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The continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV nonesmall-cell lung cancer (NSCLC) even more complex. This study primarily analyzed variations in biomarker testing in clinical practice in patients referred to a comprehensive cancer center in the Netherlands. The secondary aim was to compare the cost of biomarker testing with the cost of whole-genome sequencing. The cohort included 102 stage IV NSCLC patients who received biomarker testing in 2017 or 2018 at the comprehensive cancer center. The complete biomarker testing history of the cohort was identified using linked data from the comprehensive cancer center and the nationwide network and registry of histopathology and cytopathology in the Netherlands. Unique biomarker-test combinations, costs, turnaround times, and test utilization were examined. The results indicate substantial variation in test utilization and sequences. The mean cost per patient of biomarker testing was 2259.92 +/- 1217.10 USD, or 1881.23 +/- 1013.15 EUR. Targeted gene panels were most frequently conducted, followed by IHC analysis for programmed cell death protein ligand 1. Typically, the most common biomarkers were assessed within the first tests, and emerging biomarkers were tested further down the test sequence. At the cost of current biomarker testing, replacing current testing with whole-genome sequencing would have led to costsavings in only two patients (2%).

PurposePredictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole genome sequencing (WGS) based treatment selection is expected to rapidly increase worldwide. Detailed and comparative cost analyses of diagnostic techniques are an essential element in decision-making. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST) in the Netherlands.MethodsThe activity-based costing (ABC) method was conducted to calculate the total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs and operational costs. Outcome measures were total cost per cancer patient per included technique, and the total cost per cancer patient per most commonly applied technique (combination) for each cancer type.ResultsThe total cost per cancer patient per technique varied from € 58 (Sanger sequencing, 3 amplicons) to € 4738 (paired tumor-normal WGS). The operational costs accounted for the vast majority over 90 % of the total per cancer patient technique costs. The most important operational cost drivers were consumables followed by personnel (for sample preparation and primary data analysis).ConclusionThis study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making on implementation of WGS and other diagnostic modalities in routine clinical practice.

Background: The clinical utility of the 70-gene signature (MammaPrint®) to guide chemotherapy use in T1-3N0-1M0 breast cancer was demonstrated in the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) study. One thousand four ninety seven of 3356 (46.2%) enrolled patients with high clinical risk (in accordance with the modified Adjuvant! Online clinical-pathological assessment) had a low-risk 70-gene signature. Using patient-level data from the MINDACT trial, the cost-effectiveness of using the 70-gene signature to guide adjuvant chemotherapy selection for clinical high risk, estrogen receptor positive (ER+), human epidermal growth factor 2 negative (HER2-) patients was analysed. Patients and methods: A hybrid decision tree-Markov model simulated treatment strategies in accordance with the 70-gene signature with clinical assessment versus clinical assessment alone, over a 10-year time horizon. Primary outcomes were quality-adjusted life years (QALYs), country-specific costs and incremental cost-effectiveness ratios (ICERs) for six countries: Belgium, France, Germany, Netherlands, UK and the US. Results: Treatment strategies guided by the 70-gene signature result in more QALYs compared with clinical assessment alone. Costs of the 70-gene signature strategy were lower in five of six countries. This led to dominance of the 70-gene signature in Belgium, France, Germany, Netherlands and the US and to a cost-effective situation in the UK (ICER £22,910/QALY). Annual national cost savings were €4.2M (Belgium), €24.7M (France), €45.1M (Germany), €12.7M (Netherlands) and $244M (US). UK budget increase was £8.4M. Conclusion: Using the 70-gene signature to safely guide chemotherapy de-escalation in clinical high risk patients with ER+/HER2- tumours is cost-effective compared with using clinical assessment alone. Long-term follow-up and outcomes from the MINDACT trial are necessary to address uncertainties in model inputs., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Advanced non-small-cell lung cancer (NSCLC) harbours many genetic aberrations that can be targeted with systemic treatments. Whole-genome sequencing (WGS) can simultaneously detect these (and possibly new) molecular targets. However, the exact added clinical value of WGS is unknown. Objective The objective of this study was to determine the early cost effectiveness of using WGS in diagnostic strategies compared with currently used molecular diagnostics for patients with inoperable stage IIIB,C/IV non-squamous NSCLC from a Dutch healthcare perspective. Methods A decision tree represented the diagnostic pathway, and a cohort state transition model represented disease progression. Three diagnostic strategies were modelled: standard of care (SoC) alone, WGS as a diagnostic test, and SoC followed by WGS. Treatment effectiveness was based on a systematic review. Probabilistic cost-effectiveness analyses were performed, and threshold analyses (using €80,000 per quality-adjusted life-year [QALY]) was used to explore the early cost effectiveness of WGS. Results WGS as a diagnostic test resulted in more QALYs (0.002) and costs (€1534 [incremental net monetary benefit –€1349]), and SoC followed by WGS resulted in fewer QALYs (–0.002) and more costs (€1059 [–€1194]) compared with SoC alone. WGS as a diagnostic test was only cost effective if it was priced at €2000 per patient and identified 2.7% more actionable patients than SoC alone. Treating these additional identified patients with new treatments costing >€4069 per month decreased the probability of cost effectiveness. Conclusions Our analysis suggests that providing WGS as a diagnostic test is cost effective compared with SoC followed by WGS and SoC alone if costs for WGS decrease and additional patients with actionable targets are identified. This cost-effectiveness model can be used to incorporate new findings iteratively and to support ongoing decision making regarding the use of WGS in this rapidly evolving field. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01073-y.

PURPOSE: Internet-based cognitive behavioral therapy (iCBT), with and without therapist support, is effective in reducing treatment-induced menopausal symptoms and perceived impact of hot flushes and night sweats (HF/NS) in breast cancer survivors. The aim of the current study was to evaluate the cost-utility, cost-effectiveness, and budget impact of both iCBT formats compared to a waiting list control group from the Dutch healthcare perspective.METHODS: A Markov model was constructed with a 5-year time horizon. Costs and health outcomes were measured alongside a randomized controlled clinical trial and included quality-adjusted life years (QALYs), overall levels of menopausal symptoms, and perceived impact of HF/NS. Uncertainty was examined using probabilistic and deterministic sensitivity analyses, together with a scenario analysis incorporating a different perspective.RESULTS: iCBT was slightly more expensive than the waiting list control, but also more effective, resulting in incremental cost-utility ratios of €23,331/QALY and €11,277/QALY for the guided and self-managed formats, respectively. A significant reduction in overall levels of menopausal symptoms or perceived impact of HF/NS resulted in incremental costs between €1460 and €1525 for the guided and €500-€753 for the self-managed format. The estimated annual budget impact for the Netherlands was €192,990 for the guided and €74,592 for the self-managed format.CONCLUSION: Based on the current trial data, the results indicate that both guided and self-managed iCBT are cost-effective with a willingness-to-pay threshold of well below €30,000/QALY. Additionally, self-managed iCBT is the most cost-effective strategy and has a lower impact on healthcare budgets.

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.

BACKGROUND: Since 2011, a tailored, interdisciplinary head and neck rehabilitation (IHNR) program, covered by the basic healthcare insurance, is offered to advanced head and neck cancer (HNC) patients in the Netherlands Cancer Institute (NKI). This program is developed to preserve or restore patients' functioning, and to optimize health-related quality of life (HRQoL). It applies an integrated approach to define patients' individual goals and provide rehabilitation care throughout the cancer care continuum. The aim of the current study is to assess the (cost-) effectiveness of the IHNR approach compared to usual supportive care (USC) consisting of monodisciplinary and multidisciplinary care in advanced HNC patients.METHODS: This multicenter prospective observational study is designed to compare (cost-)effectiveness of the IHNR to USC for advanced HNC patients treated with chemoradiotherapy (CRT) or bioradiotherapy (BRT). The primary outcome is HRQoL represented in the EORTC QLQ-C30 summary score. Functional HRQoL, societal participation, utility values, return to work (RTW), unmet needs (UN), patient satisfaction and clinical outcomes are secondary outcomes, assessed using the EORTC QLQ-H&N35, USER-P, EQ-5D-5 L, and study-specific questionnaires, respectively. Both patient groups (required sample size: 64 per arm) are requested to complete the questionnaires at: diagnosis (baseline; T0), 3 months (T1), 6 months (T2), 9 months (T3) and 12 months (T4) after start of medical treatment. Differences in outcomes between the intervention and control group will be analyzed using mixed effects models, Chi-square test and descriptive statistics. In addition, a cost-effectiveness analysis (CEA) will be performed by means of a Markov decision model. The CEA will be performed using a societal perspective of the Netherlands.DISCUSSION: This prospective multicenter study will provide evidence on the effectiveness and cost-effectiveness of IHNR compared to USC. RTW and societal participation, included as secondary outcomes, have not been studied sufficiently yet in cancer rehabilitation. Interdisciplinary rehabilitation has not yet been implemented as usual care in all centers, which offers the opportunity to perform a controlled clinical study. If demonstrated to be (cost-)effective, national provision of the program can probably be advised.TRIAL REGISTRATION: The study has been retrospectively registered in the Netherlands Trial Registry on April 24th 2018 ( NTR7140 ).

Simple Summary Preferences for treatment strategies for low-risk ductal carcinoma in situ (DCIS), a potential precursor of invasive breast cancer (IBC) including a new active surveillance strategy, were elicited with a discrete choice experiment among recently-diagnosed women and oncologists involved in the care of women with DCIS. Patients exhibited strong preferences for active surveillance and seemed prepared to accept much higher levels of 10-year risk of developing ipsilateral invasive breast cancer than oncologists. Both patients and oncologists showed a strong aversion toward more extensive locoregional treatments (i.e., breast conserving surgery followed by radiotherapy, and mastectomy), while both groups demonstrated a strong preference toward shorter follow-up intervals. Abstract As ongoing trials study the safety of an active surveillance strategy for low-risk ductal carcinoma in situ (DCIS), there is a need to explain why particular choices regarding treatment strategies are made by eligible women as well as their oncologists, what factors enter the decision process, and how much each factor affects their choice. To measure preferences for treatment and surveillance strategies, women with newly-diagnosed, primary low-risk DCIS enrolled in the Dutch CONTROL DCIS Registration and LORD trial, and oncologists participating in the Dutch Health Professionals Study were invited to complete a discrete choice experiment (DCE). The relative importance of treatment strategy-related attributes (locoregional intervention, 10-year risk of ipsilateral invasive breast cancer (iIBC), and follow-up interval) were discerned using conditional logit models. A total of n = 172 patients and n = 30 oncologists completed the DCE. Patient respondents had very strong preferences for an active surveillance strategy with no surgery, irrespective of the 10-year risk of iIBC. Extensiveness of the locoregional treatment was consistently shown to be an important factor for patients and oncologists in deciding upon treatment strategies. Risk of iIBC was least important to patients and most important to oncologists. There was a stronger inclination toward a twice-yearly follow-up for both groups compared to annual follow-up.

Simple Summary Many cancer survivors have difficulties in attaining and maintaining physical activity (PA) after treatment. Therefore, we developed an Internet-based PA support program (IPAS), embedded in a patient portal. The aim of this study is to evaluate the effectiveness and costs of IPAS alone (online only) or IPAS combined with physiotherapist telephone counselling (blended care), compared to a control group. Our RCT included 137 breast and prostate cancer survivors. IPAS in its current form did not prove to be effective in increasing moderate to vigorous PA levels or secondary outcomes, compared to a control group, either as a standalone intervention or offered as blended care. We observed low to moderate satisfaction scores, with better scores for blended care. Recruitment and adherence to the study were challenging. Lessons learned led to suggestions for future trials, such as improved accessibility of the support program, increased frequency of support and use of activity trackers. Abstract 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.

Background Selecting patients with peritoneal metastases from colorectal cancer (CRCPM) who might benefit from cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is challenging. Computed tomography generally underestimates the peritoneal tumor load. Diagnostic laparoscopy is often used to determine whether patients are amenable for surgery. Magnetic resonance imaging (MRI) has shown to be accurate in predicting completeness of CRS. The aim of this study is to determine whether MRI can effectively reduce the need for surgical staging. Methods The study is designed as a multicenter randomized controlled trial (RCT) of colorectal cancer patients who are deemed eligible for CRS-HIPEC after conventional CT staging. Patients are randomly assigned to either MRI based staging (arm A) or to standard surgical staging with or without laparoscopy (arm B). In arm A, MRI assessment will determine whether patients are eligible for CRS-HIPEC. In borderline cases, an additional diagnostic laparoscopy is advised. The primary outcome is the number of unnecessary surgical procedures in both arms defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI Conclusion This randomized trial determines whether MRI can effectively replace surgical staging in patients with CRCPM considered for CRS-HIPEC. Trial registration Registered in the clinical trials registry of U.S. National Library of Medicine under NCT04231175.

Outcomes used for the effectiveness (median) and cost-effectiveness (mean) on overall survival (OS) are different and can vary from one another. Therefore, we compared median and mean OS gains of targeted therapies and immunotherapies for stage IIIB/IV Non-small cell lung cancer and explored underlying aspect. Eligible trials were searched in PubMed, survival curves were digitized, and parametric survival models fitted to model the mean OS. Twenty-seven trials were found for targeted therapies (n = 17) and immunotherapies (n = 10). Differences between median and mean OS gains in months ranged from -2.8 to 6.8 and -4.9 to 0.3 for two different subgroups of targeted therapies, and -2.4 to 11.4 for immunotherapies. The mean OS gain was substantially larger for most immunotherapy trials, due to relatively long survival. Median and mean OS gains did not differ for targeted therapies. Our findings imply a potential discrepancy between the estimates of effectiveness and cost-effectiveness of cancer treatments.

Background In its 2006 report, From cancer patient to cancer survivor: lost in transition, the U.S. Institute of Medicine raised the need for a more coordinated and comprehensive care model for cancer survivors. Given the ever increasing number of cancer survivors, in general, and prostate cancer survivors, in particular, there is a need for a more sustainable model of follow-up care. Currently, patients who have completed primary treatment for localized prostate cancer are often included in a specialist-based follow-up care program. General practitioners already play a key role in providing continuous and comprehensive health care. Studies in breast and colorectal cancer suggest that general practitioners could also consider to provide survivorship care in prostate cancer. However, empirical data are needed to determine whether follow-up care of localized prostate cancer survivors by the general practitioner is a feasible alternative. Methods This multicenter, randomized, non-inferiority study will compare specialist-based (usual care) versus general practitioner-based (intervention) follow-up care of prostate cancer survivors who have completed primary treatment (prostatectomy or radiotherapy) for localized prostate cancer. Patients are being recruited from hospitals in the Netherlands, and randomly (1:1) allocated to specialist-based (N = 195) or general practitioner-based (N = 195) follow-up care. This trial will evaluate the effectiveness of primary care-based follow-up, in comparison to usual care, in terms of adherence to the prostate cancer surveillance guideline for the timing and frequency of prostate-specific antigen assessments, the time from a biochemical recurrence to retreatment decision-making, the management of treatment-related side effects, health-related quality of life, prostate cancer-related anxiety, continuity of care, and cost-effectiveness. The outcome measures will be assessed at randomization (≤6 months after treatment), and 12, 18, and 24 months after treatment. Discussion This multicenter, prospective, randomized study will provide empirical evidence regarding the (cost-) effectiveness of specialist-based follow-up care compared to general practitioner-based follow-up care for localized prostate cancer survivors. Trial registration Netherlands Trial Registry, Trial NL7068 (NTR7266). Prospectively registered on 11 June 2018

Background: An intact homologous repair (HR) pathway is essential for error-free repair of DNA double strand breaks (DSB). Preclinical and clinical data have shown that breast cancer (BC) cells with a defect in the HR pathway are a target for DNA DSB inducing agents and PARP inhibition. HR deficiency (HRD) causes genomic instability with a typical profile of DNA copy number aberrations (CNA) as seen in tumors of patients with a BRCA1 germline mutation. In the Netherlands Cancer Institute (NKI) the BRCA1-like test, a biomarker for HRD, was developed. The test calculates the probability that the genomic profile of DNA CNA of a breast tumor is similar to that of BRCA1 mutated BCs. When this probability is above a certain cutoff, depending on the platform, the test is positive in a small percentage of estrogen receptor positive and over 50% of triple negative BCs. In retrospective analyses, the test appeared to be a predictive biomarker for sensitivity to adjuvant intensified alkylating chemotherapy with autologous stem cell rescue (IA-CT). For example in stage III HER2-negative BRCA1-like BC, the 7-year recurrence free survival improved from 30% with 5 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC) to 78% when treated with 4 cycles of FEC followed by IA-CT (adjusted hazard rate 0.12; p=0.001). There was no benefit in non-BRCA1-like patients. Prospective validation in a randomized phase III trial is eagerly awaited and will possibly result in a practice changing outcome. We hypothesize that, although treatment with IA-CT is controversial, by selecting the right patients, we may substantially improve survival in high risk BRCA1-like BC. Eligibility criteria: Patients, 18 to 66 years old, with HER2-negative BRCA1-like or germline BRCA1 or BRCA 2 related stage III BC, who are fit to undergo IA-CT. Trial Design: In this phase III trial, patients will be randomized to (neo)adjuvant treatment with 4 cycles of dose dense doxorubicin-cyclophosphamide (ddAC) followed by two cycles of IA-CT or followed by 4 cycles of carboplatin(q3)-paclitaxel(q1) and one year of olaparib (300mg twice daily). Adjuvant endocrine treatment is added according to guidelines. Primary outcome is overall survival (OS), analyzed with the intention to treat principle. To detect an improvement of 35% OS (40% vs 75%) with a 2-sided alpha of 0.05 and a power of 0.8 at 10 years, 174 patients should be enrolled. Secondary outcomes are toxicity, quality of life, cost-effectiveness and cognitive function. Additionally we plan to analyze potential biomarkers, like 53BP1 and cancer-immune interaction. The SUBITO trial is part of a Coverage with Evidence Development program, which is a policy which allows conditional funding of a promising health intervention while more conclusive evidence is gathered to prove its (cost-)effectiveness. Since January 2017 we recruited 8 patients in 2 hospitals. Ten other hospitals, including two in France and one in Germany, are expected to start enrollment soon. The Medical Ethical Committee approved the trial. The trial is registered at clinicaltrials.gov (NCT02810743). Contact information for people with a specific interest in the trial: e-mail: subito@nki.nl Citation Format: Vliek S, Jager A, Jonge-Lavrencic M, Lotz J-P, Gonçalves A, Graeser M, Nitz U, Mandjes IAM, Holtkamp MJ, Schot M, Retel VP, Kuip EJ, Wymenga MN, Konings IR, Tjan-Heijnen VCG, Kroep JR, Schroeder CP, Van der Wall E, Linn SC. Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-08.

Rationale: The 70-gene signature (MammaPrint®, MP) is a prognostic test which guides treatment decisions in patients with early breast cancer. After level 1A evidence for clinical utility of MP has been proven, cost-effectiveness data is important to inform reimbursement. Research objectives: To compare cost-effectiveness of adding MP to clinical risk assessment versus clinical risk assessment alone for the US and EU. Clinical risk was assessed by Adjuvant Online! (AOL) as described in Cardoso et al. NEJM 2016. We used prospective survival data from the large randomized phase 3 trial 'Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy' (MINDACT). Methods: We used a Markov decision model to estimate the expected costs and outcomes (quality adjusted life years; QALYs) for MP versus AOL in early breast cancer patients from a payers perspective in the US and a societal perspective in the EU over a 5 year time horizon. Five year breast cancer overall- and distant metastasis free survival was calculated based on the MINDACT population (n=6,693). Utility scores were collected by means of the EuroQol-5D in the pilot phase of MINDACT(the first n=800 MINDACT patients). Cost data were for the US based on published insurance claim data, for the EU on published health care- and societal costs. The cost-effectiveness was calculated for: (1) total early stage breast cancer population, (2) clinical high risk population and (3) clinical high risk group in the ER+/HER2- population. Finally, budget impact for a high-low range of different countries was calculated, as the application and costs of chemotherapy can be highly variable between countries. Results: For all groups (1,2,and 3) in the US, using MINDACT survival data and insurance claim data, adding MP to AOL saved costs and gained more QALYs compared to AOL alone (total costs per patient $42,223 vs $45,566 and 4.035 vs 4.031 QALYs respectively). Thus, a small difference in quality adjusted life years (0,0041) was observed, whereas a large difference in costs ($3,342) renders MP a highly cost-effective test (less costly & more effective in 64% of the cases). The largest cost-benefit effect was seen for group 3. The cut-off point for MP being cost-effective in the total population (group 1) is when the chemotherapy costs (and consequences) together are above $30,000. In the US, with approximately 250,000 new breast cancer patients per year, and a cost saving of $3,342, annual budget savings are expected to be $836M. Similar results for the Netherlands (15,000 breast cancer patients per year), reveal a cost difference of $300 per patient, and overall annual budget savings are expected to be $4,5M. Conclusion: Adding MP to clinical risk assessment is highly cost-effective compared to clinical risk assessment alone, based on the MINDACT survival data and US insurance claim data, for all above mentioned groups. When costs for chemotherapy (and consequences) exceed $30,000, MP is cost-effective for the total early breast cancer population. When costs for chemotherapy (and consequences) are below $30,000, the MP is cost-effective for the clinical high risk early breast cancer group. The separate results for EU countries will follow. Citation Format: Retèl VP, Joore MA, van 't Veer LJ, Cardoso F, Piccart MJ, Rutgers EJ, Tryfonidis K, Poncet C, van Harten WH. MammaPrint is cost-effective compared to clinical risk assessment in early stage breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-12-01.

The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-grade DCIS can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be low-grade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. Management by active surveillance also may save many low-grade DCIS patients intensive treatment. Therefore, we will compare active surveillance with conventional treatment, being either mastectomy, wide local excision (WLE) only, or WLE plus radiotherapy, possibly followed by hormonal therapy for primary low-grade DCIS. For this, we conduct a phase III, open-label, non-inferiority, multi-center, randomized clinical trial sponsored by the European Organization for Research and Treatment of Cancer (EORTC-1401-BCG). The Dutch Centers are coordinated by the Dutch Breast Cancer Research Group (BOOG) (BOOG 2014-04). This trial is developed and implemented in close collaboration with patient advocates. Randomization will be in a 1:1 ratio among one of the following arms: (1) active surveillance or (2) standard treatment per local policy. In total, 1,240 women (≥ 45 years) will be included without prior breast cancer, but with asymptomatic, pure, low-grade DCIS, based on a minimum of tissue harvested by biopsy from calcifications detected by population-based or opportunistic screening. Assuming 25% of randomized women qualified to enroll in the study will drop out or will be excluded from per protocol evaluation, at least 1,240 women need to be randomized to obtain the 930 patients required for the evaluation of the primary endpoint. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of 10 years. The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years. Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate, patient reported outcomes and cost-effectiveness. Accrual has started in the Netherlands in February 2017 and will start internationally in over 30 centers shortly. Acknowledgements: This trial is funded by Pink Ribbon Netherlands, the Dutch Cancer Society and Dutch Cancer Society/Alpe d'HuZes, and Cancer Research UK. Citation Format: Wesseling J, Elshof LE, Tryfonidis K, Poncet C, Aalders K, van Leeuwen-Stok E, Skinner V, Loo C, Winter-Warnars G, Bleiker E, Retèl V, Pijnappel R, Bijker N, Rutgers E, van Duijnhoven F. Update of the randomized, non-inferiority LORD trial testing safety of active surveillance for women with screen-detected low risk ductal carcinoma in situ (EORTC-1401-BCG/BOOG 2014-04, DCIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-07-01.

Background Approximately 40% of the newly diagnosed patients with advanced ovarian cancer are aged 70 years or older. Standard treatment for advanced disease consists of cytoreductive surgery and combination chemotherapy. In older patients, standard treatment is often withheld or prematurely stopped due to suspected frailty. It remains challenging to distinguish fit elderly patients who can endure standard therapy from frail patients who may benefit from an adapted treatment strategy. As a comprehensive geriatric assessment (CGA) can contribute to the identification of frail patients and improve tailored therapy in this population, screening tests were developed to select those who may benefit from a CGA. However, the use of these geriatric screening tests has rarely been compared with usual clinical care. The GERSOC-trial will evaluate whether geriatric screening in elderly patients with advanced-stage ovarian cancer improves treatment completion and quality of life. Methods This pragmatic, cluster randomised controlled trial will be conducted at a minimum of 20 hospitals in the Netherlands. Hospitals are randomly assigned to geriatric screening care (in which a geriatric screening comprised of the G8 questionnaire and the Timed Up and Go test is performed), or care as usual (in which current usual care is continued). A total of 320 patients aged ≥ 70 years with primary, advanced-stage ovarian carcinoma will be included. Patients considered fit on geriatric screening will receive standard treatment; patients who are considered unfit will be referred to a geriatrician for analysis and treatment advice. The primary outcome is the percentage difference in completed standard and adapted therapies between the two study arms. Secondary outcomes include quality of life, cost-effectiveness and survival. Discussion This trial aims to gather evidence for the use of geriatric screening in treatment decision-making in elderly patients with advanced ovarian cancer. If proven feasible, beneficial and cost-effective, geriatric screening may be implemented in routine clinical practice. Trial registration Netherlands Trial Registry, ID: NL6745. Registered on 2 August 2017.

Introduction Current localization techniques used in breast conserving surgery for non-palpable tumors show several disadvantages. Magnetic Seed Localization (MSL) is an innovative localization technique aiming to overcome these disadvantages. This study evaluated the expected budget impact of adopting MSL compared to standard of care. Methods Standard of care with Wire-Guided Localization (WGL) and Radioactive Seed Localization (RSL) use was compared with a future situation gradually adopting MSL next to RSL or WGL from a Dutch national perspective over 5 years (2017-2022). The intervention costs for WGL, RSL and MSL and the implementation costs for RSL and MSL were evaluated using activity-based costing in eight Dutch hospitals. Based on available list prices the price of the magnetic seed was ranged €100-€500. Results The intervention costs for WGL, RSL and MSL were respectively: €2,617, €2,834 and €2,662 per patient and implementation costs were €2,974 and €26,826 for MSL and RSL respectively. For standard of care the budget impact increased from €14.7m to €16.9m. Inclusion of MSL with a seed price of €100 showed a budget impact of €16.7m. Above a price of €178 the budget impact increased for adoption of MSL, rising to €17.6m when priced at €500. Conclusion MSL could be a cost-efficient localization technique in resecting non-palpable tumors in the Netherlands. The online calculation model can inform adoption decisions internationally. When determining retail price of the magnetic seed, cost-effectiveness should be considered.

Contains fulltext : 229798.pdf (Publisher’s version ) (Open Access) With the introduction of targeted therapies and immunotherapy, molecular diagnostics gained a more profound role in the management of non-small cell lung cancer (NSCLC). This study aimed to systematically search for studies reporting on the use of liquid biopsies (LB), the correlation between LBs and tissue biopsies, and finally the predictive value in the management of NSCLC. A systematic literature search was performed, including results published after 1 January 2014. Articles studying the predictive value or validity of a LB were included. The search (up to 1 September 2019) retrieved 1704 articles, 1323 articles were excluded after title and abstract screening. Remaining articles were assessed for eligibility by full-text review. After full-text review, 64 articles investigating the predictive value and 78 articles describing the validity were included. The majority of studies investigated the predictive value of LBs in relation to therapies targeting the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) receptor (n = 38). Of studies describing the validity of a biomarker, 55 articles report on one or more EGFR mutations. Although a variety of blood-based biomarkers are currently under investigation, most studies evaluated the validity of LBs to determine EGFR mutation status and the subsequent targeting of EGFR tyrosine kinase inhibitors based on the mutation status found in LBs of NSCLC patients.

Most breast cancer patients undergoing mastectomy are candidates for breast reconstruction. Deciding about breast reconstruction is complex and the preference-sensitive nature of this decision requires an approach of shared decision making between patient and doctor. Women considering breast reconstruction have expressed a need for decision support. We developed an online patient decision aid (pDA) to support decision making in women considering immediate breast reconstruction. The primary aim of this study is to assess the impact of the pDA in reducing decisional conflict, and more generally, on the decision-making process and the decision quality. Additionally, we will investigate the pDA’s impact on health outcomes, explore predictors, and assess its cost-effectiveness. A multicenter, two-armed randomized controlled trial (1:1) will be conducted. Women with breast cancer or ductal carcinoma in situ who will undergo a mastectomy and are eligible for immediate breast reconstruction will be invited to participate. The intervention group will receive access to the online pDA, whereas the control group will receive a widely available free information leaflet on breast reconstruction. Participants will complete online questionnaires at: baseline (T0), 1 week after consultation with a plastic surgeon (T1), and 3 (T2) and 12 months (T3) after surgery. The primary outcome is decisional conflict. Secondary outcomes include other measures reflecting the decision-making process and decision quality (e.g., decision regret), patient-reported health outcomes (e.g., satisfaction with the breasts) and costs. This study will provide evidence about the impact of an online pDA for women who will undergo mastectomy and are deciding about breast reconstruction. It will contribute to the knowledge on how to optimally support women in making this difficult decision. This study is retrospectively registered at ClinicalTrials.gov ( NCT03791138 ).

Despite advancements in treatment modalities, the 10-year survival rate of women diagnosed with advanced-stage ovarian cancer has remained between 10% and 15% for the past 20 years. This is in part due to the majority of cases being diagnosed when disease has reached International Federation of Gynecology and Obstetrics stages III to IV. Approximately 70% of patients treated with cytoreductive surgery (CRS) and platinum-based chemotherapy experience recurrence within 18 months. The OVHIPEC trial, a randomized phase III trial found improved recurrence-free survival and overall survival with the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval CRS. This study aimed to conduct a cost-effectiveness analysis (CEA) to determine the incremental cost-effectiveness ratio (ICER) of treatment with a combination of interval CRS and HIPEC compared with interval CRS alone in patients with stage III ovarian cancer. Data for the CEAwere extracted fromthe OVHIPEC trial (n = 245), which compared survival outcomes for patients with stage III ovarian cancer receiving either combination therapy (n = 122) or interval CRS alone (n = 123). Treatment costs from diagnosis to the time of disease recurrence were calculated using the treatment schedule in the OVHIPEC trial. Unit costs for disease-related procedures and events such as hospital admissions were calculated from multiple sources including national registries. All costs were initially retrieved in 2017 euros or converted to 2017 euros using the inflation rate established by the Consumer Price Index. Three different treatment protocols were analyzed: (1) standard chemotherapy, considered carboplatin and paclitaxel and/or gemcitabine and/or doxorubicin; (2) carboplatin-gemcitabine-bevacizumab and maintenance bevacizumab for platinum-sensitive disease; (3) maintenance poly (ADP-ribose) polymerase inhibitors for high-grade serous recurrent disease. The Makov model built to perform the analysis consisted of 3 mutually exclusive health states with corresponding utilities: Recurrence-free survival, disease recurrence, and death. The duration of each cycle in the model was 3 months, and a 10-year time duration was selected. The difference between the 2 groups in terms of qualityadjusted life-years (QALY) and incremental mean costs was calculated using 1000 replicas, made by extrapolating data from OVHIPEC survival outcomes, representing women at 60 years of age. The primary outcome for this trial was the ICER, calculated by dividing the mean incremental costs by the mean incremental QALY. Mean health care costs of interval CRS and HIPEC were €85,791 (95% credibility interval [CrI], €78,776-93,935) compared with €70,046 (95% CrI, €64,016-€76,661) for the interval CRS group. Treatment with interval CRS and HIPEC resulted in mean life-years of 5.07 (95% CrI, 4.80-5.34) compared with 4.07 (95% CrI, 3.83-4.33) for the interval CRS group. Adjusting for health-related quality-of-life data from the OVHIPEC trial, the mean QALY for the interval CRS and HIPEC group was 2.68 (95% CrI, 2.11-3.28) compared with 2.12 (95% CrI, 1.66-2.64) in the CRS group. The results showed an ICER of €28,299 per QALYover the first 5 years for patients treated with CRS and HIPEC. Probabilistic sensitivity analysis showed the likelihood of interval CRS combined with HIPEC being cost-effective was 83% using the Dutch WTP threshold of €80,000 per QALY. These results show that treatment with interval CRS and HIPEC shows a robust incremental QALY benefit compared with CRS alone. The probabilistic sensitivity analysis found that treatment with this combination therapy falls within the accepted values for cost-effective treatment costs in the Netherlands.

Background At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. Methods In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index

Contains fulltext : 207396.pdf (Publisher’s version ) (Open Access)

6516 Background: Due to the elevated risk of ipsilateral invasive breast cancer (iIBC) after diagnosis with primary ductal carcinoma in situ (DCIS), professional guidelines recommend surveillance screening within 6-12 months (mo) after completion of initial local treatment and annually thereafter. To characterize adherence to these guidelines, we explored longitudinal patterns of utilization and factors associated with the use of surveillance imaging (mammography, MRI, ultrasound) for women with primary DCIS treated with breast conserving surgery (BCS) ± radiotherapy (RT) within 6 mo of diagnosis. Methods: A treatment-stratified random sample of patients diagnosed with screen-detected and biopsy-confirmed DCIS in 2008-15 was selected from 1,330 Commission on Cancer-accredited facilities (up to 20/site) in the US. All imaging exams coded as asymptomatic were collected from 6 mo up to 10 years (yr) post-diagnosis. Time was defined according to 12-mo long surveillance periods. To be included in a given surveillance period, women had to be alive and free of a new breast cancer diagnosis through the end of the period. Women were classified as “consistent” screeners if they had at least one surveillance screen during each period, for the first 5 yr post-treatment or until censoring, whichever occurred first. Repeated measures multivariable logistic regression with generalized estimating equations was used to model receipt of surveillance breast imaging over time. The model included clinical and socioeconomic features. Results: The final analytic cohort contained 12,559 women; 8,989 (71.6%) received RT after BCS. Median age was 60 yr (interquartile range: 52-69) and median follow-up was 5.6 yr (95% confidence interval [CI] 5.6-5.7). Among women who received BCS (instead of BCS+RT), 62.5% (79.7%) underwent surveillance imaging within 6-18 mo after diagnosis. 38.7% (54.0%) were categorized as “consistent” screeners. Compared to white women, Black women were less likely to receive surveillance screening after treatment for primary DCIS (odds ratio [OR] 0.85, 95% CI 0.77-0.94). Hispanic ethnicity had a similar association (OR 0.86, 95% CI 0.74-0.99) compared to non-Hispanic ethnicity. Women with private insurance, compared to government insurance, were more likely to receive screening (OR 1.20, 95% CI 1.11-1.30). Prognostic tumor features indicative of a higher risk of subsequent iIBC, including higher grade, presence of comedonecrosis, and hormone receptor-negative DCIS, were not associated with screening uptake. Conclusions: Despite guidelines recommending annual surveillance imaging, many women with primary DCIS do not undergo regular imaging after BCS. The findings from this US-based study suggest that disparities in screening uptake are associated with race/ethnicity and insurance status rather than prognostic tumor features.

Predictive biomarkers can guide treatment decisions in breast cancer. Many studies are undertaken to discover and translate these biomarkers, yet few biomarkers make it to practice. Before use in clinical decision making, predictive biomarkers need to demonstrate analytical validity, clinical validity and clinical utility. While attaining analytical and clinical validity is relatively straightforward, by following methodological recommendations, the achievement of clinical utility is extremely challenging. It requires demonstrating three associations: the biomarker with the outcome (prognostic association), the effect of treatment independent of the biomarker, and the differential treatment effect between the prognostic and the predictive biomarker (predictive association). In addition, economical, ethical, regulatory, organizational and patient/doctor-related aspects are hampering the translational process. Traditionally, these aspects do not receive much attention until formal approval or reimbursement of a biomarker test (informed by Health Technology Assessment (HTA)) is at stake, at which point the clinical utility and sometimes price of the test can hardly be influenced anymore. When HTA analyses are performed earlier, during biomarker research and development, they may prevent further development of those biomarkers unlikely to ever provide sufficient added value to society, and rather facilitate translation of the promising ones. Early HTA is particularly relevant for the predictive biomarker field, as expensive medicines are under pressure and the need for biomarkers to guide their appropriate use is huge. Closer interaction between clinical researchers and HTA experts throughout the translational research process will ensure that available data and methodologies will be used most efficiently to facilitate biomarker translation.

Objectives: To inform decisions about the design and priority of further studies of emerging predictive biomarkers of high-dose alkylating chemotherapy (HDAC) in triple-negative breast cancer (TNBC) using value-of-information analysis. Methods: A state transition model compared treating women with TNBC with current clinical practice and four biomarker strategies to personalize HDAC: 1) BRCA1-like profile by array comparative genomic hybridization (aCGH) testing; 2) BRCA1-like profile by multiplex ligation-dependent probe amplification (MLPA) testing; 3) strategy 1 followed by X-inactive specific transcript gene (XIST) and tumor suppressor p53 binding protein (53BP1) testing; and 4) strategy 2 followed by XIST and 53BP1 testing, from a Dutch societal perspective and a 20-year time horizon. Input data came from literature and expert opinions. We assessed the expected value of partial perfect information, the expected value of sample information, and the expected net benefit of sampling for potential ancillary studies of an ongoing randomized controlled trial (RCT; NCT01057069). Results: The expected value of partial perfect information indicated that further research should be prioritized to the parameter group including “biomarkers’ prevalence, positive predictive value (PPV), and treatment response rates (TRRs) in biomarker-negative patients and patients with TNBC” (€639 million), followed by utilities (€48 million), costs (€40 million), and transition probabilities (TPs) (€30 million). By setting up four ancillary studies to the ongoing RCT, data on 1) TP and MLPA prevalence, PPV, and TRR; 2) aCGH and aCGH/MLPA plus XIST and 53BP1 prevalence, PPV, and TRR; 3) utilities; and 4) costs could be simultaneously collected (optimal size = 3000). Conclusions: Further research on predictive biomarkers for HDAC should focus on gathering data on TPs, prevalence, PPV, TRRs, utilities, and costs from the four ancillary studies to the ongoing RCT.

e15053 Background: With the introduction of targeted therapies and immunotherapy, molecular diagnostics gained a more profound role in the management of non-small cell lung cancer (NSCLC). Currently, tissue biopsies (TB) are used as primary source for molecular testing and generally require an invasive procedure. The introduction of liquid biopsies (LB) not only decreases patient burden, but it also allows for more frequent testing. Which might be of value in the monitoring of treatment response. This study aimed to systematically search for studies reporting on the use of LB, the correlation between LB and TB, and finally the predictive value in the management of NSCLC. Methods: A systematic literature search was performed using Scopus and PubMed, including results published in English after 01-01-2014. Articles were included when 1) describing the predictive value of a LB with regard to overall and/or progression-free survival, or 2) describing the validity of a marker by comparing LBs to TBs regarding sensitivity, specificity, or concordance. Results: 1705 articles were identified in the search, 1323 articles were excluded after title and abstract screening, leaving 382 articles for full-text evaluation. Of the 137 articles included after full-text evaluation, 78 articles described the validity, and 65 articles described the predictive value of LBs. In studies describing the predictive value of LBs, the majority of articles reported on the predictive value of biomarkers in relation to targeted therapies (n = 31). In studies describing the validity of LBs, the majority of studies report on EGFR mutations including, exon 19 deletion (n = 23) and L858R (n = 26). Looking at the validity of LBs, we saw a large variation in reported sensitivity (range 20-100%), specificity (range 30-100%), and concordance (range 40-99%). Conclusions: Although a variety of blood-based biomarkers has been investigated, most studies have limited their evaluation to sensitivity and specificity of liquid biopsies to determine EGFR mutation status compared to tissue and the subsequent targeting of EGFR tyrosine kinase inhibitors based on the mutation status found in LBs of NSCLC patients. The first adoption of LBs in practice is expected to involve the detection of EGFR mutations by LB analysis in addition to TBs.

Background An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. Methods We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. Results TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M. Conclusions TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.

Laryngectomized patients, lacking conditioning of the breathing air in the upper respiratory tract, have reported considerable pulmonary complaints. It is assumed that these patients also run a higher risk of developing severe respiratory infections. Unfortunately, there is little scientific information available about the occurrence of respiratory infections and related health costs in these patients with and without the use of an HME. Therefore, the occurrence of respiratory infections in laryngectomized patients was investigated in the Netherlands Cancer Institute and by means of a survey among head and neck oncology surgeons throughout Europe. The number of tracheobronchitis and/or pneumonia events was retrospectively scored between 1973 and 2013 in medical records of 89 laryngectomized patients treated in our institute. To assess expert experiences and opinions regarding these pulmonary problems, a study-specific survey was developed. The survey was sent by email to head and neck surgeons from ten different countries. In the medical record study, an average of 0.129 respiratory infections per patient/year was found in non-HME users and 0.092 in HME users. In the survey (response rate HN surgeons 20 %; countries 90 %) 0.285 episodes per patient/year in non-HME users was statistically higher than the 0.066 episodes per patient/year in HME users. The average mortality in the HME user group per entire career of each physician was estimated at 0.0045, and for the non-HME user group this was 0.0152. There is a tendency that the number of tracheobronchitis and pneumonia episodes in non-HME users is higher than in HME users.

Background: The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint (R)) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates. Methods: Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n = 427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 1030 mm, grade II, age 40-70; (2) ductal, oestrogen receptor-positive, tumour diameter 530 mm, grade II/III and age 40-70. Results: Based on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were (sic)26,786 for the 70-gene and (sic)29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature. Conclusions: The use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.

The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1-3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability

BackgroundMenopausal symptoms are common and may be particularly severe in younger women who undergo treatment-induced menopause. Medications to reduce menopausal symptoms are either contra-indicated or have bothersome side effects. Previous studies have demonstrated that face-to-face cognitive behavioral therapy (CBT) is effective in alleviating menopausal symptoms in women with breast cancer. However, compliance with face-to-face CBT programs can be problematic. A promising approach is to use the Internet to make this form of CBT more accessible and feasible for patients. This study is evaluating the efficacy and cost-effectiveness of an Internet-based CBT program, with or without therapist guidance, in alleviating or reducing the severity of menopausal symptoms.Methods/designIn a multicenter, randomized controlled trial we are evaluating the efficacy of two Internet-based CBT programs in alleviating or reducing the impact of menopausal symptoms, and particularly hot flushes and night sweats, in breast cancer survivors who have experienced a treatment-induced menopause. Secondary outcomes include sexual functioning, sleep quality, hot flush frequency, psychological distress, health-related quality of life and cost-effectiveness. We will recruit 248 women who will be randomized to either a therapist guided or a self-management version of the 6-week Internet-based CBT program, or to a usual care, waiting list control group. Self-administered questionnaires are completed at baseline (T0), and at 10 weeks (T1) and 24 weeks (T2) post-randomization.DiscussionInternet-based CBT is a potentially useful treatment for reducing menopausal symptoms in breast cancer survivors. This study will provide evidence on the efficacy and cost-effectiveness of such an Internet-based CBT program, with or without therapist support. If demonstrated to be efficacious and cost-effective, the availability of such structured supportive intervention programs will be a welcome addition to standard medical treatment offered to cancer patients with treatment-induced menopause.Trial registrationThe study is retrospectively registered at ClinicalTrials.gov on January 26th 2016 (NCT02672189).

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.

Monitoring therapeutic response to neoadjuvant chemotherapy(NAC) is likely to improve NAC effectiveness in breast cancer(BC). Imaging performance seems to vary per tumour subtype(by ER and HER2 status), therefore we performed a systematic review on subtype specific imaging performance in monitoring NAC in BC. Studies examining imaging performance in predicting pathologic complete response(pCR) during NAC in BC subtypes were selected. Per study, negative- and positive predictive value, sensitivity(se) and specificity(sp), AUC and accuracy were derived. Fifteen/106 articles were included. Inter-study variability was revealed in: monitoring interval, response and pCR definitions. In ER-positive/HER2-negative BC, 181F FDG-PET/CT showed se/sp of 38%–89%/74%–100%, MRI showed se/sp of 35%–37%/87%–89%. In triple negative BC, 181F FDG-PET/CT showed se/sp of 0%–79%/95%–100%. 181F FDG-PET/CT showed in ER-positive/HER2-positive BC se/sp of 59%/80% and in ER-negative/HER2-positive 27%/88%. Evidence on imaging performance in monitoring NAC according BC subtypes is lacking. Consensus should be reached in: definitions of pCR, response and monitoring interval before starting well-designed studies.

Both the 70-gene signature and the 21-gene assay are novel prognostic tests used to guide adjuvant chemotherapy decisions in patients with early breast cancer. Although the results of ongoing prospective trials will only become available in some years, the tests have already been included in clinical guidelines such as St. Gallen’s. In literature, the cost-effectiveness (CE) of both tests as compared to conventional prognostic tests has been described. We report on a direct comparison of CE; as different compliance rates were reported, we also taken these into account. A Markov decision model with a time horizon of 20 years was developed to assess the effects, costs and CE of three alternatives; 21-gene, 70-gene, and St. Gallen (SG) or Adjuvant Online (AO), dependent on the dataset used in patients with early, node-negative, breast cancer. Sensitivity and specificity were based on two datasets, incorporating compliances rates based on literature. For both datasets, whereas the 70-gene signature yielded more quality adjusted life years (QALYs) and was less costly; the 21-gene amounted more life years (LYs) but was more costly. The decision uncertainty surrounding the probability of CE of the Thomassen-series amounted 55% for both cost/LY and cost/QALY, for the Fan-series 80% for LY and 65% for QALYs. Taking reported compliance with discordant test results into account, in general, the effect of all strategies decreased, while the costs increased, without relatively influencing the CEA performance. This comparison indicates that the performances of the 70-gene and the 21-gene based on reported studies are close. The 21-gene has the highest probability of being cost-effective when focusing on cost/LY, while focusing on cost/QALY, the 70-gene signature was most cost-effective. The level of compliance can have serious impact on the CE. With additional data, preferably from head-to-head outcome studies and especially on compliance concerning discordant test results, calculations can be made with higher degrees of certainty.

We sought to compare the molecular signature of node negative cancers from two cohorts 15 years apart, to determine if there is molecular evidence of increase in low and ultralow risk cancers over time. We studied the impact of age, time period of diagnosis, and mammographic screening on biology of tumors where The Netherlands Cancer Institute 70-gene prognosis signature was generated as part of 2 validation series, one retrospective (1984-1992), Cohort 1, and one prospective (2004-2006), Cohort 2. A total of 866 patients were analyzed. Regardless of time period of diagnosis, the proportion of T1, grade 1, hormone receptor positive (HR) tumors, and good prognosis by 70-gene signature significantly increases as age increases (P < 0.01). In women aged 49-60, the time period of diagnosis significantly affects the proportion of cancers that were NKI 70-gene low risk: 40.6% (67/165) compared with 58% (119/205) for Cohorts 1 and 2, respectively. This is in contrast to the absence of a significant change for women under age 40, where 25% (17/68) and 30% (17/56) were low risk in Cohorts 1 and 2, respectively. In women aged 49-60, using an ultralow risk threshold of the 70-gene signature, 10% of tumors in Cohort 1 were ultralow risk compared with 30% for women with screen-detected cancers in Cohort 2. Older age and method of detection (screening) are associated with a higher likelihood of a biologically low risk tumor. In women over age 50, biologically low risk tumors are frequent and tools that classify risk may minimize overtreatment.

Smoking is the main causative factor for development of head and neck and lung cancer. In addition, other malignancies such as bladder, stomach, colorectal, kidney and pancreatic cancer have a causative relation with smoking. Continued smoking after having been diagnosed with cancer has many negative consequences: effectiveness of radiotherapy is diminished, survival time is shortened and risks of recurrence, second primary malignancies and treatment complications are increased. In view of the significant health consequences of continued smoking, therefore, additional support for patients to stop smoking seems a logical extension of the present treatment protocols for smoking-related cancers. For prospectively examining the effect of nursing-delivered smoking cessation programme for patients with head and neck or lung cancer, 145 patients with head and neck or lung cancer enrolled into this programme over a 2-year period. Information on smoking behaviour, using a structured, programme specific questionnaire, was collected at baseline, and after 6 and 12 months. At 6 months, 58 patients (40%) had stopped smoking and at 12 months, 48 patients (33%) still had refrained from smoking. There were no differences in smoking cessation results between patients with head and neck and lung cancer. The only significant factor predicting success was whether the patient had made earlier attempts to quit smoking. A nurse-managed smoking cessation programme for patients with head and neck or lung cancer shows favourable long-term success rates. It seems logical, therefore, to integrate such a programme in treatment protocols for smoking-related cancers.

Background: Genomic recurrence risk test results now inform clinical decisions about adjuvant treatment for women with early-stage breast cancer. We sought to understand patients' knowledge of these tests and correlates of their knowledge. Methods: Participants in this cross-sectional study were 78 women, treated for early-stage, estrogen receptor-positive breast cancer with 0–3 positive lymph nodes, whose medical records indicated they received Oncotype DX testing earlier. We mailed a questionnaire that assessed knowledge of genomic recurrence risk testing (13 item scale, alpha=0.83) and reviewed medical charts of consenting patients. Results: Knowledge about genomic recurrence risk testing was low (mean knowledge score=67%, SD=0.23). Low knowledge scores were more commonly due to responses of ‘don't know’ than incorrect answers. Most women (91%) clearly understood that test results can aid decisions about chemotherapy, and few (22%) understood that the test's estimate of the chance of metastasis assumes the patient is receiving hormone therapy. Higher knowledge about genomic recurrence risk testing was associated with higher education, reading ability, and numeracy. Knowledge was higher among women who recalled receiving both verbal and printed information about the test and among women who had active roles in deciding about their treatments. Higher knowledge was also associated with having fewer concerns about genomic testing. Discussion: Among early-stage breast cancer patients who received Oncotype DX, we found low knowledge about many aspects of genomic recurrence risk testing. Research is needed to understand testing information provided to patients and best practices for patient education. Copyright © 2010 John Wiley & Sons, Ltd.

Background: The 70-gene signature (MammaPrint (R)) is a prognostic test used to guide adjuvant treatment decisions in patients with node-negative breast cancer. In order to decide upon its use, a systematic comparative analysis of the effects of the 70-gene signature, the Sankt Gallen guidelines and the Adjuvant Online Software for these patients on survival, quality of life and costs is warranted. Methods: A Markov decision model was used to simulate the 20-year costs and outcomes (survival and quality-of-life adjusted survival (QALYs)) in a hypothetical cohort of node-negative, estrogen receptor positive breast cancer patients. Sensitivity and specificity of the three prognostic tools were based on 5 and 10 years breast cancer specific survival and distant metastasis as first event, derived from a pooled analysis consisting of 305 tumour samples from 3 previously reported validation studies concerning the 70-gene signature. Results: Small differences in survival, but substantial differences in quality-adjusted survival between the prognostic tools were observed. Quality-adjusted survival was highest when using the 70-gene signature. Based on costs per QALY, the 70-gene has the highest probability of being cost-effective for a willingness to pay for a QALY higher than (sic)4600. Sankt Gallen showed the highest survival rates compared to the 70-gene signature, but leads to a substantial larger amount of adjuvant chemotherapy and hence higher costs, thus demanding a willingness to pay of (sic)29.326 to save a life year. Conclusions: When deciding upon the cost-effectiveness of the prognostic tests, the 70-gene signature improves quality-adjusted survival and has the highest probability of being cost-effective.

Objectives:Constructive Technology Assessment (CTA) is a means to guide early implementation of new developments in society, and can be used as an evaluation tool for Coverage with Evidence Development (CED). We used CTA for the introduction of a new diagnostic test in the Netherlands, the 70-gene prognosis signature (MammaPrint®) for node-negative breast cancer patients.Methods:Studied aspects were (organizational) efficiency, patient-centeredness and diffusion scenarios. Pre-post structured surveys were conducted in fifteen community hospitals concerning changes in logistics and teamwork as a consequence of the introduction of the 70-gene signature. Patient-centeredness was measured by questionnaires and interviews regarding knowledge and psychological impact of the test. Diffusion scenarios, which are commonly applied in industry to anticipate on future development and diffusion of their products, have been applied in this study.Results:Median implementation-time of the 70-gene signature was 1.2 months. Most changes were seen in pathology processes and adjuvant treatment decisions. Physicians valued the addition of the 70-gene signature information as beneficial for patient management. Patient-centeredness (n= 77, response 78 percent): patients receiving a concordant high-risk and discordant clinical low/high risk-signature showed significantly more negative emotions with respect to receiving both test-results compared with concordant low-risk and discordant clinical high/low risk-signature patients. The first scenario was written in 2004 before the introduction of the 70-gene signature and identified hypothetical developments that could influence diffusion; especially the “what-if” deviation describing a discussion on validity among physicians proved to be realistic.Conclusions:Differences in speed of implementation and influenced treatment decisions were seen. Impact on patients seems especially related to discordance and its successive communication. In the future, scenario drafting will lead to input for model-based cost-effectiveness analysis. Finally, CTA can be useful as a tool to guide CED by adding monitoring and anticipation on possible developments during early implementation, to the assessment of promising new technologies.

Previous studies have shown that a “Preventive Exercise Program” (PREP) is cost-effective compared to the standard exercise program provided in “Usual Care” (UC) in patients with advanced head and neck cancer. The current paper specifically estimates the cost-effectiveness of the TheraBite jaw rehabilitation device (TB) which is used as part of the PREP, compared to Speech Language Pathology (SLP) sessions as part of UC, and herewith intents to inform reimbursement discussions regarding the TheraBite device. Costs and outcomes [quality-adjusted life-years (QALYs)] of the TB compared to SLP were estimated using a Markov model of advanced head and neck cancer patients. Secondary outcome variables were trismus, feeding substitutes, facial pain, and pneumonia. The incremental cost-effectiveness ratio (ICER) was estimated from a health care perspective of the Netherlands, with a time horizon of 2 years. The total health care costs per patient were estimated to amount to €5,129 for the TB strategy and €6,915 for the SLP strategy. Based on the current data, the TB strategy yielded more quality-adjusted life-years (1.28) compared to the SLP strategy (1.24). Thus, the TB strategy seems more effective (+0.04) and less costly (−€1,786) than the SLP only strategy. At the prevailing threshold of €20,000/QALY the probability for the TB strategy being cost-effective compared to SLP was 70 %. To conclude, analysis of presently available data indicates that TB is expected to be cost-effective compared to SLP in a preventive exercise program for concomitant chemo-radiotherapy for advanced head and neck cancer patients.

Purpose Guiding response to neoadjuvant chemotherapy (guided-NACT) allows for an adaptative treatment approach likely to improve breast cancer survival. In this study, our primary aim is to explore the expected cost-effectiveness of guided-NACT using as a case study the first randomized controlled trial that demonstrated effectiveness (GeparTrio trial). Materials and Methods As effectiveness was shown in hormone-receptor positive (HR+) early breast cancers (EBC), our decision model compared the health-economic outcomes of treating a cohort of such women with guided-NACT to conventional-NACT using clinical input data from the GeparTrio trial. The expected cost-effectiveness and the uncertainty around this estimate were estimated via probabilistic cost-effectiveness analysis (CEA), from a Dutch societal perspective over a 5-year time-horizon. Results Our exploratory CEA predicted that guided-NACT as proposed by the GeparTrio, costs additional €110, but results in 0.014 QALYs gained per patient. This scenario of guided-NACT was considered cost-effective at any willingness to pay per additional QALY. At the prevailing Dutch willingness to pay threshold (€80.000/QALY) cost-effectiveness was expected with 78% certainty. Conclusion This exploratory CEA indicated that guided-NACT (as proposed by the GeparTrio trial) is likely cost-effective in treating HR+ EBC women. While prospective validation of the GeparTrio findings is advisable from a clinical perspective, early CEAs can be used to prioritize further research from a broader health economic perspective, by identifying which parameters contribute most to current decision uncertainty. Furthermore, their use can be extended to explore the expected cost-effectiveness of alternative guided-NACT scenarios that combine the use of promising imaging techniques together with personalized treatments.

In a recent report, Bonastre et al1 calculated the cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer and concluded that, under the present circumstances in France, the 70-gene signature (MammaPrint) is unlikely to be cost effective.

Background: Metastatic melanoma has a poor prognosis with 10 year survival being < 5%. Standard therapy in the Netherlands is the effective but costly Ipilimumab. An emerging 1st line immunotherapy is Tumor Infiltrating Lymphocytes (TIL)-treatment, with response rates > 50% and expected survival rates of 25%-42% versus 45% (1yr) and 23.5% (2yr) for Ipilimumab. TIL is highly personalized, however complex and requests substantial upfront investments from the hospital in expensive lab-equipment, staff expertise and training. Therefore, an exploratory projection of its impact on patient outcomes and health care costs was made using health economic modelling. Methods: A Markov decision model including three health states (stable disease, progressive disease and death) was developed to estimate the expected costs and outcomes (quality adjusted life years; QALYs) for TIL versus Ipilimumab in metastatic melanoma patients from a societal perspective over a life long time horizon. Data sources include a pilot study and published literature. Technical failures and treatment non-compliance were incorporated in the analysis to reflect real world effectiveness. Results: TIL is expected to improve QALYs (+0.39) compared to Ipilimumab at higher incremental cost (+€12.416) with an ICER of €31.000/QALY. It has the highest probability of being cost-effective at WTP values of €30k/QALY (50% certainty) and higher, up to 90% certainty at a WTP of €80k/QALY. The model outcomes are most sensitive to changes in survival estimates. Conclusions: Based on an exploratory analysis,TIL is expected to improve QALYs compared to Ipilimumab at lower incremental cost and has the highest probability of being cost-effective. To reduce decision uncertainty, a future clinical trial to investigate survival should be prioritized.

Objectives: 18F-FDG-PET/CT is accurate in detecting distant metastases (DM) in breast cancer patients scheduled for neoadjuvant chemotherapy. If DMs are screen-detected in an early phase, morbidity and mortality may be reduced. Because 18F-FDG-PET/CT comes at a significant cost, we compared its expected cost-effectiveness in stage II/III breast cancer patients of the UK, the US and the Netherlands (NL) vs. the gold-standard (X-thorax/liver sonography/bone scan (UK/NL) and CT-thorax-abdomen/bone scan (US)). Methods: A time-dependent Markov model compared expected Life Year (LY) and cost/Quality-adjusted Life Year (QALY) gained in four breast cancer subtypes (ER-/HER2+;ER+/HER2+;ER-/HER2-;ER+/HER2-) over a 5-year time horizon from a hospital perspective. Sensitivity and specificity of imaging and type of systemic and local treatments were derived from the Netherlands Cancer Institute. Epidemiological, survival and utility data were estimated from literature or informed by expert assumptions. Costs (2013) were derived from national tariffs (UK and NL), and from the Centres for Medicaid and Medicare Services (US). Results: 18F-FDG-PET/CT is more sensitive (53% vs. 15%) and specific (97% vs. 94%) than the gold-standard. LYs and QALYs gained were similar across subtypes, ranging from 0.025 to 0.027 and 0.0037 to 0.0044 respectively. In all countries, ER+HER2+ was the least and ER+HER2- the most costly group. 18F-FDG-PET/CT is expected to be cost-effective in the NL and the US (with highest ICERs of €165/QALY in ER+/HER2+ and $750 in ER-HER2+), with probabilities of cost-effectiveness ranging from 46-52% and 62-72% respectively, but not in the UK, with a 66-75% probability, depending on tumor subtype. Conclusions: Using 18F-FDG-PET/CT for DM screening in stage II/III breast cancer is expected to result in incremental QALY gains in all subtypes and countries. Due to costs differences between countries, 18F-FDG-PET/CT is expected to be cost-effective in the US and the NL, but not in the UK.

Background: In early stage breast cancer patients, with axillary lymph node metastasis, the 70-gene signature, MammaPrint® (MP) identifies patients with a High or Low Risk of distant breast cancer (BC) recurrence. For MP Low Risk (G(enomic)-low) in patients with up to 3 positive lymph nodes (N1-3), the MINDACT trial (Cardoso, NEJM 2016) showed that it might be safe to forgo adjuvant chemotherapy. Here we evaluated the prognostic value of MP at 10 years follow-up in patients with lymph node positive early stage BC. Methods: Between 2004 and 2006 812 women with early stage BC participated in the observational RASTER trial (Bueno de Mesquita, Lancet Oncol, 2007). 181 patients were node positive and not included in the primary analysis, 176 of them gave consent for future research. On 164 tumor samples (FFPE) MP was performed retrospectively. Survival data was collected and samples were allocated to clinical high (C-high) or C-low risk as used in MINDACT. Patients with over 3 axillary lymph node metastases (N4+) were all considered C-high. 10-year distant-recurrence-free-interval (DRFI) was compared between subgroups based on the MP and clinical assessment. Results: In 3 patients the clinical assesment could not be determined. Over 95% of patients received chemotherapy, 82.9% (136/164) of tumors were ER-positive and 18.3% (30/164) of patients had N4+. MP identified 47% (n = 77/164) as Low Risk, including 16,9% (13/77) with N4+. 10-year DRFI in patients N1-3 and G-Low or G-High was 94.9% and 80.7% respectively (HR 4.7; 95%CI 1.3-16.2). With the clinical assessment 13.7% (n = 22/161) were low risk, only one was diagnosed with distant BC recurrence. 10-years DRFI was 94.4% in C-low and 85.8% in C-high (HR 3.7 95%CI 0.5-28.5). In N4+ 10-years DRFI was 69.7%. Combining the clinical assessment with MP risk assessment in patients N1-3 the 10-years DRFI in clinical high risk patients was 95.2% for G-Low (n = 44) and 79.6% for G-High (n = 65) (HR 4.83 95%CI 1.1-21.4). Conclusions: We again confirm the prognostic value of Mammaprintin BC patients with axillary lymph node involvement after 10 years follow up. In N1-3 patients with clinical high risk, MP can identify a subgroup with excellent prognosis after standard adjuvant systemic therapy

Background: The objective of this population-based study was to assess patient, physician and tumour determinants associated with positive surgical margins after prostatectomy, and to assess the effects of positive surgical margins on prostate cancer-specific survival. Methods: We included 1’254 prostate cancer patients recorded at the Geneva Cancer Registry who had radical prostatectomy during 1990–2008. To assess factors associated with positive margins, we used logistic regression. We assessed the effects of positive margins on prostate cancer-specific survival by Cox proportional hazard models accounting for numerous other prognostics factors including prostate and tumour volume, the total percentage of tumour, radiotherapy, surgical approach and surgeon’s caseload. Results: Among men undergoing prostatectomy, 479 (38%) had positive margins. In the multivariate logistic regression analysis, period, clinical- and pathological T stage, Prostate Specific Antigen (PSA) level, Gleason score and percentage of tumour in the prostate were significantly associated to positive margins. Ten-year prostate cancer-specific survival was 96.6% for the negative margins group and 92.0% for the positive margins group (log rank p = 0.008). In the Cox survival analysis adjusted for tumour characteristics, surgical margin status per se was not an independent prognostic factor while age, pathological T, PSA level and Gleason score remained associated with prostate cancer-specific survival. Conclusions: More aggressive tumour characteristics were strong determinants for positive margins. Furthermore, surgical margin status per se was not an independent prognostic factor for prostate cancer-specific survival after adjusting by the gravity of the disease in the multivariate analysis.