings innovative treatments faster to the patient with a greater chance of reimbursement.

Innovations that reach the patient: early health technology assessment and improving the chances of coverage and implementation.

With growing concerns for the sustainability of the financial burden that health care-and especially cancer services-poses on the national budgets, the role of health economic analyses in coverage decisions is likely to grow. One of the strategies for the biomedical research field-also in oncology research-to foster coverage and health system implementation, is to anticipate this new role and to involve health technology assessment techniques earlier in various stages of translational research. In this article, we elaborate on the early involvement of health technology assessment in translational research and the concept of Coverage with Evidence Development in The Netherlands Cancer Institute and give two case examples that are currently ongoing: (1) tumour infiltrating lymphocytes therapy for metastatic melanoma; and (2) high-dose chemotherapy for BRCA1-like subgroup in triple-negative breast cancer. We conclude with recommendations for institutional policy.

Scenario drafting for early technology assessment of next generation sequencing in clinical oncology.

BACKGROUND: Next Generation Sequencing (NGS) is expected to lift molecular diagnostics in clinical oncology to the next level. It enables simultaneous identification of mutations in a patient tumor, after which targeted therapy may be assigned. This approach could improve patient survival and/or assist in controlling healthcare costs by offering expensive treatment to only those likely to benefit. However, NGS has yet to make its way into the clinic. Health Technology Assessment can support the adoption and implementation of a novel technology, but at this early stage many of the required variables are still unknown. METHODS: Scenario drafting and expert elicitation via a questionnaire were used to identify factors that may act as a barrier or facilitate adoption of NGS-based molecular diagnostics. Attention was paid to predominantly elicit quantitative answers, allowing their use in future modelling of cost-effectiveness. RESULTS: Adequately informing patients and physicians, the latters' opinion on clinical utility and underlying evidence as well as presenting sequencing results within a relevant timeframe may act as pivotal facilitators. Reimbursement for NGS-based testing and accompanying therapies (both general and in case of off-label prescription) was found to be a potential barrier. Competition on the market and demonstrating clinical utility may also be challenging. Importantly, numerous quantitative values for variables related to each of these potential barriers/facilitators, such as such as desired panel characteristics, willingness to pay or the expected number of targets identified per person, were also elicited. CONCLUSIONS: We have identified several factors that may either pose a barrier or facilitate the adoption of NGS in the clinic. We believe acting upon these findings, for instance by organizing educational events, advocating new ways of evidence generation and steering towards the most cost-effective solution, will accelerate the route from bench-to-bedside. Moreover, due to the methodology of expert elicitation, this study provides parameters that can be incorporated in future cost-effectiveness modeling to steer the development of NGS gene panels towards the most optimal direction.

Excellent translational research in oncology: A journey towards novel and more effective anti-cancer therapies.

Comprehensive Cancer Centres (CCCs) serve as critical drivers for improving cancer survival. In Europe, we have developed an Excellence Designation System (EDS) consisting of criteria to assess "excellence" of CCCs in translational research (bench to bedside and back), with the expectation that many European CCCs will aspire to this status.

Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.