External beam radiation therapy versus radical prostatectomy for high-risk prostate cancer: protocol of the RECOVER study

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Bangma, Maarten J. Bijlsma, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3999440/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2025 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Background: This paper describes the rationale and design of the RECOVER study. Currently, there is no consensus regarding the optimal treatment for high-risk, non-metastatic prostate cancer (PCa). The study primarily aims to evaluate and compare the impact of treatment with robot-assisted radical prostatectomy (RP) versus external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT) for men with high-risk, non-metastatic PCa regarding health-related quality of life (HRQoL) and functional outcomes. Secondary objectives are progression-free survival (PFS), distant metastasis-free survival (DMFS), costs and cost-effectiveness. Methods: The RECOVER study is a comparative effectiveness study that prospectively includes newly diagnosed high-risk (cT3a-bN0M0, ISUP-grade ≥ 4 and/or PSA >20 ng/mL), non-metastatic PCa patients. Four Dutch prostate cancer networks, comprising 28 hospitals, are currently participating in the study. Patient reported outcomes are collected before treatment initiation, 12 months and 36 months after treatment initiation and include the EORTC-QLQ-C30, the EPIC-26, an adapted version of the SCQ, an adapted version of the iMTA Productivity Cost Questionnaire and several specific questions regarding patient characteristics, treatment of PCa specific complaints and health resources used. Clinical data regarding patient-, tumor- and treatment characteristics and oncological outcomes are collected up to 5 years after diagnosis. For sufficient power, patient reported outcomes of 471 patients must be collected 36 months after treatment initiation. Descriptive statistics and mixed-effects models are used to assess differences in HRQoL and functional outcomes over time between the patients treated with radical prostatectomy versus EBRT (+ ADT). Inverse probability of treatment weighting or the g-formula are used to adjust for confounding covariates associated with treatment. Secondary endpoints PFS and DMFS are evaluated using a competing risk analysis and cost-utility and budget-impact analyses will be performed to determine cost and cost-effectiveness. Discussion: An observational prospective design was chosen since a randomized controlled trial comparing surgery and radiotherapy was not deemed feasible. This study evaluates effectiveness of treatment in a routine clinical setting (with adjustment for confounding) and its findings will enhance patients’ and healthcare professionals’ awareness for the impact of both treatment modalities on (long-term) daily functioning and HRQoL and aid treatment decision making. Trial registration: This study is registered at ClinicalTrials.gov (NCT05931419). Prostate cancer Patient Reported Outcomes Health-Related Quality Of Life Prostatectomy / methods Prostatic neoplasm / radiotherapy Prostatic neoplasms / surgery androgens Cost Effectiveness Progression Free Survival Distant metastasis free survival Background Approximately 15–18% of all prostate cancer diagnoses concern high-risk, non-metastatic prostate cancer (PCa) ( 1 – 3 ). High-risk PCa is a heterogenous disease with increased risk of biochemical recurrence, metastatic progression and death from PCa as compared to low- or intermediate-risk localized disease ( 4 – 6 ). Treatment modalities widely used for high-risk PCa are (robot-assisted) radical prostatectomy (RP) and external beam radiation therapy (EBRT), the latter generally combined with androgen deprivation therapy (ADT). Currently, there is no consensus regarding the optimal treatment for high-risk PCa ( 7 ). This is also reflected in the substantial interhospital treatment variation in the Netherlands ( 8 ). High-level comparative evidence regarding the optimal treatment for high-risk PCa is lacking. Several non-randomized studies have compared oncological outcomes between treatment with RP versus EBRT. Most were retrospective in nature and were performed in a single-institution. These studies did not show clear differences in five-year prostate cancer specific survival (PCSS) and overall survival (OS) ( 9 – 14 ). Due to variation in the definition of high-risk prostate cancer and differences in applied surgical and radiotherapy treatment strategies, definitive conclusions cannot be drawn ( 9 ). However, survival was generally good with reported five-year OS and PCSS rates exceeding 90% ( 9 – 14 ). In a recent systematic review we summarized evidence for patient reported functional outcomes and HRQoL after RP compared to EBRT for high-risk, non-metastatic PCa ( 9 ). Three observational studies focused on differences in functional outcomes and HRQoL between RP and EBRT with ADT for high-risk PCa. Overall, sexual dysfunction and genitourinary toxicity were reported more often after RP, while reduced hormonal function and gastro-intestinal toxicity were more common after EBRT combined with ADT ( 12 , 15 , 16 ). However, due to the limited number of studies, the variation in the definition of high-risk PCa and the differences in methods and measurement instruments, the extent of the effect of both treatment modalities on functional outcomes and HRQoL remains largely unknown. Hence, it remains uncertain whether either treatment is superior with respect to functional outcomes and HRQoL as well as oncological outcomes. Here we present the RECOVER study (High-Risk prostatE Cancer radiatiOn Versus surgERy) as a means to address these knowledge gaps. The study is primarily designed to evaluate and compare the impact of treatment with RP versus EBRT with ADT on functional outcomes and HRQoL for men with high-risk, non-metastatic PCa. Our study aims to enhance awareness of both patients and healthcare professionals regarding these effects of treatment. By incorporating our findings into a patient decision aid, it could support patients in making a well-informed treatment decision. Moreover, providing insight into the impact of both treatments could lead to a reduction in interhospital and inter-physician variability and improvement in quality of care facilitated by the adjustment and/or refinement of treatment recommendations concerning this patient population in (inter)national guidelines. Methods Design and collaboration The RECOVER study is a comparative effectiveness study that prospectively includes patients with high-risk, non-metastatic PCa to compare treatment with robot assisted radical prostatectomy (RARP) versus EBRT combined with ADT. The study is executed by a cooperation of the Netherlands Comprehensive Cancer Organization (IKNL), the Dutch Association for Urology (NVU) and the Dutch Society of Radiotherapy and Oncology (NVRO). The study is performed in close collaboration with the Dutch Prostate Cancer Foundation (Prostaatkankerstichting [PKS]). Currently, 28 hospitals collaborating in four Dutch prostate cancer networks participate in the study, collectively covering 40% of all newly diagnosed prostate cancer patients in the Netherlands. ClinicalTrials.gov provides an up-to-date overview of all participating hospitals ( 17 ). Healthcare providers from hospitals in a prostate cancer network discuss patient, tumor and other relevant characteristics in multidisciplinary team meetings (MDTMs) to achieve the most optimal treatment based on evidence-based guidelines and tailored to the patient. For this study, eligibility of a patient for treatment with both RARP and EBRT with ADT is discussed in these meetings. The participating networks are geographically distributed across the Netherlands and each network consists of at least one university hospital and several non-university teaching hospitals and general hospitals. In the Netherlands, surgical treatment of PCa is centralized in 14 hospitals that meet the minimum hospital volume norm of 100 RARP procedures per year ( 18 ). Within each prostate cancer network, all RARP treatments are centralized in one hospital. Radiation therapy is centralized to 20 institutions across the Netherland and is performed in nine of the participating hospitals. Patient population Patients with histologically confirmed high-risk, non-metastatic PCa diagnosed or treated in one of the participating hospitals are eligible for inclusion. Various (inter)national risk classifications and guidelines define high-risk PCa with subtle differences. In this study, high-risk, non-metastatic PCa is defined as cT3a-bN0M0 disease, and/or ISUP grade ≥ 4 and/or a PSA value at diagnosis above 20 ng/mL. Prostate cancer is staged according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification with the exception that T-stage will be based on either digital rectal examination (DRE) or magnetic resonance imaging (MRI), whichever is highest ( 19 , 20 ). Patients must be aged 50 to 75 years, fit (WHO performance status 0–1) and eligible (i.e. no contra-indications) for both RARP and ERBT with ADT. Moreover, patients have to reside in the Netherlands and be able to read and understand Dutch language. Patients with histological PCa types other than adenocarcinoma and those that are diagnosed or treated in a hospital abroad are excluded. Patients treated with androgen receptor signaling inhibitor (ARSI)/androgen receptor targeted agents (ARTA) as part of the initial treatment plan are also excluded. Treatment RARP may be part of a multimodal therapy with (neo)adjuvant ADT and/or adjuvant radiotherapy. A pelvic lymph node dissection (PLND) may be performed for staging purposes. The presence of positive lymph nodes (pN1) upon PLND is not a reason for exclusion and may be followed by adjuvant treatment e.g. lymph node irradiation and/or ADT. Regarding EBRT, the study allows for dose-escalation using intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) or stereotactic radiation. Dose-escalation is defined as a biologically effective dose (BED) converted to 2Gy fractions (using a α/β ratio of 1.5) of at least 76Gy. Both conventionally fractionated and hypofractionated regimens may be used and patients may receive an integrated boost to visible intraprostatic lesions, a low dose rate (LDR) brachytherapy boost or a high dose rate (HDR) brachytherapy boost. In addition, treatment with ADT should be given for a period of at least 6 months. Similar to radical prostatectomy, PLND may be performed for staging purposes and pN1 is no reason for exclusion. Study endpoints The primary endpoints of the RECOVER study are functional outcomes and HRQoL 36 months after treatment initiation. These endpoints are measured with the validated Dutch versions of the Expanded Prostate Cancer Index Composite-26 (EPIC-26) ( 21 ) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30) ( 22 ). We assume that the long-term effects of treatment, including the effects of ADT (patients eligible for inclusion generally receive ADT for 6 to 24 months), have stabilized 36 months after treatment initiation. Secondary study endpoints are progression-free survival (PFS), distant metastasis-free survival (DMFS), cost and cost-effectiveness. Cost and cost-effectiveness will be evaluated 36 months after treatment initiation. PFS and DMFS are evaluated at 5 years after diagnosis. Patient inclusion Eligible patients are informed about the study by their physician (or research nurse/nurse specialist) shortly after diagnosis. Study information is provided to the patient after which the patient has time to decide whether to participate in the study. Patient information is set up in such a way that it appeals to patients of diverse backgrounds. Patients willing to participate provide written informed consent and administrative data are entered in an online registration tool. Inclusion is finalized when the patient completes the first questionnaires before treatment initiation (baseline measurement). In some hospitals, the EPIC-26 and EORTC-QLQ-C30 are administered as part of the regular care. To minimize patient burden, these questionnaires are reused if possible. Data collection Patient reported outcome measures (PROMs) The EPIC-26 is an instrument developed and validated for the comprehensive assessment of HRQoL in men with PCa ( 21 ). It is one of the best rated instruments for this purpose ( 23 ) and consists of 5 symptom domains: urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal. Questionnaire items are converted to domain scores between 0 to 100, with a higher score representing a better function. Threshold values for a clinically meaningful change (minimal clinically important difference [MCID]) have been determined for each EPIC-26 domain: 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, 4 to 6 for bowel function, 10 to 12 for sexual function and 4 to 6 for hormonal function ( 24 ). The EORTC-QLQ-C30 is a widely used measurement instrument to assess HRQoL of cancer patients ( 22 ). The questionnaire includes five functional domains (physical, role, cognitive, emotional and social), three symptom domains (fatigue, pain, nausea and vomiting) a global health/quality of life scale and several single-item measures. For each domain and single item measure, a score from 0 to 100 can be calculated. For the functional domains and global score, higher scores indicate a better quality of life. In contrast, for the symptom domains and single item measures, a higher score represents a higher level of symptomatology ( 22 ). Musoro et al. have provided minimal important differences for within-group change and between-group change per EORTC QLQ-C30 scale for nine cancer types, amongst which prostate cancer ( 25 ). In addition, patients are asked to complete an edited version of the self-administered comorbidity questionnaire (SCQ) and an adapted version of the Institute for Medical Technology Assessment Productivity Cost Questionnaire (iMTA PCQ). The SCQ is a generic questionnaire developed to assess common comorbidities which might impact an individual’s functioning. For each condition, the presence, severity and functional limitation is self-assessed ( 26 ). We have extended the SCQ with conditions that are considered a (relative) contra-indication for RARP or EBRT, e.g. inflammatory bowel disease. The iMTA PCQ is a standardized questionnaire developed to measure and value productivity loss. Productivity loss is measured in three modules being absenteeism, presenteeism and productivity loss of unpaid work ( 27 ). The iMTA PCQ was slightly adapted in collaboration with an expert in health technology assessment by focusing questions regarding unpaid work on volunteer work only. Moreover, we reformulated some questions to make them more easily understandable for the patient. The iMTA PCQ is used to determine indirect non-medical costs. Finally, information is collected regarding patient characteristics, such as living situation, alcohol and smoking behavior and education level, and used health resources for prostate-cancer related problems such as erectile or urinary complaints (e.g. urinary pads, catheter, medication). Information regarding used health resources is collected to determine healthcare costs. Table 1 presents the collected PROs at the various measurement moments. The patient can complete either paper or web-based questionnaires based on their preference. Web-based questionnaires are collected by use of the Profiles Registry (Patient Reported Outcomes Following Initial treatment and Long term Evaluation). Profiles is specialized in collecting, processing and storing PROs of cancer patients ( 28 ) and all data are handled according to the General and Dutch Data Protection Act. Data from the PROFILES registry can be linked to the Netherlands Cancer Registry (NCR), which allows the merging of PROs and clinical data ( 29 ). In order to achieve good response rates, a research assistant monitors the questionnaire response. Patients with incomplete questionnaires will be contacted and information will be complemented as far as possible. Table 1 Overview of the collection of patient reported outcomes in the RECOVER study at the subsequent measurement moments (baseline, T12 and T36) Category Included topics / patient reported outcome measures Baseline T12 T36 Patient characteristics Age, length, height, living situation, alcohol and smoking behavior, education level, participatory decision making style X Comorbidities Adapted version of the SCQ X X X HRQOL and functional outcomes EPIC-26 and EORTC-QLQ-C30 X X X Treatment of PCa specific complaints / additional treatment information Catheter, medication for lower urinary tract symptoms, pelvic floor physical therapy, surgery for urinary loss, erectile medication, use of vacuum pump erectile device, androgen deprivation therapy X X X Productivity loss Adapted version of the iMTA PCQ X X Clinical data In addition to PROs, clinical data regarding patient and tumor characteristics, as well as treatment information, is needed to meet our research objectives. These data are extracted from the Netherlands Cancer Registry (NCR). Maintained by the Netherlands Comprehensive Cancer Organisation (IKNL), the NCR is a nationwide population-based registry that contains information on all newly diagnosed cancer patients in the Netherlands. Clinical data are retrieved from patients electronic health records in the hospitals by well-trained, independent data managers of the NCR. The standard data collection in the NCR is expanded for patients included in this study and includes patient characteristics (i.e. age, height, weight, comorbidities), tumor characteristics (i.e. TNM staging, PSA at diagnosis and Gleason grade on biopsy and prostatectomy if applicable), diagnostic procedures (i.e. imaging, biopsy technique, pelvic lymph node dissection) and treatment information for prostatectomy (i.e. nerve sparing procedure, positive margins, complications) and EBRT (i.e. type of radiotherapy, dose per fraction, integrated/brachytherapy boost, toxicity). In addition, data is collected on all post-treatment PSA measurements, disease progression, subsequent treatments and cause of death until 5 years after diagnosis. Vital status of all patients is updated annually by linkage to the personal records database (BRP) which contains data on the vital status, date of death and emigration status of all Dutch citizens. Moreover, additional clinical data related to volumes of care are collected from the electronic health records to evaluate healthcare costs. In addition to the treatments for prostate cancer, these data include treatments for adverse events, consultations with medical specialists, hospitalizations and medication use. Statistical analysis and sample size Descriptive analyses will be used to provide insight in patient and clinical characteristics of the total study population and of both treatment groups. Mixed-effects models will be used to compare functional outcomes and HRQoL between the two treatment groups over time. Differences in functional outcomes and HRQoL between treatment modalities as measured by the EPIC-26 will be considered clinically meaningful if they are equivalent to or exceed the MCID and are statistically significant at the 0.05 level. The p-value maintained for statistical significance will be adjusted for multiple testing if appropriate. For the EORTC-QLQ-C30, the between-group anchor-based minimally important differences per scale as reported by Musoro et al. will be used to compare treatment groups over time. For scales for which no anchor-based estimates are available, distribution-based estimates will be used ( 25 ). Due to the observational design of the study, we will adjust for confounding covariates associated with treatment with RARP versus EBRT (and ADT) using inverse probability of treatment weighting or the g-formula ( 30 – 33 ). In case of missing values in covariates, multiple imputation procedures will be used ( 34 , 35 ). Competing risk survival analyses will be used to evaluate PFS and DMFS with the competing event being a non-PCa related death. To evaluate incremental cost-effectiveness of EBRT combined with ADT versus RARP over a time horizon of 36 months, a cost-utility analysis (CUA) will be conducted both from a societal and a medical perspective. Costs are assessed by multiplying the voluminal with the unit prices. Utilities will be derived by means of a mapping algorithm from the EORTC QLQ-C30 at each time point. The derived utility will be used for the estimation of a quality adjusted life year (QALY) according to the trapezium rule. Incremental costs between treatments will be related to incremental QALYs in a cost-utility ratio (ICUR) to determine the additional costs that need to be spent to gain one QALY. Subsequently, a budget impact analysis (BIA) will be performed to predict the financial consequences related to the adaption and implementation of the favored strategy based on the cost-effectiveness analysis. Assuming that the effect of treatment on HRQoL is predominantly determined by functional outcomes, the sample size was calculated to demonstrate the mean or upper limit of the MCID-range for each domain of the EPIC-26. A two sided T-test (alpha = 0.05, power 80%) using expected standard deviations, derived from previous research evaluating the impact of RP versus EBRT and ADT on functional outcomes, yielded a required total response of 471 patients at T36 ( 12 ). To account for confounding factors, the sample size was increased by 15%. Based on previous experience with collecting PROs, we assume that 75% of men who are willing to participate in the study and complete the baseline questionnaire will do so again at each subsequent measurement moment. Therefore, 837 patients need to be included in the study (response at T0) for sufficient power. Patient and public involvement The Dutch Prostate Cancer Foundation (Prostaatkankerstichting, [PKS]) was involved in the design of this study. A patient representative of the foundation is part of the RECOVER study steering committee and therefore involved throughout the whole study. Next to this, PKS facilitates the communication of study-related information and research findings via their channels to patients. Ethical approval and consent to participate The Medical Research Ethics Committee Oost-Nederland declared that the study is not subject to the Medical Research involving Human Subjects Act and Medical Treatment Contracts Act in June 2022. (2022–13682). An informed consent is filled out by all patients willing to participate in the study. Moreover, this study was approved by the Privacy Review Board of the NCR (k23.0170). Results Start-up and patient accrual Patient recruitment is set up in a step-wise fashion; patient accrual started in February 2023 in the first prostate cancer network (including 3 hospitals), followed by the second network (6 hospitals) in June 2023. The third network (8 hospitals) started patient accrual in October 2023 and the final network (11 hospitals) started in January 2024. An up-to-date overview of the participating hospitals is accessible from ClinicalTrials.gov ( 17 ). We anticipate that patient accrual will be completed by 2025, collection of PROs will be finalized by 2028 and collection of clinical follow-up data by 2030. Currently (February 2024), 4 prostate cancer networks and 107 patients participate in the RECOVER study. Discussion RARP and EBRT (often combined with ADT) are frequently used treatment modalities for high-risk, non-metastatic PCa. Research is needed to provide further insight into differences in functional outcomes, HRQoL, oncological outcomes and costs. By evaluating and comparing both treatments we aim to enhance patients’ and healthcare professionals’ awareness regarding the impact of both treatment modalities and aid treatment decision making. Moreover, our results could contribute to a reduction in inter-hospital and inter-physician variability and an improvement in the quality of care, facilitated by the adjustment and/or refinement of treatment recommendations concerning this patient population in (inter)national guidelines. When designing the RECOVER study, a prospective observational design was purposely chosen over a randomized controlled trial. Randomized controlled trials are the mainstay and gold standard for efficacy studies as they can provide compelling evidence for cause-effect relationships, have the potential for great internal validity and minimize confounding. Patient accrual, however, has shown to be difficult for trials randomizing over surgical and radiation based treatment arms for PCa ( 36 – 38 ). Both patients and their treating physicians often have a preference for treatment with RARP or EBRT and patients do not want to be randomly assigned to a treatment ( 36 , 39 ). As low patient accrual can lead to early termination of the study and consequently no or inconclusive results, a RCT was not deemed feasible. A prospective comparative effectiveness cohort study is the next best alternative to compare RARP and EBRT ( 40 , 41 ). Observational study designs evaluate effectiveness of treatment rather than efficacy, are more ethically feasible, reflect daily practice more closely and therefore have good generalizability and can enroll more patients due to lower costs ( 42 , 43 ). This enhances statistical power and enables the possibility to generalize results to the high-risk, non-metastatic PCa patient population at large ( 43 ). A limitation of observational studies is the risk of confounding. We aim to improve comparability between both treatment groups by means of the inclusion criteria (e.g. age, performance status). Furthermore, detailed information regarding possible confounding factors will be collected in both our clinical data and questionnaires. In our analyses, measured baseline covariates are balanced across treatment groups with inverse probability of treatment weighting or by covariate adjustment using the g-formula to create comparable populations. Through its pragmatic design, the RECOVER study accommodates variability in current clinical practice. Surgical treatment may be part of a multimodal strategy with (neo)adjuvant ADT and/or adjuvant radiotherapy. Variation in the RARP group is expected to be limited as (neo)adjuvant ADT is not commonly applied in the Netherlands and early salvage radiotherapy is often preferred over adjuvant radiotherapy even for pN1 disease. In current clinical practice, most patients treated with EBRT (> 90%) receive adjuvant ADT with a LHRH agonist for the duration of 6 to 36 months. In a recent Dutch consensus meeting, the duration of ADT for high-risk PCa was proposed to be 6 to 24 months depending on tumor characteristics. Besides QoL-related and oncological endpoints, our study will provide insight into the costs and cost-effectiveness of both treatment modalities. Costs of healthcare have been rising substantially over the past decades. A significant proportion of these costs is directed at cancer care, of which prostate cancer is indicated as one of the priciest cancers ( 44 ). In order to control the rising healthcare expenses, it is important to consider costs and cost-effectiveness of treatment. Only few studies have been performed regarding the costs of RP and EBRT for high-risk, non-metastatic PCa and these studies mostly focused on the American or Canadian health care system. This study will provide insight into the cost and cost-effectiveness of care for high-risk, non-metastatic PCa from a Dutch societal and medical perspective. Altogether, we aim to provide insight into the effects of treatment with RARP versus EBRT combined with ADT from a multidimensional view, including functional outcomes, HRQoL, PFS, DMFS and cost-effectiveness, Thereby we aim to create opportunities for the improvement of quality of life and quality of care for patients with high-risk, non-metastatic PCa. List of abbreviations ADT Androgen deprivation therapy ARSI Androgen receptor signaling inhibitor ARTA Androgen receptor targeted agents BED Biologically effective dose BIA Budget impact analysis BRP Personal records database CTCAE Common toxicity criteria for adverse events CUA Cost-utility analysis DMFS Distant metastasis free survival DRE Digital rectal examination EBRT External beam radiation therapy EORTC-QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 EPIC-26 Expanded prostate cancer index composite-26 HDR High dose rate HRQoL Heath-related quality of life ICUR Incremental cost-utility ratio IKNL Netherlands Comprehensive Cancer Organisation IMRT Intensity modulated radiation therapy iMTA Institute for medical technology assessment LDR Low dose rate MDTM Multidisciplinary team meetings MREC Medical review ethics committee MRI Magnetic resonance imaging NCR Netherlands Cancer Registry NVRO Dutch Society of Radiotherapy and Oncology NVU Dutch Association for Urology OS Overall survival PCa Prostate cancer PCSM Prostate cancer-specific mortality PCSS Prostate cancer-specific survival PCQ Productivity cost questionnaire PFS Progression-free survival PKS Dutch PCa patient foundation PLND pelvic lymph node dissection PROFILES Patient reported outcomes following initial treatment and long term evaluation PROs Patient reported outcomes PROMs Patient reported outcomes measures PSA Prostate specific antigen RARP Robot-assisted radical prostatectomy RECOVER High-Risk prostatE Cancer radiatiOn Versus surgERy RP Radical prostatectomy SCQ Self-administered comorbidity questionnaire VMAT Volumetric modulated arc therapy QALY Quality adjusted life year Declarations Ethics approval and consent to participate The Medical Research Ethics Committee Oost-Nederland declared that the study is not subject to the Medical Research involving Human Subjects Act and Medical Treatment Contracts Act in June 2022. (2022-13682). An informed consent is filled out by all patients willing to participate in the study. Moreover, this study was approved by the Privacy Review Board of the NCR (k23.0170). Consent for publication Not required. Availability of data and materials The data collected, generated and analyzed during the current study are available from the Netherlands Comprehensive Cancer Organisation (IKNL) upon reasonable request following the standard procedures of data requests concerning data of the Netherlands Cancer Registry and Profiles. The original study protocol of this study is also accessible upon request. Competing interests None to be declared. Funding The RECOVER study is funded by ZonMW (registered under project number 10330032010005). The protocol of the study was peer-reviewed before funding was granted. The funding agency was not involved in the design of the study or manuscript and will not be involved in the analysis and interpretation of the results. Authors' contributions All authors contributed to the conceptualization and design of the study. KA provides overall study supervision, BH coordinates the project. CvdS oversees the daily execution of the study and contributed to the data collection with the research assistant. CvdS drafted the manuscript, supported by BH. All authors have critically read and revised the manuscript. All authors approved the final version of the manuscript. Dissemination policy Scientific publications describing the findings of the RECOVER study will be available via OpenAccess (a requirement of the funding agency ZonMW). Participating hospitals are regularly updated on the study progress. Participants in the RECOVER study receive newsletters providing updates concerning the state of affairs of the study and the findings of the study. Acknowledgements We would like to express our gratitude to all patients that (will) participate in this study. We also would like to thank the participating prostate cancer networks (Prosper Prostate Cancer Clinics, Prostaatcentrum Noord Nederland, Anser and Prostaatkankernetwerk Nederland) and the collaborating hospitals for their involvement in the patient recruitment for the RECOVER study: Admiraal de Ruyter Ziekenhuis, Albert Schweitzer Ziekenhuis, Amsterdam UMC locatie AMC, Amsterdam UMC locatie VUMC, Andros Clinics, Antoni van Leeuwenhoek (AVL) / NKI, BovenIJ ziekenhuis, Canisius-Wilhelmina Ziekenhuis, Catharina Ziekenhuis, Dijklander Ziekenhuis, Erasmus MC, Franciscus Gasthuis & Vlietland, Haaglanden Medisch Centrum, Instituut Verbeeten, Leids Universitair Medisch Centrum, Maasstad Ziekenhuis, Martini Ziekenhuis, Noordwest Ziekenhuisgroep, OLVG, Ommelander Ziekenhuis Groningen, Radboudumc, Rode Kruis Ziekenhuis, Saxenburgh Groep, Spaarne Gasthuis, Treant Zorggroep, Universitair Medisch Centrum Groningen, Wilhelmina Ziekenhuis Assen, Zaans Medisch Centrum, Ziekenhuis Amstelland, Ziekenhuis St Jansdal. We are grateful to the Dutch Society for Urology, the Dutch Society of Radiotherapy and Oncology and the Dutch Prostate Cancer Foundation (Prostaatkankerstichting). We would like to thank Eveline Wijnen, our research assistant, for her efforts regarding the monitoring of patient inclusion. The authors also thank the data managers of the Netherlands Comprehensive Cancer Organization for the (additional) data collection for the Netherlands Cancer Registry. References Dee EC, Nezolosky MD, Chipidza FE, Arega MA, Butler SS, Sha ST, et al. Prostate cancer-specific mortality burden by risk group among men with localized disease: Implications for research and clinical trial priorities. Prostate. 2020;80(13):1128-33. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010;28(7):1117-23. Netherlands comprehensive cancer organisation (IKNL). 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Radical prostatectomy or radiotherapy for high- and very high-risk prostate cancer: a multidisciplinary prostate cancer clinic experience of patients eligible for either treatment. BJU Int. 2019;124(5):811-9. Tward JD, O'Neil B, Boucher K, Kokeny K, Lowrance WT, Lloyd S, et al. Metastasis, Mortality, and Quality of Life for Men With NCCN High and Very High Risk Localized Prostate Cancer After Surgical and/or Combined Modality Radiotherapy. Clin Genitourin Cancer. 2020;18(4):274-83.e5. Ciezki JP, Weller M, Reddy CA, Kittel J, Singh H, Tendulkar R, et al. A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2017;97(5):962-75. ClinicalTrials.gov. High-Risk prostatE Cancer radiatiOn Versus surgERy (RECOVER) [Available from: https://clinicaltrials.gov/study/NCT05931419. Dutch Association for Urology (Nederlandse Vereniging voor Urologie: NVU ). Kwaliteitsnormen prostaatcarcinoom versie 4. 2018. Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW, Amin MB. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers. Eur Urol. 2018;73(4):560-9. van der Poel H, van der Kwast T, Aben K, Mottet N, Mason M. Imaging and T Category for Prostate Cancer in the 8th Edition of the Union for International Cancer Control TNM Classification. Eur Urol Oncol. 2020;3(5):563-4. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology. 2000;56(6):899-905. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. JNCI: Journal of the National Cancer Institute. 1993;85(5):365-76. Schmidt S, Garin O, Pardo Y, Valderas JM, Alonso J, Rebollo P, et al. Assessing quality of life in patients with prostate cancer: a systematic and standardized comparison of available instruments. Qual Life Res. 2014;23(8):2169-81. Skolarus TA, Dunn RL, Sanda MG, Chang P, Greenfield TK, Litwin MS, et al. Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form. Urology. 2015;85(1):101-5. Musoro JZ, Coens C, Sprangers MAG, Brandberg Y, Groenvold M, Flechtner HH, et al. Minimally important differences for interpreting EORTC QLQ-C30 change scores over time: A synthesis across 21 clinical trials involving nine different cancer types. Eur J Cancer. 2023;188:171-82. Sangha O, Stucki G, Liang MH, Fossel AH, Katz JN. The Self-Administered Comorbidity Questionnaire: a new method to assess comorbidity for clinical and health services research. Arthritis Rheum. 2003;49(2):156-63. Bouwmans C, Krol M, Severens H, Koopmanschap M, Brouwer W, Hakkaart-van Roijen L. The iMTA Productivity Cost Questionnaire: A Standardized Instrument for Measuring and Valuing Health-Related Productivity Losses. Value Health. 2015;18(6):753-8. Profiel:. Wat kanker met u doet [Available from: https://www.profielstudie.nl/wat-doen-we/. van de Poll-Franse LV, Horevoorts N, van Eenbergen M, Denollet J, Roukema JA, Aaronson NK, et al. The Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship registry: scope, rationale and design of an infrastructure for the study of physical and psychosocial outcomes in cancer survivorship cohorts. Eur J Cancer. 2011;47(14):2188-94. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011;46(3):399-424. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41-55. Robins J. A new approach to causal inference in mortality studies with a sustained exposure period—application to control of the healthy worker survivor effect. Mathematical Modelling. 1986;7(9):1393-512. Snowden JM, Rose S, Mortimer KM. Implementation of G-computation on a simulated data set: demonstration of a causal inference technique. Am J Epidemiol. 2011;173(7):731-8. Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017;17(1):162. Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. Bmj. 2009;338:b2393. Penson DF. An update on randomized clinical trials in localized and locoregional prostate cancer. Urol Oncol. 2005;23(4):280-8. Collaborators P. Early closure of a randomized controlled trial of three treatment approaches to early localised prostate cancer: the MRC PR06 trial. BJU Int. 2004;94(9):1400-1. Wallace K, Fleshner N, Jewett M, Basiuk J, Crook J. Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial. J Clin Oncol. 2006;24(25):4158-62. Ritchie A, et al. Early closure of a randomized controlled trial of three treatment approaches to early localised prostate cancer: the MRC PR06 trial. BJU Int. 2004;94(9):1400-1. Concato J, Lawler EV, Lew RA, Gaziano JM, Aslan M, Huang GD. Observational methods in comparative effectiveness research. Am J Med. 2010;123(12 Suppl 1):e16-23. Yang W, Zilov A, Soewondo P, Bech OM, Sekkal F, Home PD. Observational studies: going beyond the boundaries of randomized controlled trials. Diabetes Res Clin Pract. 2010;88 Suppl 1:S3-9. Lobo FS, Wagner S, Gross CR, Schommer JC. Addressing the issue of channeling bias in observational studies with propensity scores analysis. Res Social Adm Pharm. 2006;2(1):143-51. Barocas DA, Chen V, Cooperberg M, Goodman M, Graff JJ, Greenfield S, et al. Using a population-based observational cohort study to address difficult comparative effectiveness research questions: the CEASAR study. J Comp Eff Res. 2013;2(4):445-60. Kang R, Goodney PP, Wong SL. Importance of cost-effectiveness and value in cancer care and healthcare policy. J Surg Oncol. 2016;114(3):275-80. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Jan, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Accepted 13 Jan, 2025 Submission checks completed at journal 06 Mar, 2024 Editor assigned by journal 06 Mar, 2024 First submitted to journal 29 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3999440","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":276931346,"identity":"de9cddae-fa05-4d40-891d-3a8c54849f31","order_by":0,"name":"Caroline M. van der Starre","email":"","orcid":"","institution":"Netherlands Comprehensive Cancer Organisation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"M. van der","lastName":"Starre","suffix":""},{"id":276931347,"identity":"4dc2a409-e8ef-434b-a589-946e239de208","order_by":1,"name":"Chris H. Bangma","email":"","orcid":"","institution":"Erasmus University Medical Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chris","middleName":"H.","lastName":"Bangma","suffix":""},{"id":276931348,"identity":"d78167f4-02d7-4757-a0f6-4cf30237c3ea","order_by":2,"name":"Maarten J. Bijlsma","email":"","orcid":"","institution":"Netherlands Comprehensive Cancer Organisation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maarten","middleName":"J.","lastName":"Bijlsma","suffix":""},{"id":276931349,"identity":"e4fb575d-8585-4f3c-9a90-877b981e2f92","order_by":3,"name":"Alfons C.M. van den Bergh","email":"","orcid":"","institution":"The Netherlands Cancer Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alfons","middleName":"C.M. van den","lastName":"Bergh","suffix":""},{"id":276931350,"identity":"4270e2ff-267c-49a5-a83e-d26c4780757b","order_by":4,"name":"Lambertus A.L.M. 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Aben","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArklEQVRIiWNgGAWjYBACCQYGNiBlwyPBwNzAwFBAvJY0oBZGoBYD4rUcZiBei2QD87MHH3ecl5Gc3djAXECMFmkGNnPDmWdu80jLHGxgnkGMFjkGBjNp3rbbPHISiQ3MPMRpYf8m/bftHAlapBl4zKQZ2w7wSBOtRbKZp9ywty2ZR3JGYsNhorRIHG/f9uBnm529xI3kg495KojQwsCMxD5AjIZRMApGwSgYBUQAAFAFKrrrb5j1AAAAAElFTkSuQmCC","orcid":"","institution":"Netherlands Comprehensive Cancer Organisation","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Katja","middleName":"K.H.","lastName":"Aben","suffix":""},{"id":276931356,"identity":"51892ada-99c4-44b7-acba-df5ac6f61517","order_by":10,"name":"Igle J. Jong","email":"","orcid":"","institution":"University Medical Center Groningen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Igle","middleName":"J.","lastName":"Jong","suffix":""},{"id":276931357,"identity":"3c1c3fc9-1073-45fa-8895-9f8d14f56f4e","order_by":11,"name":"Floris J. Pos","email":"","orcid":"","institution":"The Netherlands Cancer Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Floris","middleName":"J.","lastName":"Pos","suffix":""},{"id":276931358,"identity":"f41bf2ce-e153-4367-b603-dd6bcea8184f","order_by":12,"name":"Berdine L. Heesterman","email":"","orcid":"","institution":"Netherlands Comprehensive Cancer Organisation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Berdine","middleName":"L.","lastName":"Heesterman","suffix":""}],"badges":[],"createdAt":"2024-02-29 11:02:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3999440/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3999440/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-025-13511-7","type":"published","date":"2025-01-27T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75351187,"identity":"63434dee-346d-4792-9f98-b451582cabe1","added_by":"auto","created_at":"2025-02-03 16:07:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":691424,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3999440/v1/10828474-aa1f-42a4-832e-d3a685136972.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"External beam radiation therapy versus radical prostatectomy for high-risk prostate cancer: protocol of the RECOVER study","fulltext":[{"header":"Background","content":"\u003cp\u003eApproximately 15\u0026ndash;18% of all prostate cancer diagnoses concern high-risk, non-metastatic prostate cancer (PCa) (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). High-risk PCa is a heterogenous disease with increased risk of biochemical recurrence, metastatic progression and death from PCa as compared to low- or intermediate-risk localized disease (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Treatment modalities widely used for high-risk PCa are (robot-assisted) radical prostatectomy (RP) and external beam radiation therapy (EBRT), the latter generally combined with androgen deprivation therapy (ADT). Currently, there is no consensus regarding the optimal treatment for high-risk PCa (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). This is also reflected in the substantial interhospital treatment variation in the Netherlands (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHigh-level comparative evidence regarding the optimal treatment for high-risk PCa is lacking.\u003c/p\u003e \u003cp\u003eSeveral non-randomized studies have compared oncological outcomes between treatment with RP versus EBRT. Most were retrospective in nature and were performed in a single-institution. These studies did not show clear differences in five-year prostate cancer specific survival (PCSS) and overall survival (OS) (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Due to variation in the definition of high-risk prostate cancer and differences in applied surgical and radiotherapy treatment strategies, definitive conclusions cannot be drawn (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, survival was generally good with reported five-year OS and PCSS rates exceeding 90% (\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In a recent systematic review we summarized evidence for patient reported functional outcomes and HRQoL after RP compared to EBRT for high-risk, non-metastatic PCa (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Three observational studies focused on differences in functional outcomes and HRQoL between RP and EBRT with ADT for high-risk PCa. Overall, sexual dysfunction and genitourinary toxicity were reported more often after RP, while reduced hormonal function and gastro-intestinal toxicity were more common after EBRT combined with ADT (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, due to the limited number of studies, the variation in the definition of high-risk PCa and the differences in methods and measurement instruments, the extent of the effect of both treatment modalities on functional outcomes and HRQoL remains largely unknown. Hence, it remains uncertain whether either treatment is superior with respect to functional outcomes and HRQoL as well as oncological outcomes.\u003c/p\u003e \u003cp\u003eHere we present the RECOVER study (High-Risk prostatE Cancer radiatiOn Versus surgERy) as a means to address these knowledge gaps. The study is primarily designed to evaluate and compare the impact of treatment with RP versus EBRT with ADT on functional outcomes and HRQoL for men with high-risk, non-metastatic PCa. Our study aims to enhance awareness of both patients and healthcare professionals regarding these effects of treatment. By incorporating our findings into a patient decision aid, it could support patients in making a well-informed treatment decision. Moreover, providing insight into the impact of both treatments could lead to a reduction in interhospital and inter-physician variability and improvement in quality of care facilitated by the adjustment and/or refinement of treatment recommendations concerning this patient population in (inter)national guidelines.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign and collaboration\u003c/h2\u003e \u003cp\u003eThe RECOVER study is a comparative effectiveness study that prospectively includes patients with high-risk, non-metastatic PCa to compare treatment with robot assisted radical prostatectomy (RARP) versus EBRT combined with ADT. The study is executed by a cooperation of the Netherlands Comprehensive Cancer Organization (IKNL), the Dutch Association for Urology (NVU) and the Dutch Society of Radiotherapy and Oncology (NVRO). The study is performed in close collaboration with the Dutch Prostate Cancer Foundation (Prostaatkankerstichting [PKS]). Currently, 28 hospitals collaborating in four Dutch prostate cancer networks participate in the study, collectively covering 40% of all newly diagnosed prostate cancer patients in the Netherlands. ClinicalTrials.gov provides an up-to-date overview of all participating hospitals (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Healthcare providers from hospitals in a prostate cancer network discuss patient, tumor and other relevant characteristics in multidisciplinary team meetings (MDTMs) to achieve the most optimal treatment based on evidence-based guidelines and tailored to the patient. For this study, eligibility of a patient for treatment with both RARP and EBRT with ADT is discussed in these meetings. The participating networks are geographically distributed across the Netherlands and each network consists of at least one university hospital and several non-university teaching hospitals and general hospitals. In the Netherlands, surgical treatment of PCa is centralized in 14 hospitals that meet the minimum hospital volume norm of 100 RARP procedures per year (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Within each prostate cancer network, all RARP treatments are centralized in one hospital. Radiation therapy is centralized to 20 institutions across the Netherland and is performed in nine of the participating hospitals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003ePatients with histologically confirmed high-risk, non-metastatic PCa diagnosed or treated in one of the participating hospitals are eligible for inclusion. Various (inter)national risk classifications and guidelines define high-risk PCa with subtle differences. In this study, high-risk, non-metastatic PCa is defined as cT3a-bN0M0 disease, and/or ISUP grade\u0026thinsp;\u0026ge;\u0026thinsp;4 and/or a PSA value at diagnosis above 20 ng/mL. Prostate cancer is staged according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification with the exception that T-stage will be based on either digital rectal examination (DRE) or magnetic resonance imaging (MRI), whichever is highest (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Patients must be aged 50 to 75 years, fit (WHO performance status 0\u0026ndash;1) and eligible (i.e. no contra-indications) for both RARP and ERBT with ADT. Moreover, patients have to reside in the Netherlands and be able to read and understand Dutch language. Patients with histological PCa types other than adenocarcinoma and those that are diagnosed or treated in a hospital abroad are excluded. Patients treated with androgen receptor signaling inhibitor (ARSI)/androgen receptor targeted agents (ARTA) as part of the initial treatment plan are also excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eRARP may be part of a multimodal therapy with (neo)adjuvant ADT and/or adjuvant radiotherapy. A pelvic lymph node dissection (PLND) may be performed for staging purposes. The presence of positive lymph nodes (pN1) upon PLND is not a reason for exclusion and may be followed by adjuvant treatment e.g. lymph node irradiation and/or ADT.\u003c/p\u003e \u003cp\u003eRegarding EBRT, the study allows for dose-escalation using intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) or stereotactic radiation. Dose-escalation is defined as a biologically effective dose (BED) converted to 2Gy fractions (using a α/β ratio of 1.5) of at least 76Gy. Both conventionally fractionated and hypofractionated regimens may be used and patients may receive an integrated boost to visible intraprostatic lesions, a low dose rate (LDR) brachytherapy boost or a high dose rate (HDR) brachytherapy boost. In addition, treatment with ADT should be given for a period of at least 6 months. Similar to radical prostatectomy, PLND may be performed for staging purposes and pN1 is no reason for exclusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy endpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoints of the RECOVER study are functional outcomes and HRQoL 36 months after treatment initiation. These endpoints are measured with the validated Dutch versions of the Expanded Prostate Cancer Index Composite-26 (EPIC-26) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). We assume that the long-term effects of treatment, including the effects of ADT (patients eligible for inclusion generally receive ADT for 6 to 24 months), have stabilized 36 months after treatment initiation.\u003c/p\u003e \u003cp\u003eSecondary study endpoints are progression-free survival (PFS), distant metastasis-free survival (DMFS), cost and cost-effectiveness. Cost and cost-effectiveness will be evaluated 36 months after treatment initiation. PFS and DMFS are evaluated at 5 years after diagnosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient inclusion\u003c/h2\u003e \u003cp\u003eEligible patients are informed about the study by their physician (or research nurse/nurse specialist) shortly after diagnosis. Study information is provided to the patient after which the patient has time to decide whether to participate in the study. Patient information is set up in such a way that it appeals to patients of diverse backgrounds. Patients willing to participate provide written informed consent and administrative data are entered in an online registration tool. Inclusion is finalized when the patient completes the first questionnaires before treatment initiation (baseline measurement). In some hospitals, the EPIC-26 and EORTC-QLQ-C30 are administered as part of the regular care. To minimize patient burden, these questionnaires are reused if possible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003ePatient reported outcome measures (PROMs)\u003c/h2\u003e \u003cp\u003eThe EPIC-26 is an instrument developed and validated for the comprehensive assessment of HRQoL in men with PCa (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). It is one of the best rated instruments for this purpose (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and consists of 5 symptom domains: urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal. Questionnaire items are converted to domain scores between 0 to 100, with a higher score representing a better function. Threshold values for a clinically meaningful change (minimal clinically important difference [MCID]) have been determined for each EPIC-26 domain: 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, 4 to 6 for bowel function, 10 to 12 for sexual function and 4 to 6 for hormonal function (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe EORTC-QLQ-C30 is a widely used measurement instrument to assess HRQoL of cancer patients (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The questionnaire includes five functional domains (physical, role, cognitive, emotional and social), three symptom domains (fatigue, pain, nausea and vomiting) a global health/quality of life scale and several single-item measures. For each domain and single item measure, a score from 0 to 100 can be calculated. For the functional domains and global score, higher scores indicate a better quality of life. In contrast, for the symptom domains and single item measures, a higher score represents a higher level of symptomatology (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Musoro et al. have provided minimal important differences for within-group change and between-group change per EORTC QLQ-C30 scale for nine cancer types, amongst which prostate cancer (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition, patients are asked to complete an edited version of the self-administered comorbidity questionnaire (SCQ) and an adapted version of the Institute for Medical Technology Assessment Productivity Cost Questionnaire (iMTA PCQ). The SCQ is a generic questionnaire developed to assess common comorbidities which might impact an individual\u0026rsquo;s functioning. For each condition, the presence, severity and functional limitation is self-assessed (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). We have extended the SCQ with conditions that are considered a (relative) contra-indication for RARP or EBRT, e.g. inflammatory bowel disease.\u003c/p\u003e \u003cp\u003eThe iMTA PCQ is a standardized questionnaire developed to measure and value productivity loss. Productivity loss is measured in three modules being absenteeism, presenteeism and productivity loss of unpaid work (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). The iMTA PCQ was slightly adapted in collaboration with an expert in health technology assessment by focusing questions regarding unpaid work on volunteer work only. Moreover, we reformulated some questions to make them more easily understandable for the patient. The iMTA PCQ is used to determine indirect non-medical costs.\u003c/p\u003e \u003cp\u003eFinally, information is collected regarding patient characteristics, such as living situation, alcohol and smoking behavior and education level, and used health resources for prostate-cancer related problems such as erectile or urinary complaints (e.g. urinary pads, catheter, medication). Information regarding used health resources is collected to determine healthcare costs. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the collected PROs at the various measurement moments.\u003c/p\u003e \u003cp\u003eThe patient can complete either paper or web-based questionnaires based on their preference. Web-based questionnaires are collected by use of the Profiles Registry (Patient Reported Outcomes Following Initial treatment and Long term Evaluation). Profiles is specialized in collecting, processing and storing PROs of cancer patients (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) and all data are handled according to the General and Dutch Data Protection Act. Data from the PROFILES registry can be linked to the Netherlands Cancer Registry (NCR), which allows the merging of PROs and clinical data (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In order to achieve good response rates, a research assistant monitors the questionnaire response. Patients with incomplete questionnaires will be contacted and information will be complemented as far as possible.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverview of the collection of patient reported outcomes in the RECOVER study at the subsequent measurement moments (baseline, T12 and T36)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncluded topics / patient reported outcome measures\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT36\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge, length, height, living situation, alcohol and smoking behavior, education level, participatory decision making style\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdapted version of the SCQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRQOL and functional outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEPIC-26 and EORTC-QLQ-C30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment of PCa specific complaints / additional treatment information\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCatheter, medication for lower urinary tract symptoms,\u003c/p\u003e \u003cp\u003epelvic floor physical therapy, surgery for urinary loss, erectile medication, use of vacuum pump erectile device, androgen deprivation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProductivity loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdapted version of the iMTA PCQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinical data\u003c/h2\u003e \u003cp\u003eIn addition to PROs, clinical data regarding patient and tumor characteristics, as well as treatment information, is needed to meet our research objectives. These data are extracted from the Netherlands Cancer Registry (NCR). Maintained by the Netherlands Comprehensive Cancer Organisation (IKNL), the NCR is a nationwide population-based registry that contains information on all newly diagnosed cancer patients in the Netherlands. Clinical data are retrieved from patients electronic health records in the hospitals by well-trained, independent data managers of the NCR. The standard data collection in the NCR is expanded for patients included in this study and includes patient characteristics (i.e. age, height, weight, comorbidities), tumor characteristics (i.e. TNM staging, PSA at diagnosis and Gleason grade on biopsy and prostatectomy if applicable), diagnostic procedures (i.e. imaging, biopsy technique, pelvic lymph node dissection) and treatment information for prostatectomy (i.e. nerve sparing procedure, positive margins, complications) and EBRT (i.e. type of radiotherapy, dose per fraction, integrated/brachytherapy boost, toxicity). In addition, data is collected on all post-treatment PSA measurements, disease progression, subsequent treatments and cause of death until 5 years after diagnosis. Vital status of all patients is updated annually by linkage to the personal records database (BRP) which contains data on the vital status, date of death and emigration status of all Dutch citizens.\u003c/p\u003e \u003cp\u003eMoreover, additional clinical data related to volumes of care are collected from the electronic health records to evaluate healthcare costs. In addition to the treatments for prostate cancer, these data include treatments for adverse events, consultations with medical specialists, hospitalizations and medication use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis and sample size\u003c/h2\u003e \u003cp\u003eDescriptive analyses will be used to provide insight in patient and clinical characteristics of the total study population and of both treatment groups. Mixed-effects models will be used to compare functional outcomes and HRQoL between the two treatment groups over time. Differences in functional outcomes and HRQoL between treatment modalities as measured by the EPIC-26 will be considered clinically meaningful if they are equivalent to or exceed the MCID and are statistically significant at the 0.05 level. The p-value maintained for statistical significance will be adjusted for multiple testing if appropriate. For the EORTC-QLQ-C30, the between-group anchor-based minimally important differences per scale as reported by Musoro et al. will be used to compare treatment groups over time. For scales for which no anchor-based estimates are available, distribution-based estimates will be used (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Due to the observational design of the study, we will adjust for confounding covariates associated with treatment with RARP versus EBRT (and ADT) using inverse probability of treatment weighting or the g-formula (\u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In case of missing values in covariates, multiple imputation procedures will be used (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Competing risk survival analyses will be used to evaluate PFS and DMFS with the competing event being a non-PCa related death.\u003c/p\u003e \u003cp\u003eTo evaluate incremental cost-effectiveness of EBRT combined with ADT versus RARP over a time horizon of 36 months, a cost-utility analysis (CUA) will be conducted both from a societal and a medical perspective. Costs are assessed by multiplying the voluminal with the unit prices. Utilities will be derived by means of a mapping algorithm from the EORTC QLQ-C30 at each time point. The derived utility will be used for the estimation of a quality adjusted life year (QALY) according to the trapezium rule. Incremental costs between treatments will be related to incremental QALYs in a cost-utility ratio (ICUR) to determine the additional costs that need to be spent to gain one QALY. Subsequently, a budget impact analysis (BIA) will be performed to predict the financial consequences related to the adaption and implementation of the favored strategy based on the cost-effectiveness analysis.\u003c/p\u003e \u003cp\u003eAssuming that the effect of treatment on HRQoL is predominantly determined by functional outcomes, the sample size was calculated to demonstrate the mean or upper limit of the MCID-range for each domain of the EPIC-26. A two sided T-test (alpha\u0026thinsp;=\u0026thinsp;0.05, power 80%) using expected standard deviations, derived from previous research evaluating the impact of RP versus EBRT and ADT on functional outcomes, yielded a required total response of 471 patients at T36 (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). To account for confounding factors, the sample size was increased by 15%. Based on previous experience with collecting PROs, we assume that 75% of men who are willing to participate in the study and complete the baseline questionnaire will do so again at each subsequent measurement moment. Therefore, 837 patients need to be included in the study (response at T0) for sufficient power.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePatient and public involvement\u003c/h2\u003e \u003cp\u003eThe Dutch Prostate Cancer Foundation (Prostaatkankerstichting, [PKS]) was involved in the design of this study. A patient representative of the foundation is part of the RECOVER study steering committee and therefore involved throughout the whole study. Next to this, PKS facilitates the communication of study-related information and research findings via their channels to patients.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe Medical Research Ethics Committee Oost-Nederland declared that the study is not subject to the Medical Research involving Human Subjects Act and Medical Treatment Contracts Act in June 2022. (2022\u0026ndash;13682). An informed consent is filled out by all patients willing to participate in the study. Moreover, this study was approved by the Privacy Review Board of the NCR (k23.0170).\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStart-up and patient accrual\u003c/h2\u003e \u003cp\u003ePatient recruitment is set up in a step-wise fashion; patient accrual started in February 2023 in the first prostate cancer network (including 3 hospitals), followed by the second network (6 hospitals) in June 2023. The third network (8 hospitals) started patient accrual in October 2023 and the final network (11 hospitals) started in January 2024. An up-to-date overview of the participating hospitals is accessible from ClinicalTrials.gov (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). We anticipate that patient accrual will be completed by 2025, collection of PROs will be finalized by 2028 and collection of clinical follow-up data by 2030. Currently (February 2024), 4 prostate cancer networks and 107 patients participate in the RECOVER study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRARP and EBRT (often combined with ADT) are frequently used treatment modalities for high-risk, non-metastatic PCa. Research is needed to provide further insight into differences in functional outcomes, HRQoL, oncological outcomes and costs. By evaluating and comparing both treatments we aim to enhance patients\u0026rsquo; and healthcare professionals\u0026rsquo; awareness regarding the impact of both treatment modalities and aid treatment decision making. Moreover, our results could contribute to a reduction in inter-hospital and inter-physician variability and an improvement in the quality of care, facilitated by the adjustment and/or refinement of treatment recommendations concerning this patient population in (inter)national guidelines.\u003c/p\u003e \u003cp\u003eWhen designing the RECOVER study, a prospective observational design was purposely chosen over a randomized controlled trial. Randomized controlled trials are the mainstay and gold standard for efficacy studies as they can provide compelling evidence for cause-effect relationships, have the potential for great internal validity and minimize confounding. Patient accrual, however, has shown to be difficult for trials randomizing over surgical and radiation based treatment arms for PCa (\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Both patients and their treating physicians often have a preference for treatment with RARP or EBRT and patients do not want to be randomly assigned to a treatment (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). As low patient accrual can lead to early termination of the study and consequently no or inconclusive results, a RCT was not deemed feasible. A prospective comparative effectiveness cohort study is the next best alternative to compare RARP and EBRT (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Observational study designs evaluate effectiveness of treatment rather than efficacy, are more ethically feasible, reflect daily practice more closely and therefore have good generalizability and can enroll more patients due to lower costs (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). This enhances statistical power and enables the possibility to generalize results to the high-risk, non-metastatic PCa patient population at large (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). A limitation of observational studies is the risk of confounding. We aim to improve comparability between both treatment groups by means of the inclusion criteria (e.g. age, performance status). Furthermore, detailed information regarding possible confounding factors will be collected in both our clinical data and questionnaires. In our analyses, measured baseline covariates are balanced across treatment groups with inverse probability of treatment weighting or by covariate adjustment using the g-formula to create comparable populations.\u003c/p\u003e \u003cp\u003eThrough its pragmatic design, the RECOVER study accommodates variability in current clinical practice. Surgical treatment may be part of a multimodal strategy with (neo)adjuvant ADT and/or adjuvant radiotherapy. Variation in the RARP group is expected to be limited as (neo)adjuvant ADT is not commonly applied in the Netherlands and early salvage radiotherapy is often preferred over adjuvant radiotherapy even for pN1 disease. In current clinical practice, most patients treated with EBRT (\u0026gt;\u0026thinsp;90%) receive adjuvant ADT with a LHRH agonist for the duration of 6 to 36 months. In a recent Dutch consensus meeting, the duration of ADT for high-risk PCa was proposed to be 6 to 24 months depending on tumor characteristics.\u003c/p\u003e \u003cp\u003eBesides QoL-related and oncological endpoints, our study will provide insight into the costs and cost-effectiveness of both treatment modalities. Costs of healthcare have been rising substantially over the past decades. A significant proportion of these costs is directed at cancer care, of which prostate cancer is indicated as one of the priciest cancers (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). In order to control the rising healthcare expenses, it is important to consider costs and cost-effectiveness of treatment. Only few studies have been performed regarding the costs of RP and EBRT for high-risk, non-metastatic PCa and these studies mostly focused on the American or Canadian health care system. This study will provide insight into the cost and cost-effectiveness of care for high-risk, non-metastatic PCa from a Dutch societal and medical perspective.\u003c/p\u003e \u003cp\u003eAltogether, we aim to provide insight into the effects of treatment with RARP versus EBRT combined with ADT from a multidimensional view, including functional outcomes, HRQoL, PFS, DMFS and cost-effectiveness, Thereby we aim to create opportunities for the improvement of quality of life and quality of care for patients with high-risk, non-metastatic PCa.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eADT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eAndrogen deprivation therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eARSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eAndrogen receptor signaling inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eARTA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eAndrogen receptor targeted agents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eBED\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eBiologically effective dose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eBIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eBudget impact analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eBRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003ePersonal records database\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eCTCAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eCommon toxicity criteria for adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eCUA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eCost-utility analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eDMFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eDistant metastasis free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eDRE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eDigital rectal examination\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eEBRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eExternal beam radiation therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eEORTC-QLQ-C30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eEuropean Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eEPIC-26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eExpanded prostate cancer index composite-26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eHDR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eHigh dose rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eHRQoL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eHeath-related quality of life\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eICUR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eIncremental cost-utility ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eIKNL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eNetherlands Comprehensive Cancer Organisation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eIMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eIntensity modulated radiation therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eiMTA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eInstitute for medical technology assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eLDR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eLow dose rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eMDTM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eMultidisciplinary team meetings\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eMREC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eMedical review ethics committee\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eNCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eNetherlands Cancer Registry\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eNVRO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eDutch Society of Radiotherapy and Oncology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eNVU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eDutch Association for Urology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePCa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProstate cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePCSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProstate cancer-specific mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePCSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProstate cancer-specific survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePCQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProductivity cost questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProgression-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePKS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eDutch PCa patient foundation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePLND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003epelvic lymph node dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePROFILES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003ePatient reported outcomes following initial treatment and long term evaluation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePROs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003ePatient reported outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePROMs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003ePatient reported outcomes measures\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003ePSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eProstate specific antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eRARP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eRobot-assisted radical prostatectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eRECOVER\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eHigh-Risk prostatE Cancer radiatiOn Versus surgERy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eRadical prostatectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eSCQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eSelf-administered comorbidity questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eVMAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eVolumetric modulated arc therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.027113237639554%\" valign=\"top\"\u003e\n \u003cp\u003eQALY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"70.97288676236045%\" valign=\"top\"\u003e\n \u003cp\u003eQuality adjusted life year\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Medical Research Ethics Committee Oost-Nederland declared that the study is not subject to the Medical Research involving Human Subjects Act and Medical Treatment Contracts Act in June 2022. (2022-13682). An informed consent is filled out by all patients willing to participate in the study. Moreover, this study was approved by the Privacy Review Board of the NCR (k23.0170).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot required.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data collected, generated and analyzed during the current study are available from the Netherlands Comprehensive Cancer Organisation (IKNL) upon reasonable request following the standard procedures of data requests concerning data of the Netherlands Cancer Registry and Profiles. The original study protocol of this study is also accessible upon request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNone to be declared.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe RECOVER study is funded by ZonMW (registered under project number 10330032010005). The protocol of the study was peer-reviewed before funding was granted. The funding agency was not involved in the design of the study or manuscript and will not be involved in the analysis and interpretation of the results.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conceptualization and design of the study. KA provides overall study supervision, BH coordinates the project. CvdS oversees the daily execution of the study and contributed to the data collection with the research assistant. CvdS drafted the manuscript, supported by BH. All authors have critically read and revised the manuscript. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDissemination policy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eScientific publications describing the findings of the RECOVER study will be available via OpenAccess (a requirement of the funding agency ZonMW). Participating hospitals are regularly updated on the study progress. Participants in the RECOVER study receive newsletters providing updates concerning the state of affairs of the study and the findings of the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to all patients that (will) participate in this study. We also would like to thank the participating prostate cancer networks (Prosper Prostate Cancer Clinics, Prostaatcentrum Noord Nederland, Anser and Prostaatkankernetwerk Nederland) and the collaborating hospitals for their involvement in the patient recruitment for the RECOVER study: Admiraal de Ruyter Ziekenhuis, Albert Schweitzer Ziekenhuis, Amsterdam UMC locatie AMC, Amsterdam UMC locatie VUMC, Andros Clinics, Antoni van Leeuwenhoek (AVL) / NKI, BovenIJ ziekenhuis, Canisius-Wilhelmina Ziekenhuis, Catharina Ziekenhuis, Dijklander Ziekenhuis, Erasmus MC, Franciscus Gasthuis \u0026amp; Vlietland, Haaglanden Medisch Centrum, Instituut Verbeeten, Leids Universitair Medisch Centrum, Maasstad Ziekenhuis, Martini Ziekenhuis, Noordwest Ziekenhuisgroep, OLVG, Ommelander Ziekenhuis Groningen, Radboudumc, Rode Kruis Ziekenhuis, Saxenburgh Groep, Spaarne Gasthuis, Treant Zorggroep, Universitair Medisch Centrum Groningen, Wilhelmina Ziekenhuis Assen, Zaans Medisch Centrum, Ziekenhuis Amstelland, Ziekenhuis St Jansdal. We are grateful to the Dutch Society for Urology, the Dutch Society of Radiotherapy and Oncology and the Dutch Prostate Cancer Foundation (Prostaatkankerstichting). We would like to thank Eveline Wijnen, our research assistant, for her efforts regarding the monitoring of patient inclusion.\u003c/p\u003e\n\u003cp\u003eThe authors also thank the data managers of the Netherlands Comprehensive Cancer Organization for the (additional) data collection for the Netherlands Cancer Registry.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDee EC, Nezolosky MD, Chipidza FE, Arega MA, Butler SS, Sha ST, et al. Prostate cancer-specific mortality burden by risk group among men with localized disease: Implications for research and clinical trial priorities. Prostate. 2020;80(13):1128-33.\u003c/li\u003e\n\u003cli\u003eCooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. 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Using a population-based observational cohort study to address difficult comparative effectiveness research questions: the CEASAR study. J Comp Eff Res. 2013;2(4):445-60.\u003c/li\u003e\n\u003cli\u003eKang R, Goodney PP, Wong SL. Importance of cost-effectiveness and value in cancer care and healthcare policy. J Surg Oncol. 2016;114(3):275-80.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Prostate cancer, Patient Reported Outcomes, Health-Related Quality Of Life, Prostatectomy / methods, Prostatic neoplasm / radiotherapy, Prostatic neoplasms / surgery, androgens, Cost Effectiveness, Progression Free Survival, Distant metastasis free survival","lastPublishedDoi":"10.21203/rs.3.rs-3999440/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3999440/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cem\u003e \u003c/em\u003eThis paper describes the rationale and design of the RECOVER study. Currently, there is no consensus regarding the optimal treatment for high-risk, non-metastatic prostate cancer (PCa). The study primarily aims to evaluate and compare the impact of treatment with robot-assisted radical prostatectomy (RP) versus external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT) for men with high-risk, non-metastatic PCa regarding health-related quality of life (HRQoL) and functional outcomes. Secondary objectives are progression-free survival (PFS), distant metastasis-free survival (DMFS), costs and cost-effectiveness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe RECOVER study is a comparative effectiveness study that prospectively includes newly diagnosed high-risk (cT3a-bN0M0, ISUP-grade ≥ 4 and/or PSA \u0026gt;20 ng/mL), non-metastatic PCa patients. Four Dutch prostate cancer networks, comprising 28 hospitals, are currently participating in the study. Patient reported outcomes are collected before treatment initiation, 12 months and 36 months after treatment initiation and include the EORTC-QLQ-C30, the EPIC-26, an adapted version of the SCQ, an adapted version of the iMTA Productivity Cost Questionnaire and several specific questions regarding patient characteristics, treatment of PCa specific complaints and health resources used. Clinical data regarding patient-, tumor- and treatment characteristics and oncological outcomes are collected up to 5 years after diagnosis. For sufficient power, patient reported outcomes of 471 patients must be collected 36 months after treatment initiation. Descriptive statistics and mixed-effects models are used to assess differences in HRQoL and functional outcomes over time between the patients treated with radical prostatectomy versus EBRT (+ ADT). Inverse probability of treatment weighting or the g-formula are used to adjust for confounding covariates associated with treatment. Secondary endpoints PFS and DMFS are evaluated using a competing risk analysis and cost-utility and budget-impact analyses will be performed to determine cost and cost-effectiveness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eAn observational prospective design was chosen since a randomized controlled trial comparing surgery and radiotherapy was not deemed feasible. This study evaluates effectiveness of treatment in a routine clinical setting (with adjustment for confounding) and its findings will enhance patients’ and healthcare professionals’ awareness for the impact of both treatment modalities on (long-term) daily functioning and HRQoL and aid treatment decision making.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eThis study is registered at ClinicalTrials.gov (NCT05931419).\u003c/p\u003e","manuscriptTitle":"External beam radiation therapy versus radical prostatectomy for high-risk prostate cancer: protocol of the RECOVER study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-11 17:29:12","doi":"10.21203/rs.3.rs-3999440/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-01-13T10:09:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-06T13:50:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-06T13:50:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-02-29T10:49:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e9a67a9b-4357-4bca-8aff-294f81008e7e","owner":[],"postedDate":"March 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-03T16:00:05+00:00","versionOfRecord":{"articleIdentity":"rs-3999440","link":"https://doi.org/10.1186/s12885-025-13511-7","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-01-27 15:57:09","publishedOnDateReadable":"January 27th, 2025"},"versionCreatedAt":"2024-03-11 17:29:12","video":"","vorDoi":"10.1186/s12885-025-13511-7","vorDoiUrl":"https://doi.org/10.1186/s12885-025-13511-7","workflowStages":[]},"version":"v1","identity":"rs-3999440","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3999440","identity":"rs-3999440","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}