Organization of head and neck cancer rehabilitation care: a national survey among healthcare professionals in Dutch head and neck cancer centers.

PURPOSE: Head and neck cancer (HNC) treatment often leads to physical and psychosocial impairments. Rehabilitation can overcome these limitations and improve quality of life. The aim of this study is to obtain an overview of rehabilitation care for HNC, and to investigate factors influencing rehabilitation provision, in Dutch HNC centers, and to some extent compare it to other countries. METHODS: An online survey, covering five themes: organizational structure; rehabilitation interventions; financing; barriers and facilitators; satisfaction and future improvements, among HNC healthcare- and financial professionals of Dutch HNC centers. RESULTS: Most centers (86%) applied some type of rehabilitation care, with variations in organizational structure. A speech language therapist, physiotherapist and dietitian were available in all centers, but other rehabilitation healthcare professionals in less than 60%. Facilitators for providing rehabilitation services included availability of a contact person, and positive attitude, motivation, and expertise of healthcare professionals. Barriers were lack of reimbursement, and patient related barriers including comorbidity, travel (time), low health literacy, limited financial capacity, and poor motivation. CONCLUSION: Although all HNC centers included offer rehabilitation services, there is substantial practice variation, both nationally and internationally. Factors influencing rehabilitation are related to the motivation and expertise of the treatment team, but also to reimbursement aspects and patient related factors. More research is needed to investigate the extent to which practice variation impacts individual patient outcomes and how to integrate HNC rehabilitation into routine clinical pathways.

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Introduction of a Post-Anaesthesia Care Unit in a Teaching Hospital Is Associated with a Reduced Length of Hospital Stay in Noncardiac Surgery: A Single-Centre Interrupted Time Series Analysis.

BACKGROUND: A post-anaesthesia care unit (PACU) may improve postoperative care compared with intermediate care units (IMCU) due to its dedication to operative care and an individualized duration of postoperative stay. The effects of transition from IMCU to PACU for postoperative care following intermediate to high-risk noncardiac surgery on length of hospital stay, intensive care unit (ICU) utilization, and postoperative complications were investigated. METHODS: This single-centre interrupted time series analysis included patients undergoing eleven different noncardiac surgical procedures associated with frequent postoperative admissions to an IMCU or PACU between January 2018 and March 2019 (IMCU episode) and between October 2019 and December 2020 (PACU episode). Primary outcome was hospital length of stay, secondary outcomes included postoperative complications and ICU admissions. RESULTS: In total, 3300 patients were included. The hospital length of stay was lower following PACU admission compared to IMCU admission (IMCU 7.2 days [4.2-12.0] vs. PACU 6.0 days [3.6-9.1]; p < 0.001). Segmented regression analysis demonstrated that the introduction of the PACU was associated with a decrease in hospital length of stay (GMR 0.77 [95% CI 0.66-0.91]; p = 0.002). No differences between episodes were detected in the number of postoperative complications or postoperative ICU admissions. CONCLUSIONS: The introduction of a PACU for postoperative care of patients undergoing intermediate to high-risk noncardiac surgery was associated with a reduction in the length of stay at the hospital, without increasing postoperative complications.

Effects of physical exercise during adjuvant chemotherapy for breast cancer on long-term tested and perceived cognition: results of a pragmatic follow-up study.

PURPOSE: Cancer-related cognitive impairment (CRCI) following chemotherapy is commonly reported in breast cancer survivors, even years after treatment. Data from preclinical studies suggest that exercise during chemotherapy may prevent or diminish cognitive problems; however, clinical data are scarce. METHODS: This is a pragmatic follow-up study of two original randomized trials, which compares breast cancer patients randomized to exercise during chemotherapy to non-exercise controls 8.5 years post-treatment. Cognitive outcomes include an online neuropsychological test battery and self-reported cognitive complaints. Cognitive performance was compared to normative data and expressed as age-adjusted z-scores. RESULTS: A total of 143 patients participated in the online cognitive testing. Overall, cognitive performance was mildly impaired on some, but not all, cognitive domains, with no significant differences between groups. Clinically relevant cognitive impairment was present in 25% to 40% of all participants, regardless of study group. We observed no statistically significant effect of exercise, or being physically active during chemotherapy, on long-term cognitive performance or self-reported cognition, except for the task reaction time, which favored the control group (ß = -2.04, 95% confidence interval: -38.48; -2.38). We observed no significant association between self-reported higher physical activity levels during chemotherapy or at follow-up and better cognitive outcomes. CONCLUSION: In this pragmatic follow-up study, exercising and being overall more physically active during or after adjuvant chemotherapy for breast cancer was not associated with better tested or self-reported cognitive functioning, on average, 8.5 years after treatment. Future prospective studies are needed to document the complex relationship between exercise and CRCI in cancer survivors.

Differences in time to patient access to innovative cancer medicines in six European countries.

Patients across Europe face inequity regarding access to anticancer medicines. While access is typically evaluated through reimbursement status or sales data, patients can receive first access through early access programs (EAPs) or off-label use. This study aims to assess the time to patient access at the hospital level, considering different indications and countries. (Pre-)registered access to six innovative medicines (Olaparib, Niraparib, Ipilimumab, Osimeritinib, Nivolumab and Ibritunib) was measured using a cross-sectional survey. First patient access to medicines and indications were collected using the hospital databases. Nineteen hospitals from Hungary, Italy, the Netherlands, Belgium, Switzerland and France participated. Analysis showed that some hospitals achieved patient access before national reimbursement, primarily through EAPs. The average time from EMA-approval to patient access for these medicines was 2.1 years (Range: -0.9-7.1 years). Hospitals in Italy and France had faster access compared to Hungary and Belgium. Variation was also found within countries, with specialized hospitals (x̄: -0.9 years; SD: 2.0) more likely to provide patient access prior to national reimbursement than general hospitals (x̄: 0.4 years; SD: 2.9). Contextual differences were observed, with EAPs or off-label use being more prevalent in Switzerland than Hungary. Recent EMA-approved indications and drug combinations reached patients at a later stage. Substantial variation in patient access time was observed between and within countries. Improving pricing and reimbursement timelines, fostering collaboration between national health authorities and market authorization holders, and implementing nationally harmonized, data-generating EAPs can enhance timely and equitable patient access to innovative cancer treatments in Europe.

Early Cost-Effectiveness Analysis of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer Patients with Limited Peritoneal Carcinomatosis.

BACKGROUND: Gastric cancer patients with peritoneal carcinomatosis (PC) have a poor prognosis, with a median overall survival of 10 months when treated with systemic chemotherapy only. Cohort studies showed that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) might improve the prognosis for gastric cancer patients with limited PC. Besides generating trial data on clinical effectiveness, it is crucial to timely collect information on economic aspects to guide the reimbursement decision-making process. No previous data have been published on the cost(-effectiveness) of CRS/HIPEC in this group of patients. Therefore, we performed an early model-based cost-effectiveness analysis of CRS/HIPEC for gastric cancer patients with limited PC in the Dutch setting. METHODS: We constructed a two-state (alive-dead) Markov transition model to evaluate costs and clinical outcomes from a Dutch healthcare perspective. Clinical outcomes, transition probabilities and utilities were derived from literature and verified by clinical experts in the field. Costs were measured using two available representative cohorts (2010-2017): one 'systemic chemotherapy only' cohort and one 'CRS/HIPEC' cohort (n = 10 each). Incremental cost-utility ratios (ICURs) were expressed as Euros per quality-adjusted life-year (QALY). We performed probabilistic and deterministic sensitivity, scenario, and value-of-information analyses using a willingness-to-pay (WTP) threshold of €80,000/QALY, which reflects the Dutch norm for severe diseases. RESULTS: In the base-case analysis, CRS/HIPEC yielded more QALYs (increment of 0.68) and more costs (increment of €34,706) compared with systemic chemotherapy only, resulting in an ICUR of €50,990/QALY. The probability that CRS/HIPEC was cost effective compared with systemic chemotherapy alone was 64%. To reduce uncertainty, the expected value of perfect information amounted to €4,021,468. The scenario analyses did not alter the results and showed that treatment costs, lifetime health-related quality of life and overall survival had the largest influence on the model. CONCLUSIONS: The presented early cost-effectiveness analysis suggests that adding CRS/HIPEC to systemic chemotherapy for gastric cancer patients with limited PC has a good chance of being cost-effectiveness compared with systemic chemotherapy alone when using a WTP of €80,000/QALY. However, there is substantial uncertainty in view of the current available data on effectiveness. Results from the ongoing phase III PERISCOPE II trial are therefore crucial for further decisions on treatment policy and its cost-effectiveness.

Strengthening the evidence base for mHealth in clinical practice: Conducting research with standalone or interoperable systems - a viewpoint.

Objective: The aim of this viewpoint is to inform mobile health (mHealth) evidence development in using standalone or interoperable systems in hospital practice. Methods: There is a gap between mHealth research and its widespread uptake in clinical practice. Evidence generation is not keeping up with the introduction and implementation of technologies. This is partly a consequence of the technology characteristics and the way research is conducted in a clinical setting. Research and development of mHealth technology can be conducted standalone in a laboratory like setting, standalone in a clinical setting or interoperable with already existing technology in hospital practice. Results: Standalone systems operate relatively independent from an organizations' existing infrastructure. Using laboratory settings does not reflect the complexity of real-life, but in clinical practice this may be suitable for research assessing usability, feasibility or even clinical and process outcomes at a small scale. Realizing research and development on interoperable mHealth technology solutions, especially with operational EMR systems, is a challenging, time- and resource intensive process and requires large(r) investments, as it is often complicated by a myriad of interfering factors. Interoperable systems are however a more sustainable option in the long run, and generated evidence reflects the real hospital care setting and this option may therefore facilitate dissemination. Choosing either a standalone or interoperable setting affects the research design, the implementation pace and ultimately widespread adoption of the mHealth technology. Conclusion: We recommend to include these technology characteristics in implementation frameworks and think of evaluation research designs in an early phase.

Effects of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity.

OBJECTIVE: Animal data suggest that exercise during chemotherapy is cardioprotective, but clinical evidence to support this is limited. This study evaluated the effect of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity. METHODS: This is a follow-up study of two previously performed randomised trials in patients with breast cancer allocated to exercise during chemotherapy or non-exercise controls. Cardiac imaging parameters, including T1 mapping (native T1, extracellular volume fraction (ECV)), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), cardiorespiratory fitness, and physical activity levels, were acquired 8.5 years post-treatment. RESULTS: In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years), of whom 99% and 18% were treated with anthracyclines and trastuzumab, respectively. ECV and Native T1 were 25.3%±2.5% and 1026±51 ms in the control group, and 24.6%±2.8% and 1007±44 ms in the exercise group, respectively. LVEF was borderline normal in both groups, with an LVEF<50% prevalence of 22.5% (n=40/178) in all participants. Compared with control, native T1 was statistically significantly lower in the exercise group (ß=-20.16, 95% CI -35.35 to -4.97). We found no effect of exercise on ECV (ß=-0.69, 95% CI -1.62 to 0.25), LVEF (ß=-1.36, 95% CI -3.45 to 0.73) or GLS (ß=0.31, 95% CI -0.76 to 1.37). Higher self-reported physical activity levels during chemotherapy were significantly associated with better native T1 and ECV. CONCLUSIONS: In long-term breast cancer survivors, exercise and being more physically active during chemotherapy were associated with better structural but not functional cardiac parameters. The high prevalence of cardiac dysfunction calls for additional research on cardioprotective measures, including alternative exercise regimens. TRIAL REGISTRATION NUMBER: NTR7247.

Moderators of exercise effects on self-reported cognitive functioning in cancer survivors: an individual participant data meta-analysis.

PURPOSE: This individual participant data meta-analysis (IPD-MA) assesses exercise effects on self-reported cognitive functioning (CF) and investigates whether effects differ by patient-, intervention-, and exercise-related characteristics. METHODS: IPD from 16 exercise RCTs, including 1987 patients across multiple types of non-metastatic cancer, was pooled. A one-stage IPD-MA using linear mixed-effect models was performed to assess exercise effects on self-reported CF (z-score) and to identify whether the effect was moderated by sociodemographic, clinical, intervention- and exercise-related characteristics, or fatigue, depression, anxiety, and self-reported CF levels at start of the intervention (i.e., baseline). Models were adjusted for baseline CF and included a random intercept at study level to account for clustering of patients within studies. A sensitivity analysis was performed in patients who reported cognitive problems at baseline. RESULTS: Minimal significant beneficial exercise effects on self-reported CF (ß=-0.09 [-0.16; -0.02]) were observed, with slightly larger effects when the intervention was delivered post-treatment (n=745, ß=-0.13 [-0.24; -0.02]), and no significant effect during cancer treatment (n=1,162, ß=-0.08 [-0.18; 0.02]). Larger effects were observed in interventions of 12 weeks or shorter (ß=-0.14 [-0.25; -0.04]) or 24 weeks or longer (ß=-0.18 [-0.32; -0.02]), whereas no effects were observed in interventions of 12-24 weeks (ß=0.01 [-0.13; 0.15]). Exercise interventions were most beneficial when provided to patients without anxiety symptoms (ß=-0.10 [-0.19; -0.02]) or after completion of treatment in patients with cognitive problems (ß=-0.19 [-0.31; -0.06]). No other significant moderators were identified. CONCLUSIONS: This cross-cancer IPD meta-analysis observed small beneficial exercise effects on self-reported CF when the intervention was delivered post-treatment, especially in patients who reported cognitive problems at baseline. IMPLICATIONS FOR CANCER SURVIVORS: This study provides some evidence to support the prescription of exercise to improve cognitive functioning. Sufficiently powered trials are warranted to make more definitive recommendations and include these in the exercise guidelines for cancer survivors.

Duty to recontact in genomic cancer care: A tool helping to assess the professional's responsibility.

Tumour DNA and germline testing, based on DNA-wide sequencing analysis, are becoming more and more routine in clinical-oncology practice. A promising step in medicine, but at the same time leading to challenging ethicolegal questions. An important one is under what conditions individuals (patients and their relatives, research participants) should be recontacted with new information, even if many years have passed since the last contact. Based on legal- and ethical study, we developed a tool to help professionals to decide whether or not to recontact an individual in specific cases. It is based on four assessment criteria: (1) professional relationship (2) clinical impact (3) individual's preferences and (4) feasibility. The tool could also serve as a framework for guidelines on the topic.

EffectiveNess of a multimodal preHAbilitation program in patieNts with bladder canCEr undergoing radical cystectomy: protocol of the ENHANCE multicentre randomised controlled trial.

INTRODUCTION: Radical cystectomy (RC) is the standard treatment for patients with non-metastatic muscle-invasive bladder cancer, as well as for patients with therapy refractory high-risk non-muscle invasive bladder cancer. However, 50-65% of patients undergoing RC experience perioperative complications. The risk, severity and impact of these complications is associated with a patient's preoperative cardiorespiratory fitness, nutritional and smoking status and presence of anxiety and depression. There is emerging evidence supporting multimodal prehabilitation as a strategy to reduce the risk of complications and improve functional recovery after major cancer surgery. However, for bladder cancer the evidence is still limited. The aim of this study is to investigate the superiority of a multimodal prehabilitation programme versus standard-of-care in terms of reducing perioperative complications in patients with bladder cancer undergoing RC. METHODS AND ANALYSIS: This multicentre, open label, prospective, randomised controlled trial, will include 154 patients with bladder cancer undergoing RC. Patients are recruited from eight hospitals in The Netherlands and will be randomly (1:1) allocated to the intervention group receiving a structured multimodal prehabilitation programme of approximately 3-6 weeks, or to the control group receiving standard-of-care. The primary outcome is the proportion of patients who develop one or more grade ≥2 complications (according to the Clavien-Dindo classification) within 90 days of surgery. Secondary outcomes include cardiorespiratory fitness, length of hospital stay, health-related quality of life, tumour tissue biomarkers of hypoxia, immune cell infiltration and cost-effectiveness. Data collection will take place at baseline, before surgery and 4 and 12 weeks after surgery. ETHICS AND DISSEMINATION: Ethical approval for this study was granted by the Medical Ethics Committee NedMec (Amsterdam, The Netherlands) under reference number 22-595/NL78792.031.22. Results of the study will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05480735.

Detecting Patient Deterioration Early Using Continuous Heart rate and Respiratory rate Measurements in Hospitalized COVID-19 Patients.

BACKGROUND: Presenting symptoms of COVID-19 patients are unusual compared with many other illnesses. Blood pressure, heart rate, and respiratory rate may stay within acceptable ranges as the disease progresses. Consequently, intermittent monitoring does not detect deterioration as it is happening. We investigated whether continuously monitoring heart rate and respiratory rate enables earlier detection of deterioration compared with intermittent monitoring, or introduces any risks. METHODS: When available, patients admitted to a COVID-19 ward received a wireless wearable sensor which continuously measured heart rate and respiratory rate. Two intensive care unit (ICU) physicians independently assessed sensor data, indicating when an intervention might be necessary (alarms). A third ICU physician independently extracted clinical events from the electronic medical record (EMR events). The primary outcome was the number of true alarms. Secondary outcomes included the time difference between true alarms and EMR events, interrater agreement for the alarms, and severity of EMR events that were not detected. RESULTS: In clinical practice, 48 (EMR) events occurred. None of the 4 ICU admissions were detected with the sensor. Of the 62 sensor events, 13 were true alarms (also EMR events). Of these, two were related to rapid response team calls. The true alarms were detected 39 min (SD = 113) before EMR events, on average. Interrater agreement was 10%. Severity of the 38 non-detected events was similar to the severity of 10 detected events. CONCLUSION: Continuously monitoring heart rate and respiratory rate does not reliably detect deterioration in COVID-19 patients when assessed by ICU physicians.

Surveillance Imaging after Primary Diagnosis of Ductal Carcinoma in Situ.

Background Guidelines recommend annual surveillance imaging after diagnosis of ductal carcinoma in situ (DCIS). Guideline adherence has not been characterized in a contemporary cohort. Purpose To identify uptake and determinants of surveillance imaging in women who underwent treatment for DCIS. Materials and Methods A stratified random sample of women who underwent breast-conserving surgery for primary DCIS between 2008 and 2014 was retrospectively selected from 1330 facilities in the United States. Imaging examinations were recorded from date of diagnosis until first distant recurrence, death, loss to follow-up, or end of study (November 2018). Imaging after treatment was categorized into 10 12-month periods starting 6 months after diagnosis. Primary outcome was per-period receipt of asymptomatic surveillance imaging (mammography, MRI, or US). Secondary outcome was diagnosis of ipsilateral invasive breast cancer. Multivariable logistic regression with repeated measures and generalized estimating equations was used to model receipt of imaging. Rates of diagnosis with ipsilateral invasive breast cancer were compared between women who did and those who did not undergo imaging in the 6-18-month period after diagnosis using inverse probability-weighted Kaplan-Meier estimators. Results A total of 12 559 women (median age, 60 years; IQR, 52-69 years) were evaluated. Uptake of surveillance imaging was 75% in the first period and decreased over time (P < .001). Across the first 5 years after treatment, 52% of women participated in consistent annual surveillance. Surveillance was lower in Black (adjusted odds ratio [OR], 0.80; 95% CI: 0.74, 0.88; P < .001) and Hispanic (OR, 0.82; 95% CI: 0.72, 0.94; P = .004) women than in White women. Women who underwent surveillance in the first period had a higher 6-year rate of diagnosis of invasive cancer (1.6%; 95% CI: 1.3, 1.9) than those who did not (1.1%; 95% CI: 0.7, 1.4; difference: 0.5%; 95% CI: 0.1, 1.0; P = .03). Conclusion Half of women did not consistently adhere to imaging surveillance guidelines across the first 5 years after treatment, with racial disparities in adherence rates. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rahbar and Dontchos in this issue.

High-dose chemotherapy with stem cell rescue to treat stage III homologous deficient breast cancer: factors influencing clinical implementation.

BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDCT) is a promising treatment for patients with stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer. Clinical effectiveness and cost-effectiveness are currently under investigation in an international multicenter randomized controlled trial. To increase the chance of successful introduction of HDCT into daily clinical practice, we aimed to identify relevant factors for smooth implementation using an early comprehensive assessment framework. METHODS: This is a qualitative, multi-stakeholder, exploratory research using semi-structured interviews guided by the Constructive Technology Assessment model, which evaluates the quality of a novel health technology by clinical, economic, patient-related, and organizational factors. Stakeholders were recruited by purposeful stratified sampling and interviewed until sufficient content saturation was reached. Two researchers independently created themes, categories, and subcategories by following inductive coding steps, these were verified by a third researcher. RESULTS: We interviewed 28 stakeholders between June 2019 and April 2021. In total, five overarching themes and seventeen categories were identified. Important findings for optimal implementation included the structural identification and referral of all eligible patients, early integration of supportive care, multidisciplinary collaboration between- and within hospitals, (de)centralization of treatment aspects, the provision of information for patients and healthcare professionals, and compliance to new regulation for the BRCA1-like test. CONCLUSIONS: In anticipation of a positive reimbursement decision, we recommend to take the highlighted implementation factors into consideration. This might expedite and guide high-quality equitable access to HDCT for patients with stage III, HER2-negative, HRD breast cancer in the Netherlands.

Cost-Effectiveness and Budget Impact of Future Developments With Whole-Genome Sequencing for Patients With Lung Cancer.

OBJECTIVES: This study aimed to investigate the cost-effectiveness, budget impact (BI), and impact of uncertainty of future developments concerning whole-genome sequencing (WGS) as a clinical diagnostic test compared with standard of care (SoC) in patients with locally advanced and metastatic non-small cell lung cancer. METHODS: A total of 3 likely scenarios to take place within 5 years (according to experts) were simulated using a previously developed, peer reviewed, and published decision model. The scenarios concerned "WGS results used for treatment selection" (scenario 1), "WGS-based biomarker for immunotherapy" (scenario 2), and "off-label drug approval for WGS results" (scenario 3). Two diagnostic strategies of the original model, "SoC" and "WGS as a diagnostic test" (base model), were used to compare our scenarios with. Outcomes were reported for the base model, all scenarios separately, combined (combined unweighted), and weighted by likelihood (combined weighted). Cost-effectiveness, BI, and value of information analyses were performed for WGS compared with SoC. RESULTS: Total costs and quality-adjusted life-years for SoC in metastatic non-small cell lung cancer were €149 698 and 1.235. Incremental outcomes of WGS were €1529/0.002(base model), -€222/0.020(scenario 1), -€2576/0.023(scenario 2), €388/0.024(scenario 3), -€5041/0.060(combined unweighted), and -€1715/0.029(combined weighted). The annual BI for adopting WGS for this population in The Netherlands ranged between €682 million (combined unweighted) and €714 million (base model). The consequences of uncertainty amounted to €3.4 million for all scenarios (combined weighted) and to €699 000 for the diagnostic yield of WGS alone (combined weighted). CONCLUSIONS: Our findings suggest that it is likely for WGS to become cost-effective within the near future if it identifies more patients with actionable targets and show the impact of uncertainty regarding its diagnostic yield. Modeling future scenarios can be useful to consider early adoption of WGS while timely anticipating on unforeseen developments before final conclusions are reached.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).

Ten-year follow-up of the observational RASTER study, prospective evaluation of the 70-gene signature in ER-positive, HER2-negative, node-negative, early breast cancer.

INTRODUCTION: Prognostic gene expression signatures can be used in combination with classical clinicopathological factors to guide adjuvant chemotherapy decisions in ER-positive, HER2-negative breast cancer. However, long-term outcome data after introduction of genomic testing in the treatment decision-making process are limited. METHODS: In the prospective RASTER study, the tumours of 427 patients with cTanyN0M0 breast cancer were tested to assess the 70-gene signature (MammaPrint). The results were provided to their treating physician to be incorporated in the decision-making on adjuvant systemic therapy. Here, we report the long-term outcome of the 310 patients with ER-positive, HER2-negative tumours by clinical and genomic risk categories at a median follow-up of 10.3 years. RESULTS: Among the clinically high-risk patients, 45 (49%) were classified as genomically low risk. In this subgroup, at 10 years, distant recurrence free interval (DRFI) was similar between patients treated with (95.7% [95% CI 87.7-100]) and without (95.5% [95% CI 87.1-100]) chemotherapy. Within the group of clinically low-risk patients, 56 (26%) were classified as genomically high risk. Within the clinically low-risk group, beyond 5 years, a difference emerged between the genomically high- and low-risk subgroup resulting in a 10-year DRFI of 84.3% (95% CI 74.8-95.0) and 93.4% (95% CI 89.5-97.5), respectively. Interestingly, genomic ultralow-risk patients have a 10-year DRFI of 96.7% (95% CI 90.5-100), largely (79%) without systemic therapy. CONCLUSIONS: These data confirm that clinically high-risk, genomically low-risk tumours have an excellent outcome in the real-world setting of shared decision-making. Together with the updated results of the MINDACT trial, these data support the use of the MammaPrint, in ER-positive, HER2-negative, node-negative, clinically high-risk breast cancer patients. REGISTRY: ISRCTN71917916.

Budget impact analysis of providing hospital inpatient care at home virtually, starting with two specific surgical patient groups.

OBJECTIVE: To determine the budget impact of virtual care. METHODS: We conducted a budget impact analysis of virtual care from the perspective of a large teaching hospital in the Netherlands. Virtual care included remote monitoring of vital signs and three daily remote contacts. Net budget impact over 5 years and net costs per patient per day (costs/patient/day) were calculated for different scenarios: implementation in one ward, in two different wards, in the entire hospital, and in multiple hospitals. Sensitivity analyses included best-case and worst-case scenarios, and reducing the frequency of daily remote contacts. RESULTS: Net budget impact over 5 years was €2 090 000 for implementation in one ward, €410 000 for two wards and €-6 206 000 for the entire hospital. Costs/patient/day in the first year were €303 for implementation in one ward, €94 for two wards and €11 for the entire hospital, decreasing in subsequent years to a mean of €259 (SD=€72), €17 (SD=€10) and €-55 (SD=€44), respectively. Projecting implementation in every Dutch hospital resulted in a net budget impact over 5 years of €-445 698 500. For this scenario, costs/patient/day decreased to €-37 in the first year, and to €54 in subsequent years in the base case. CONCLUSIONS: With present cost levels, virtual care only saves money if it is deployed at sufficient scale or if it can be designed such that the active involvement of health professionals is minimised. Taking a greenfield approach, involving larger numbers of hospitals, further decreases costs compared with implementing virtual care in one hospital alone.

Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors: A Cross-Sectional Study.

Background: Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear. Objectives: The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors. Methods: We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders. Results: In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (ß = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity. Conclusions: In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors.

Construct Validity of the Steep Ramp Test for Assessing Cardiorespiratory Fitness in Patients With Breast Cancer and the Effect of Chemotherapy-Related Symptom Burden.

OBJECTIVE: To investigate the construct validity of the Steep Ramp Test (SRT) by longitudinally comparing the correlation between maximum short exercise capacity of the SRT and direct measurements of peak oxygen consumption (Vo2peak) during or shortly after treatment in patients with breast cancer and the potential effect of chemotherapy-induced symptom burden. DESIGN: Cross-sectional. SETTING: Multicenter. PARTICIPANTS: We used data from 2 studies that included women with breast cancer treated with chemotherapy, resulting in 274 observations. A total of 161 patients (N=161) performed the cardiopulmonary exercise test and the SRT in 2 test sessions on different time points around chemotherapy treatment. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fatigue was assessed with the Multidimensional Fatigue Inventory, and nausea and vomiting and pain by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. The longitudinal correlation between the maximum short exercise capacity and Vo2peak was investigated using a linear mixed model. Interaction terms were added to the model to investigate whether the correlation varied by symptom burden. RESULTS: We found a statistically significant moderate correlation between Vo2peak and maximum short exercise capacity (0.61; 95% confidence interval, 0.51-0.70; P<.01) over time. This correlation was slightly attenuated (-0.07; 95% confidence interval, -0.13 to 0.00; P=.04) in patients with chemotherapy-related nausea and vomiting, indicating smaller correlations of Vo2peak with the maximum short exercise capacity with increasing symptom burden. Pain and fatigue did not significantly modify the correlation. CONCLUSIONS: The SRT can only be used as a proxy for changes in aerobic capacity with great caution and with attention for the level of nausea and vomiting.