Personalized surveillance and aftercare for non-metastasized breast cancer: the NABOR study protocol of a multiple interrupted time series design.

BACKGROUND: Follow-up of curatively treated primary breast cancer patients consists of surveillance and aftercare and is currently mostly the same for all patients. A more personalized approach, based on patients' individual risk of recurrence and personal needs and preferences, may reduce patient burden and reduce (healthcare) costs. The NABOR study will examine the (cost-)effectiveness of personalized surveillance (PSP) and personalized aftercare plans (PAP) on patient-reported cancer worry, self-rated and overall quality of life and (cost-)effectiveness. METHODS: A prospective multicenter multiple interrupted time series (MITs) design is being used. In this design, 10 participating hospitals will be observed for a period of eighteen months, while they -stepwise- will transit from care as usual to PSPs and PAPs. The PSP contains decisions on the surveillance trajectory based on individual risks and needs, assessed with the 'Breast Cancer Surveillance Decision Aid' including the INFLUENCE prediction tool. The PAP contains decisions on the aftercare trajectory based on individual needs and preferences and available care resources, which decision-making is supported by a patient decision aid. Patients are non-metastasized female primary breast cancer patients (N = 1040) who are curatively treated and start follow-up care. Patient reported outcomes will be measured at five points in time during two years of follow-up care (starting about one year after treatment and every six months thereafter). In addition, data on diagnostics and hospital visits from patients' Electronical Health Records (EHR) will be gathered. Primary outcomes are patient-reported cancer worry (Cancer Worry Scale) and overall quality of life (as assessed with EQ-VAS score). Secondary outcomes include health care costs and resource use, health-related quality of life (as measured with EQ5D-5L/SF-12/EORTC-QLQ-C30), risk perception, shared decision-making, patient satisfaction, societal participation, and cost-effectiveness. Next, the uptake and appreciation of personalized plans and patients' experiences of their decision-making process will be evaluated. DISCUSSION: This study will contribute to insight in the (cost-)effectiveness of personalized follow-up care and contributes to development of uniform evidence-based guidelines, stimulating sustainable implementation of personalized surveillance and aftercare plans. TRIAL REGISTRATION: Study sponsor: ZonMw. Retrospectively registered at ClinicalTrials.gov (2023), ID: NCT05975437.

Health-state utilities in long-term advanced melanoma survivors comparable with the general population.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (ß = - .82, p = .022) and fatigue burden (ß = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Clinical implementation of routine diagnostic laparoscopy to guide initial treatment in patients with advanced-stage epithelial ovarian cancer in Dutch clinical practice: Evaluation of support and a budget impact analysis.

OBJECTIVE: In patients with advanced-stage epithelial ovarian cancer (EOC), a diagnostic laparoscopy (DLS) to determine treatment regime prevents futile laparotomies and seems cost-neutral. The uptake of DLS in current practice is unknown. We evaluated the clinical application of routine DLS in treatment planning in patients with advanced-stage EOC in the Netherlands. METHODS: The implementation was evaluated over the period 2017-2019, using a health technology assessment including clinical, organizational, and economic factors. Barriers for implementation were identified and DLS use was assessed using semi-structured surveys with healthcare professionals. Data from the Dutch Gynecological Oncology Audit were used to determine (un)successful CRS rates. To assess the economic impact, we performed a budget impact analysis (BIA) of the combined interventions of DLS and primary CRS. RESULTS: The DLS use to guide treatment planning increased from 16% to 20%. The majority of the centers did not support routine DLS implementation, mainly because of logistic barriers and its invasive nature. The primary CRS rate of all CRS decreased from 44% to 36%, in favor of interval CRS. The unsuccessful primary CRS rate decreased from 15% to 9% resulting in fewer patients needed a second interval CRS. Consequently, total health care costs decreased from €4.457.496 to €4.274.751. CONCLUSIONS: The implementation of routine DLS for guiding treatment planning in patients with advanced-stage EOC has limited support in the Netherlands. Over the years, total health care costs decreased. For current practice, it is advised that a DLS is useful in case it is uncertain whether a successful primary CRS is feasible based on conventional work-up.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

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 < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

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

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

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

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

The multigene signature MammaPrint impacts on multidisciplinary team decisions in ER+, HER2- early breast cancer.

BACKGROUND: Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER(+), HER2(-) early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations. METHODS: We prospectively recruited 75 ER(+), HER2(-) breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness. RESULTS: The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective. CONCLUSIONS: The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.

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

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

Factors for a broad technology assessment of comprehensive genomic profiling in advanced cancer, a systematic review.

Comprehensive Genomic Profiling (CGP) allows for the identification of many targets. Reimbursement decision-making is, however, challenging because besides the health benefits of on-label treatments and costs, other factors related to diagnostic and treatment pathways may also play a role. The aim of this study was to identify which other factors are relevant for the technology assessment of CGP and to summarize the available evidence for these factors. After a scoping search and two expert sessions, five factors were identified: feasibility, test journey, wider implications of diagnostic results, organisation of laboratories, and "scientific spillover". Subsequently, a systematic search identified 83 studies collecting mainly evidence for the factors "test journey" and "wider implications of diagnostic results". Its nature was, however, of limited value for decision-making. We recommend the use of comparative strategies, uniformity in outcome definitions, and the inclusion of a comprehensive set of factors in future evidence generation.

A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study.

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 <90% was defined as high-risk). Median follow-up was 61.6 months. Fifteen percent (33/219) of the 70-gene signature low-risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70-gene signature high-risk patients. The 5-year DRFI probabilities for 70-gene signature low-risk (n = 219) and high-risk (n = 208) patients were 97.0% and 91.7%. The 5-year DRFI probabilities for AOL low-risk (n = 132) and high-risk (n = 295) patients were 96.7% and 93.4%. For 70-gene signature low-risk-AOL high-risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5-year DRFI was 98.4%. In the AOL high-risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70-gene signature was used. In this prospective community-based observational study, the 5-year DRFI probabilities confirmed the additional prognostic value of the 70-gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low-risk 70-gene signature result, appeared not to compromise outcome.

"One more chance to survive": the experiences of patients with advanced melanoma and their partners with tumor-infiltrating lymphocyte therapy-a qualitative study and recommendations for future care.

PURPOSE: Patients with advanced melanoma refractory to first-line treatment have a need for effective second-line treatment options. A recent phase 3 trial showed promising results for adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) as second-line therapy in patients with advanced melanoma. However, it remains unknown how patients and their partners experience TIL therapy, which is key to evaluate and improve the quality of care. METHODS: Semi-structured interviews about the experience of TIL therapy were conducted with patients with advanced melanoma and their partners 2-4 weeks post-treatment (short term) and >6 months after treatment (long term). RESULTS: In total, 25 interviews were conducted with advanced melanoma patients treated with TIL (n=13) and their partners (n=12), with the majority being short-term interviews (n=17). Overall, patients and partners experienced TIL therapy as intense (uncertainty of successful TIL culture, multiple treatment-related toxicities, and extensive hospitalization). Patients and partners with young children or other caregiving responsibilities encountered the most challenges during TIL therapy. All patients, however, reported a recovery of all treatment-related toxicities within 2-4 weeks (except fatigue). CONCLUSION: Clinical data justify the role of TIL therapy in the treatment of advanced melanoma. With the distinct nature of TIL therapy compared to the current standard of care, we have provided patient-centered recommendations that will further enhance the quality of TIL therapy. IMPLICATIONS FOR CANCER SURVIVORS: As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL.

Integration of a smoking cessation program in the treatment protocol for patients with head and neck and lung cancer.

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.

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

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

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

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