The Epithelioid Hemangioendothelioma Registry of the European Reference Network on Rare Adult Solid Cancers (EURACAN)

The Observational EURACAN Prospective Clinical Registry Dedicated to Epithelioid Hemangioendothelioma: the Protocol of an International and Collaborative Effort on an Ultra-rare Entity

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease.

The study design is a registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE.

The objectives are to improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern.

It is an hospital-based registry established in centres with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death.

The data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression.

The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.

This registry has been developed with the support of EHE Rare Cancer Charity UK, STATER (Grant Agreement number: 947604, HP-PJ-2019) and EURACAN 2022 (Grant Agreement number: 101085486, EU4H-2022-ERN-IBA) European Health and Digital Executive Agency (HaDEA)

Given its incidence of 0.038/100 000/year, EHE is an ultra-rare sarcoma, with distinctive, well-defined pathological, molecular and clinical features. It belongs to the group of vascular sarcomas and is characterized by WWTR1-CAMTA1 (90%) or YAP1-TFE3 (10%) gene fusions, which represents today a hallmark for diagnosis. EHE potentially arises everywhere in the body and shows a high tendency toward metastatic spread, especially in the lung, liver and bone. The onset is characterized by different presentations, including a unifocal lesion (usually in the soft tissues), locoregional metastases (multiple lesions in a single organ or in a single anatomic compartment) and systemic metastases (multi-organ involvement). Also, the biological behavior of the disease is unique in sarcomas and variable, with spontaneous regressions reported, patients with untreated stable disease overtime, slowly progressive variants and highly aggressive and rapidly fatal cases. Today, the relative incidence of the different presentations is undefined, the natural history of the different subtypes is poorly understood, and reliable clinical or biological prognostic factors are lacking. Retrospective data suggest that patients with EHE presenting or developing during their course serosal involvement and / or effusion, systemic associated symptoms and anemia have a worse prognosis, but a prospective validation of this observation is lacking. In terms of management, surgery is the treatment of choice for localized disease, with an excellent outcome (expected cure rate of 70-80%) and no proven role for local or systemic adjuvant therapies. For patients with advanced, asymptomatic disease, active surveillance is often the upfront choice in order to minimize the risk of overtreatment. Systemic therapies are usually considered for patients with progressive or symptomatic disease, although a standard medical approach is currently not established. Unfortunately, conventional chemotherapy, including anthracycline-based regimens widely regarded as the mainstay in the treatment of advanced soft tissue sarcomas, showed marginal activity in EHE. The use of potentially active compounds, such as m-TOR inhibitors which proved the highest activity in EHE and could therefore represent the preferred option, is limited by regulatory constraints as they are not currently labeled in Europe for this indication. Given the degree of uncertainty on EHE management, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving > 80 multidisciplinary, worldwide experts together with a patient representative, with the aim of defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE.

Since the number of patients is inherently low at the hospital level, the only way to increase knowledge about EHE and improve the diagnosis, treatment, and prognosis of this complex and heterogeneous disease is to harmonize and combine real-world data from sarcoma expert centres by leveraging a wide, international, joined effort. In this context, a unique opportunity is provided by the European Reference Networks (ERNs), virtual network established by the EU commission aiming to tackle rare conditions, including cancers. Among the three ERNs dedicated to cancer, EURACAN (https://euracan.eu) is the one focusing on the 10 families of rare adult solid cancers (RACs), including soft tissue sarcomas, bone sarcomas and gastrointestinal stromal tumour. Fostering academic research and promote epidemiological surveillance in rare cancers through setting up of shared registries is recognize as one of ERNs priorities. Within the sarcoma domain, taking into account the challenges described above, priority was given to ultra-rare sarcoma, and thanks to the strong connection, motivation and support provided by EHE Rare Cancer Charity UK, it was decided to start from EHE. We believe that in this context the collection of high-quality data by clinical registries will be crucial to improve the understanding of EHE natural history, validate and identify new prognostic factors, clarify the activity and efficacy of currently available treatment options and eventually provide and external control which might serve as a benchmark for the development of new drugs and support discussion with regulatory authorities.

The EURACAN EHE registry is a prospective clinical registry that will collect data from all new patients receiving a pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. To this aim, an EHE-focused clinical record form (CRF) was developed through the Research Electronic Data Capture (REDCap) and designed to capture the specific features of this disease.

For each patient, data collection will include:

1. A common baseline, including full details on demographic, comorbidities (special focus on immune-mediated and gynecological diseases), concomitant medications, physical examination, systemic symptoms at presentation, tumour-related pain assessment, blood tests, pathology and molecular features (on the diagnostic specimen), EHE extension at baseline (unifocal disease, loco-regional disease, systemic metastases)
2. Depending on the disease extent, detail on staging modalities, primary site and size, extension of metastatic disease (organs involved, number of lesions), presence and characterization of serosal involvement and effusion, treatment (surgery, radiation therapy, medical therapies, isolated limb perfusion, other locoregional techniques).

Although the EHE registry per se does not foresee any collection of pathological samples and / or imaging, the availability for each enrolled patient of pathological samples, massive parallel sequencing data and imaging at the contributing institution will be captured by the CRF, in order to facilitate patients' identification for future dedicated studies which will imply the use of these data.

Given the peculiar biological EHE behavior, in absence of any event, a mandatory 6-monthly update will be required at all contributing centers. In the mandatory 6-monthly update, information from the last visit will be recorded regarding: physical examination, time interval of development of systemic symptoms, assessment of tumor-related pain, blood tests, update on ongoing treatment / active surveillance (including modalities and timing of radiological monitoring and radiological response).

All events will be recorded at the time of the occurrence (for unifocal disease, local recurrence and metastatic progression; for locoregional and metastatic disease, systemic progression). For every event, information will be recorded on physical examination, time interval of development of systemic symptoms, assessment of tumor-related pain assessment, blood tests (hemoglobin and fibrinogen), radiological modalities detecting progression, extent of progression (by RECIST 1.1 and not), serosal involvement and / or effusion, update on ongoing treatment / active surveillance.

Patient status (alive with no evidence of disease, alive with disease, dead) and last follow up will be updated at any data entry.

The registry and therefore the electronic CRF have been shaped starting from what have been agreed and reported in the EHE consensus paper from the sarcoma community of experts, published in 2021. A registry kick-off meeting was held in Milan the 15th September 2023, involving the EHE prospective clinical registry coordination team, all the contributing centers and patients' associations (EHE Rare Cancer Charity UK, EHE Italia and EHE US) to present the registry and share common clinical practice guidelines, derived from the consensus paper, to be followed for the patients with EHE included in the registry.

The launch of the EHE prospective clinical registry was shared with all the reference institutions belonging as full members or associated partners to EURACAN sarcoma domain (63 institutions across Europe).

The project was also opened to EU institutions not belonging to EURACAN and extra-EU institutions. In this case, in order to ensure an adequate degree of expertise in the disease, the institutions interested in joining the registry were asked to provide the number of new EHE cases (molecularly confirmed) seen each year over 3 years (2020-2021-2022) and a threshold of at least 20% of EHE national incident cases was selected for participation.

As a result of this process, 21 institutions joined the registry in September 2023, 17 of which belonging to EURACAN, from 10 countries.

The registry is federated thus, data are stored by the health care providers contributing to the registry. At the local level, data are pseudonymised.

Statistical analyses will be performed based on a study protocol. Queries will be developed, in collaboration with clinical experts, to interrogate the EURACAN EHE registry to generate the descriptive statistics and relevant information needed to plan the analyses envisaged by the study protocol.

Data quality checks aim to assess whether data values are present, if they adhere to specific standard and if they are believable in terms of:

• Conformance: the data should be recorded in agreement with the correct formats (e.g. range of values, date formats);
• Completeness: the data should not have missing values or data records;
• Plausibility: the data should be believable (e.g. internal consistency; temporal and atemporal comparison);

Quality checks of the data conformance are included in the CRF in the form of predefined alerts and errors running during the data input. Moreover, several additional completeness and plausibility checks (e.g. completeness of variables for each patient, plausibility of temporal intervals between different dates, etc.) are implemented in an external web tool connected to the CRF by use of API key, capable of executing all data quality checks simultaneously. The API key is not transmitted outside the centre, it is used only locally to perform data quality checks. The results of these checks are available locally for each centre and periodically they will be summarized in reports that the registry coordination team (INT) will monitor and discuss with each centre.

Legal basis of the registry:

In Europe, the processing of personal data for scientific research can be grounded upon several conditions of lawfulness, established in Article 9(2) of the General Data Protection Regulation (GDPR). Among these, the most relevant ones are:

• the consent of data subjects (Art. 9(2)lit. a);
• the pursuing of a substantial public interest, on the basis of Union or Member State law (Art. 9(2)lit. g);
• the pursuing of a scientific research purpose on the basis of Union or Member State law (Art. 9(2)lit. j).

The GDPR allows or requires Member States to implement national specifications or derogations from certain rules set out in the GDPR, therefore the legal basis of the federated registry will be based in each participating hospital on the laws and regulations of its country.

Inclusion Criteria:

• New patients managed by the contributing centers with a pathological EHE diagnosis performed or verified by an expert sarcoma pathologist starting from 1 December 2023 onwards and to be performed within 6 months from the registration
• Molecular confirmation of the diagnosis (WWTR1-CAMTA1 or YAP1-TFE3)
• Adult patients (aged ≥ 18 years)