Community Research and Development Information Service - CORDIS

FP7

PANCARESURFUP Report Summary

Project ID: 257505
Funded under: FP7-HEALTH
Country: Sweden

Final Report Summary - PANCARESURFUP (PanCare Childhood and Adolescent Cancer Survivor Care and Follow-up Studies)

Executive Summary:
WP1 in PCSF has gathered the largest cohort of childhood cancer patients ever collected with 115,596 individuals, of whom 83,333 are 5-year survivors, from 13 data providers in 12 European countries. Each 5-year survivor in the cohort studies contributed data on basic demographic information, treatment details, and outcome information on cardiac disease (WP3), second malignancies (WP4) and premature mortality (WP5). In addition, based on the results outlined above, WP1 created three information databases -- one each for the cancer registry data, for the clinical data and for the PCSF cohort data. They all describe the characteristics of the collected data in order to facilitate data collection and establishment of a long-term-survivor-cohort for future research questions. WP2 received 2,481 radiation therapy records from 12 data providers of survivors who had been treated with radiotherapy for a childhood cancer and were included in the case-control studies in WP3 (n=1,212) and WP4 (n=1,269). WP2 created sophisticated models of radiation exposure to healthy organs that are being used to develop more accurate risk estimates than was possible without radiation dosimetry. Incorporation of these measures will contribute to the development of more efficient guidelines for prevention of both cardiac disease and second malignancies secondary to cancer treatment. The PCSF cardiac cohort in WP3 from 8 data providers consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009. In this largest study of childhood cancer survivors carried out so far we will show estimates of risk for each of five different types of symptomatic cardiac disease among survivors of childhood cancer. PCSF is a very large pan-European study, and shows how it is possible to obtain information on heart disease, not routinely collected in cancer registries, in many different settings. In WP4, PCSF pooled individual patient data from 13 cohorts from 12 European countries for which there was complete ascertainment of further new primary cancers. When the cohorts were combined there were 69,460 individuals who survived at least 5 years. Among these, 4,200 further new primary cancers developed. For the purposes of PCSF WP4 concentrated on new primary bone cancers, soft tissue sarcomas, digestive and genitourinary cancers as they are among those more frequently observed. WP5 got late mortality data from 12 data providers from 11 different European countries to establish the PCSF data base regarding the largest in the world cohort of 5-year survivors of childhood cancer in whom vital status was assessed and the cause of death in deceased persons was investigated. For analysis of late mortality the 5-year survivor cohort included 79,293 individuals. Out of these, in 77,279 cases the diagnosis of the primary tumor could be put into one of 13 categories. By the end of follow-up, 9,080 (11.7%) of the 5-year survivors had died. WP6 has produced guidelines in collaboration with the International Guideline Harmonization Group (IGHG) (breast cancer screening, cardiomyopathy screening, premature ovarian insufficiency and male gonadotoxicity) as well as by itself (definitions on transition, recommendations on transition, models of long-term follow-up recommendations and health promotion). Additional work is on-going both with and without the IGHG. WP7 has arranged several survivor meetings (Ireland, Italy x3) as well as a two-day European conference on survivorship issues in Brussels in May 2016. Pamphlets, brochures and banners for PCSF have been produced. Finally, WP8 (the Coordinator and the Project Manager) has lead the work in PCSF through two-yearly General Assemblies as well as through regular telephone and web conferences in on or more WPs together.
Project Context and Objectives:
Over the last 45 years, treatment for childhood and adolescent cancer improved greatly; 5- year survival after childhood cancer is now 80 % in developed countries. Approximately 1 individual in 750 of young adults is a childhood cancer survivor. A clear sense of the number of European childhood cancer long-term survivors is lacking. Estimates are that somewhere between 300,000 and 500,000 survivors of childhood cancer are living in Europe. Although overall approximately 80% of children survive cancer, this number conceals considerable variation in survival for long-term survivors across Europe and within European countries and regions. . As survival has improved, so the serious complications of curative therapies become apparent. We have known for many decades that cancer therapies, radiotherapy and chemotherapy, can injure healthy organs, especially in a growing child. By now, we can say that every organ in the body can potentially be damaged, including the brain, and psychological and behavioural functioning. Recent research from the United States shows that the frequency of late complications continues to rise as the length of follow-up increases with, so far, no evidence of a plateau of incidence. However, our ability to follow survivors of childhood cancer for the decades needed into middle age is limited, both in Europe and in the US. So we are not well informed about the excess risks to health of aging survivors added to the health risks experienced by the aging general population. Some late complications of treatment lead to chronic ill health or disability, and thereby constitute a significant burden both on individuals and families, and on health services and society. However, there is considerable opportunity for early identification and appropriate management of complications to improve the survivors’ health and quality of life, and to maximise efficient use of health services. However, medical and social services targeting survivors are not available in most European countries, making it difficult to quantify the needs of survivors and to provide for their needs. Futhermore, child cancer is rare and any one group of complications even more rare, indicating the necessity to assemble very large numbers of survivors to adequately assess their needs. PanCareSurFup is the first European project to propose an integrated group of research and service projects to meet the needs of survivors across Europe. PanCareSurFup, through the participation of existing registries and databases assembled the largest cohort of childhood cancer survivors to date. This allows PCSF to assess the risks of specific complications of cancer treatments. PCSF has evaluated the risks of two life-threatening complications, namely cardiac problems and second malignancies, together with an effort to establish the risk of overall late mortality, in relation to the survivors’ treatments. PCSF has integrated these research projects with additional projects investigated models of care and follow-up and transition to adult care. Risk prediction and guidelines for care and education based on our research and existing evidence, tailored for each country is being produced. Assembly of the largest cohort of survivors has enabled PCSF to produce accurate estimates of the risk of disease to long-term survivors, and to use these estimates to establish guidelines for follow-up care. The project also disseminates the results to the widest possible audience. The expected benefit is to provide every European childhood cancer survivor with better access to care and better long-term health.

PanCareSurFup has consisted of 16 Partners from 11 European countries with the work structured in 8 Work Packages (WPs). The project started on February 1, 2011 and with a one year no-cost extension ran until January 31, 2017. The contribution from the European Commission stopped just short of 6,000,000 Euro. The Grant Agreement number was 257505.

The 8 WPs of PCSF are organised to a) collect the data (WP1), b) do the research work to assess risks (WP2, 3, 4 and 5), c) to create guidelines (WP6) d) to disseminate the work of PCSF (WP7), and e) to manage the overall project (WP8). Over the six years of the project PCSF succeeded in each of its objectives.

Work Package 1 (Data collection and harmonisation) was established to receive all the data from each data provider in PCSF, to harmonise the different methods and software packages used for its collection and to combine all the data into a single database for the analytic work packages (WPs 2-5). Data was provided from national and regional cancer registries, with their well-developed procedures and protocols, and from hospital-based registries developed to meet local needs. Cancer registries typically collect as outcomes only mortality and cancer (both primary and subsequent cancers); they do not typically collect other clinical data, and little treatment data. On the other hand, clinical registries contain detailed clinical data on a relatively small number of survivors. To combine these different types of data WP1 the following objectives:

WP1 systematically evaluated the availability of data on long-term survivors of cancer in childhood and adolescence in the existing European databases. Then, WP1 established the retrospective pan-European cohort of long-term survivors of childhood and adolescent cancer in order to collect data on the endpoints of WPs 3, 4, and 5. Once that was done, and the data collected and validated, WP1 sent datasets for the analyses described in WP3, 4, and 5.
Finally, WP1 constructed a virtual pan-European database of late effects to enable future access to retrospective and maybe also prospective data to investigators. .

Work Package 2 (Radiation dosimetry) is concerned with establishing estimates of radiation received to organs relevant to PCSF. Damage to healthy organs from radiotherapy arises because high radiation doses are delivered not only to the original tumour site, but also to organs in the scatter field as a lower dose. As treatments improve this problem may increase, with more stray radiation being delivered to a larger volume of the body, especially in a small child. WP2 aims to reconstruct the radiation therapy treatment in order to determine the doses to each organ as part of the risk assessment of cardiac disease (WP3) and second malignancies (WP4). WP2 had the following objectives:

WP2 estimated the radiation dose received to the heart during radiotherapy, and estimates of the dose received by he specific site of the second malignant neoplasm during radiotherapy. WP2 aimed to produce a table of standardized dose estimation for organs at risk for the main types of childhood cancer. .

Work Package 3 (Cardiovascular disease: cohort and nested case-control study) carried out a large cohort study of the risks of cardiac disease among childhood cancer survivors and then a nested case-control study that incorporated radiation dose estimates to the heart. Chemotherapy with anthracycline drugs and direct radiation to the heart are the best known risk factors for cardiac disease among survivors. However previous studies do not allow a prediction of long-term risk due to small numbers, variations in follow-up time, the type of populations studied and non-validated heart disease, among other factors. To produce accurate risk estimates for cardiac disease WP3 established a pan-European cohort of survivors of childhood cancer in whom the occurrence of cardiovascular disease was systematically ascertained and validated. Then WP3 determined the incidence and absolute risk of cardiac disease in the cohort. This was followed by a case-control study of cardiac disease nested within the cohort to determine the treatment factors most strongly associated with increased risk. The nested case-control study was able to evaluate the effect of specific doses of radiation and chemotherapy. Finally, WP3 collected and stored biological material (blood or saliva) of cases and controls for future DNA studies.

Work Package 4 (Second malignant neoplasms: cohort and nested case-control studies) used a similar approach to the occurrence of other malignancies following the primary cancer, focussing particularily on second primary sarcomas and second primary “adult-type” carcinomas. WP3 also concentrated on sarcomas of bone and soft tissue and carcinomas of digestive tract and genito-urinary organs) sites, particularly among survivors who are aged over 40 years. Considerable uncertainties remain about the risks of second malignancies particularily among survivors aged over 40 years when cancer incidence in the general population begins its inexorable increase. WP4 undertook first a cohort study and then a nested case-control study of subsequent primary sarcomas developing within the cohort as these are the most frequent solid cancer observed in existing cohorts to determine aspects of radiotherapy and chemotherapy most strongly associated with increased risk. This design allowed investigations of the dose-response relationship between cumulative dose of radiation from radiotherapy, cumulative dose of specific anti-cancer drugs and the risk of subsequent primary sarcoma. A second approach involved a cohort study of
study of the subsequent primary “adult-type” carcinomas most frequently observed within the cohort to determine aspects of radiotherapy and chemotherapy most strongly associated with increased risk, followed by a nested case-control study.

Work Package 5 was concerned with deaths among childhood cancer survivors after 5 years from diagnosis. Traditionally five-year survival has been and is the benchmark for cure. However, the risk of cancer recurrence and cancer-therapy related deaths extend well beyond this arbitrary point. Late mortality, or deaths occurring more than five years from diagnosis can be regarded as the ultimate adverse effect of cancer and its treatment. The limited number of studies of late mortality indicate that the primary cause of death is cancer recurrence, then second malignancies and cardiac and pulmonary causes. However, we know little of the risk factors, and furthermore, variation across Europe has not been studied. To evaluate these aspect of cancer survival WP5 analysed mortality in this cohort, including survivors from various European countries. and to relate risk of death from specific causes to factors such as gender, type of childhood cancer, age at diagnosis and treatment. , The risks produced by WP6 will be based on official causes of death through accessing death certificates, hospital records and autopsy reports a sample of patients

To complement the assessment of risks in WPs 2-5 Work Package 6 developed guidelines based on these newly outlined risks together with those in the scientific literature. There is considerable variability across Europe in the extent and nature of long-term follow-up for childhood cancer survivors, and the means by which it is provided. Some European countries have published guidelines, but in other – most – European countries no uniform clinical guidelines are in use, meaning that survivors have limited follow-up care. Work Package 6 assembled an international collaboration besides PCSF and published a number of guidelines for different aspects of late effects, including the methodology of writing a guideline. In addition WP6 has evaluated the organisation of LTFU that will facilitate incorporation of the recommendations for follow-up in the above clinical practice guidelines, and transition care practices to optimise age-appropriate LTFU healthcare for those survivors who are approaching or have already reached adult age.

In order to bring the messages from PCSF to survivors and their families and to the scientific community and the general public Work Package 7 established a number of initiatives, including conferences for the above constituencies in Dublin and in Brussels, two cycling events in Italy for survivors representing a number of European countries, establishing new associations of survivors and parents, strengthening links with national and international organisations such as ICC (the International Childhood Cancer umbrella group). WP7 published and disseminated a number of brochures concerning the work of PCSF to help with recruitment into PCSF studies.

Organising all this work was the task of Work Package 8 (Management and Coordination) which oversaw all the scientific, financial and administrative aspects of the project., ensuring that all required reports and deliverables were completed on time and sent to the Commission; organised two project meetings at different locations across Europe twice yearly, established a project website (with WP7)’ disseminate information within the consortium; ebgaged stakeholders in policy definitions and developed strategies for external dissemination (with WP6 and WP7).

Impact
Although PanCareSurFup has included a number of quite diverse elements the consortium worked together very successfully with the intention of improving the lives of European children and adolescents who have survived cancer. The nature of the participants, uniting pediatric oncologists with epidemiologists, psychologists, statisticians, radiation biologists and survivors from 11 European countries has meant considerable numbers of meetings, face-to-face and by telephone and web, and new collegial arrangements.

Project Results:
INTRODUCTION
PanCareSurFup (now concluded) is a 6-year consortium funded through the EU’s FP7 funding mechanism. The main objective is to improve the lives of survivors of childhood cancer through learning more about the risks for specific late effects, namely, second malignancies, cardiac disease and premature mortality. With detailed risk assesment this consortium integrates development and dissemination of guidelines internationally that are intended to improve long-term follow-up. The consortium is made up of 16 partnering institutions. Table 1 shows the names of these institutions and the lead investigator in each.
TABLE 1. PCSF Partnering Institutions
Name of partnering institution Short name Country Name of lead person
Lunds Universitet ULUND Sweden Lars Hjorth (Coordinator)
University of Newcastle-upon-Tyne UNEW UK Rod Skinner
Istituto Giannina Gaslini IGG Italy Riccardo Haupt
Universität der Johannes Gutenberg-Universität Mainz U-Mainz Germany Desiree Grabow
Boyne Research Institute Boyne Ireland Julianne Byrne
St. Anna Kinderkrebsforschung CCRI Austria Eva Frey
Academisch Medisch Centrum bij de Universiteit van Amsterdam AMC Netherlands Leontien Kremer
Semmelweis University USEM Hungary Eva Bardi
Universita degli Studi di Torino UNITO Italy Carlotta Sacerdote
University College London UCL UK Gill Levitt
Universität Bern UBERN Switzerland Claudia Kuehni
Institut Gustave Roussy IGR France Florent de Vathaire
The University of Birmingham UBHAM UK Mike Hawkins
Fondazione Monza e Brianza per il Bambino e la sua Mamma MBBM Italy Momcilo Jankovic
SIOP Europe SIOPE Belgium Samira Essiaf
Centre International de Recherche sur le Cancer IARC France Eva Steliarova-Foucher
The work is organized into 8 Work Packages, briefly described here and in more detail below. Data relating to 115,596 individuals from 13 data providers and 12 European countries is sent to a central data collection and harmonization point (Work Package 1). Each individual survivor contributes data about basic demographic information, treatment details, and outcome information on cardiac disease (WP3), second malignancies (WP4) and premature mortality (WP5). A further data collection work package (WP2) uses the details from radiation records to reconstruct doses of radiation to healthy tissues. Work Package 6 uses this new data and existing data to produce guidelines for long-term care of survivors and investigations of transition and long-term care issues. WP7 deals with dissemination of the information from PCSF, raising awareness of the problems of long-term survival and communication with health care providers. Work Package 8 manages and coordinates the activities of PCSF. Details of each Work Package follow.
Work Package 1: Data Collection & Harmonisation
Introduction
There has been little systematic information on late effects after treatment for cancer during childhood or adolescence in Europe, partly due to different approaches to collection of data. Population-based cancer registries cover a large proportion of the European population, but they collect limited information on treatment and on outcomes. Hospital-based data collection systems have limited demographic information and limited numbers of subjects but they collect detailed clinical information. To meet the needs for sufficient sample size and detailed information on cardiac disease (WP3), second malignancies (WP4), and late mortality (WP5), a dataset that was supra-national in scope, yet extensive in its information on individual patients, was necessary. This task became WP1. The first objective was to survey European databases to discover how much data they had on long-term follow-up of childhood cancer survivors; this objective ran in parallel with objective 2 – the PanCareSurFup cohort, and objective 3 – the virtual PCSF database.
Objectives
to systematically evaluate the availability and quantity of data on long-term survivors of cancer in childhood and adolescence in existing European databases (population-based registries and clinical data sources);
to establish a retrospective pan-European cohort of long-term survivors of childhood and adolescent cancer (the PanCareSurFup cohort) for whom the occurrence of at least one of the endpoints: cardiac disease, second primary tumours and late mortality have been or can be ascertained and validated, and to provide datasets for these analyses;
to construct a virtual pan-European database of late effects consisting of the characteristics of data from European databases to enable future access to data in a timely and efficient manner
Methods
Objective 1. PCSF partners surveyed two different groups –cancer registries and clinical databases. Slightly different methods were used for each. The survey of cancer registries was carried out jointly with the ENCCA Network of Excellence. IARC developed the online questionnaire; this was endorsed by the European Network of Cancer Registries (ENCR) and distributed to all 178 population-based European cancer registries. It addressed ten areas describing data items collected on predisposing conditions, cancer diagnosis, and treatment, participation in a clinical trial, follow-up, outcome and late effects. Special emphasis was placed on collection of vital status, cause of death, and cardiac events.
The list of clinical databases was assembled from a SIOPE contact list, and surveyed by UMC-Mainz with a modified questionnaire. Collected information contained general database characteristics, patient data, cancer diagnosis, treatment, participation in a clinical trial, as well as selected medical conditions, late effects and included data on vital status, cause of death, and cardiac events. More than 48 chairs of clinical trial studies and 1700 members of SIOPE were invited to complete this survey online.
Objective 2. As a prelude to PCSF, the PanCare network surveyed its membership to ascertain who could provide data to this new study. The outcome was that 13 data providers from 12 countries became involved in PCSF and provided baseline data on the cohort of long-term survivors as well as information about the occurrence of the named types of late effects and treatment data (relevant for conducted nested case-control studies). A Study Protocol was agreed that established a common variable list of 74 precisely-defined variables, and that described the process of data collection and transmission and the security procedures at UMC-Mainz.
Objective 3. To report on baseline status and construct a virtual pan-European database of late effects to enable future access to retrospective and propose prospective data collection.
Results
Objective 1. Availability and quantity of data
Among the 178 population-based cancer registries 79 (46%) completed the questionnaire. Only 11 had data on any late effect and 54 would require dedicated funding for collection of these data. When asked to estimate the cost of collection of specified information on late effects the total amount required was €33.27 million with €2.26 million annual running costs. Detailed analyses of these data are underway and the results will be published.
From the SIOPE members 35 surveys were completed from 20 European countries and Israel. The databases hold between 27 and 30,000 patients (mean 3,350) each. The oldest started in 1963, and the most recent in 2015. Seven databases use the commonly accepted coding system; thirteen do not use a coding system. Information held varied considerably, both for treatment and for late effects. We plan to make this information available to researchers to facilitate planning studies on late effects after childhood and adolescent cancer and improve the long-term health of survivors in the long run.
Objective 2: The main output of WP1 is the creation of the PanCareSurFup Cohort, and its underlying cohorts of late mortality, cardiac disease, and second cancers.
The PCSF cohort consists of 115,596 individuals, of whom 83,333 are 5-year survivors and the balance are incident cases with follow-up since diagnosis. This huge cohort, and the vast amount of information collected on each survivor was assembled thanks to the vision and persistence of all concerned in PCSF over the course of approximately 4 years, and as a result of many discussions, meetings, telephone conferences and email communications.
All these data are stored in detail in internal databases that have the potential to form a PCSF or a PanCare information database. Backup data storage has been agreed. Access rights and sustainability of this databases must first be discussed before access can be given. A publication and sustainability committee representing all PCSF participants and data providers will establish rules for long-term storage and data access.
Objective 3. Virtual Pan-European Database. Based on the results outlined above we created three information databases -- one each for the cancer registry data, for the clinical data and for the PCSF cohort data. They all describe the characteristics of the collected data in order to facilitate data collection and establishment of a long-term-survivor-cohort for future research questions. The online tool “PCSurvDataReg” is being developed to enable data entry and search for late effects.
Impact
To our knowledge, this is the first EU wide resource which is intended to facilitate future studies of health of childhood cancer using information from cohorts assembled from many different sources. Given that studies of late effects are not routinely undertaken by either registries or hospitals, our project is a first attempt at raising awareness and interest in this field. We are optimistic that information on late effects can be collected by more databases in the future. It was positive to see that many databases systematically collect basic information on the health of childhood cancer survivors such as vital status or relapse and that specific late effects are collected by many databases. This will greatly help in planning studies on late effects since childhood cancer is rare, and pan-European pooling of data is necessary for analyses to be informative.
The information gathered for the PCSF cohort is a valuable resource which will help in future approaches to assemble large consortia using existing PanCare network structures in timely fashion. The PCSF cohort is the largest source of information on late effects in Europe. Its methods and procedures will be available for future investigators to establish their own cohorts to study late effects after childhood cancer. As PCSF has assembled information from different sources (the PanCareSurFup cohort, the population-based cancer registries, and the hospital-based data sources) a huge wealth of clinical information can be assembled to inspire future studies based on the legacy of PSCF.

Work Package 2: Radiation dosimetry
Objectives
Treatment with radiation is a long-standing tool of oncologists, but it exacts a high price from healthy tissues. While the radiation beam is defined to hit a specific tumour target there is a ‘scatter dose’ around the beam in which healthy tissues can be affected. The goal of radiation dosimetry is to estimate the dose received by healthy tissues, and the specific organs affected. WP2 in PCSF sets out to establish the dose and location of radiotherapy for cases and controls enrolled in studies of PCSF WP3 (cardiac disease) and PCSF WP4 (second malignancies). The objectives of WP2 are to 1) perform radiation therapy reconstruction and whole body dosimetry for subjects included in WP3 and WP4 who received radiotherapy; 2) estimate radiation dose to the heart for WP3 cases and controls; 3) estimate radiation dose to the specific site of the second malignancy for WP4 cases and controls; 4) produce a table of standardised dose estimation for organs at risk for the main types of childhood cancer.
Objective 1: Radiation therapy reconstruction
Methods
During PanCareSurFup, WP2 received 2481 radiation therapy records of survivors who had been treated with radiotherapy for a childhood cancer and were included in WP3 (cardiac diseases) and WP4 (subsequent primary neoplasms) case-control studies: 1212 included in WP3 and 1269 included WP4. Twelve data providers sent radiotherapy records (Table 2). The data from these records have been extracted and validated.
TABLE 2. Number of radiation therapy records received from each data provider for each work package.
WP3 WP4 TOTAL WP3 WP4 TOTAL
France) 304 224 528 Netherlands 183 112 295
Switzerland 38 34 72 Slovenia 32 26 58
Denmark 0 88 88 UK 486 518 1004
Hungary 106 56 162 Sweden 0 71 71
Italy 63 59 122 Finland 0 81 81
Total 1212 1269 2481

The radiation therapy reconstruction of 2031 of these 2481 patients (82%) has been performed. For each of these patients, we selected the anthropomorphic phantom, the most adapted to the patient at time of radiation therapy treatment, we interpreted the radiation therapy charts sent by data provider, then, by using a home-made software which is an extension of a Treatment Planning System (TPS), Isogray®, used by medical physicists and radiation therapists, reproduced the treatment effectively received by the patient at time of his treatment. This was done for each radiation therapy cure of each patient. For each patient, a whole-body dose distribution estimation was then performed by our home-made software.
Results
• Wrote a guideline for the benefit of data providers, with instructions about collection of the information needed to perform dose estimation.
• Built phantoms (Figure 1) for inclusion in the Treatment Planning Systems instead of the real image of each patient which is not available because patients were treated decades ago. At least one phantom was built for each treatment cancer position. All the organs of each phantoms have been contoured (delineated) by a radiation-therapist.

FIGURE 1: Illustrations of one of the primary phantoms.

• Built thousands of derived phantoms from each of these 11 so called “primary” phantoms of various gender, age and corpulence combinations, using auxological tables.
• Investigated the impact of the organ-size variability on dose distribution within and outside the irradiation field.
• Developed mathematical models of radiation fluency outside of photon and electron beams from accelerators used in external radiation therapy, and validated the prediction of the models. The results were published.( →Benadjaoud M et al., Phys Med Biol, 2012 ;→Alabdoaburas M. J Appl Clin Med Phys. 2015; 16:5616-5620. →Vũ Bezin et al., Physics in Medicine and Biology, 2015).
• Collaborated with a private company -- EqualEstro -- to perform independent validation of the model and results.
• Developed software to integrate our phantoms into a commercialised Treatment Planning System (TPS) Isogray® and to perform dose estimation in the whole body.
• Set up a procedure enabling the production of dose-volume histograms (DVH) from the data extracted and computerized using the software.
• Characterised and quantified the sources of uncertainties in dose estimations, and published the results. (→Vũ Bezin J, et al. J Radiol Prot. 2017).
• Compared our software with that developed at M.D. Anderson Hospital (Texas). Overall agreement was excellent with a statistical correlation greater than 0.9.
Objective 2: Dose estimation to the heart structures of cases and controls of WP3
Methods
In the anthropometric phantoms integrated in our home-made software, the following substructures were delineated: whole heart, left and right ventricles, left and right atriums, left anterior descending artery, left circumflex artery, right coronary artery, aortic valve, pulmonary valve, tricuspid valve and mitral valve. We estimated the radiation dose delivered to the heart and to its substructures in 939 subjects (Figure 2).
FIGURE 2. 3D reconstruction of heart structures
Results
Table 3 shows the average radiation dose received to the various heart structures. Average radiation doses to heart structures were systematically higher in cases than in controls.
TABLE 3. Average radiation dose to the heart according to the heart structures
Radiation dose (average, in Gray) WP3 - Case-control study
Arrhythmia Heart failure Ischaemia Pericarditis Valvulopathy
Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls
Whole Heart 15.4 6.8 12.3 6.1 14.5 7.5 24.7 4.9 22.5 6.4
Left Ventricle 13.4 5.9 11.6 5.3 12.4 6.3 21.9 4.1 18.8 5.7
Right Ventricle 16.6 7.1 13.2 6.6 16.0 8.3 27.0 5.3 25.0 6.7
Left Atrium 17.6 7.8 13.3 7.4 16.8 8.6 28.5 6.1 26.5 7.2
Right Atrium 16.9 7.9 12.7 6.7 16.1 8.6 26.7 5.8 25.8 7.1
Left Anterior Des Artery 13.3 5.6 11.5 4.9 12.5 6.7 23.1 4.2 18.7 6.0
Left Circumflex Artery 18.1 8.4 13.2 7.4 18.3 9.7 29.2 8.4 28.2 7.9
Right Coronary 17.7 7.8 13.1 6.7 16.8 8.8 27.8 5.3 26.8 7.0
Aortic Valve 18.1 8.4 13.2 7.4 18.3 9.7 29.2 8.4 28.2 7.9
Pulmonary Valve 17.7 7.5 13.1 6.9 17.8 8.8 29.5 7.0 27.7 7.1
Mitral Valve 16.8 7.6 13.3 7.0 17.0 8.2 28.4 6.1 26.5 7.0
Tricuspid Valve 18.2 7.7 13.4 7.1 17.0 8.6 29.0 5.4 27.0 7.1

Objective 3: Dose estimation to the sites of the second primary neoplasm (SPN) of cases and controls of WP4
Methods
The estimation of the radiation dose to the site of a second primary neoplasm (SPN) needs to define the localisation of the second primary cancer during radiation treatment, not only at time of its discovery, but also at the time of childhood cancer treatment, i.e. a long time (frequently some decades) before.
Delineation of SPN contours was performed by radiation therapists, who used all information sent by data providers: histology/pathology reports, surgical/operative reports, reports of scans, treatment charts and/or treatment diagrams in the medical records. Because we received the radiation therapy records very late, most during the last year of the project, we were not able to complete this task, but only those included in the bone sarcomas, digestive carcinomas, and genitourinary carcinomas studies. The remaining SPN sites will be completed in 2017 at the expense of WP2.

FIGURE 3. Example of distribution of radiotherapy dose (pink) for the first cancer for both case (left) and the matched control (right). Only the case has a second primary cancer, in dark blue; an imaginary second cancer is placed in the corresponding position on the control, in order to obtain precise dose estimates. In this example the second cancer is within the radiation field of the first cancer for the case, but not for the control.
Results
Table 4 presents the average radiation dose received to the anatomical site of the SPN and to the corresponding site of their controls. Average radiation doses were consistently higher in cases than in controls.
TABLE 4. Average estimated radiation dose for different second malignancies
Radiation dose (average, in Gy) WP4 - Case-control study
Bone sarcomas Digestive carcinomas Genito-urinary carcinoma
Cases Controls Cases Controls Cases Controls
SPN site and corresponding site in controls 18.3 6.5 13.9 5.8 7.0 3.5

Objective 4: Standardised dosimetric tables
A standardised dosimetric database was planned for subjects for whom it was not possible to access medical records and for whom no information was available about the radiation therapy protocol. However, almost all subjects had radiotherapy or medical records of sufficient quality to perform radiation dose estimation. Thus, there was no need to produce these tables for PanCareSurFup, so this objective was rendered unnecessary.

FIGURE 4. RADIATION DOSIMETRY TEAM FROM INSTITUT GUSTAVE ROUSSY, PARIS

Conclusions
WP2 has demonstrated the feasibility of carrying out a complex data retrieval exercise across Europe. WP2 has created sophisticated models of radiation exposure by healthy organs that are being used to develop more accurate risk estimates than was possible without radiation dosimetry. Incorporation of these measures will contribute to development of more efficient guidelines for prevention of both second malignancies and cardiac disease secondary to cancer treatment.

Work Package 3: Cardiovascular disease: cohort and nested case-control study
Objectives
Childhood cancer survivors (CCS) are at high risk of long-term adverse effects of cancer and its treatment, including cardiac events (CE). The objectives of the PanCareSurFup (PCSF) cardiac study (WP3) are to 1) determine the incidence and absolute risk for symptomatic CEs in European CCS; in addition, to 2) determine the treatment-related risk factors for developing symptomatic CEs, and 3) confirm earlier identified risk factors and to identify new risk factors that could be related to treatment, survivor characteristics, lifestyle and co-morbidity issues.
Methods
Eight data providers (France, Hungary, Italy (2 cohorts), the Netherlands, Slovenia, Switzerland and the United Kingdom; these data providers were able to find the necessary information) who participated in PCSF identified and validated symptomatic cardiac events in their cohorts of CCS. Data for five cardiac events were collected: symptomatic heart failure, ischemia, pericarditis, valvular disease and arrhythmia. They were graded according to the internationally-recognised Criteria for Adverse Events. From all CCSs the patient- and treatment-related variables were collected. We used two types of study designs to reach our objectives: first, we used a cohort design, to which all research subjects contribute and crude risk factors are obtained; second, we carried out a nested case-control study, in which survivors with cardiac disease were termed ‘cases’ and a set of ‘controls’ was drawn for comparison from the remainder of the cohort who did not develop cardiac disease. This provided better precision on estimates of risk. Details of the methods have been published (→ Feijen, PLOSOne, September 2016 11(9):e0162778. doi: 10.1371)
Results
The PanCareSurFup cardiac cohort consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009 and classified according to the International Classification of Childhood Cancer (ICCC3). Different strategies were used to identify cardiac events such as record linkage to population/ hospital or regional based databases, and patient- and general practitioner-based questionnaires. The results are being prepared for publication. A cohort analysis will provide descriptive information on the rates of occurrence of cardiac disease according to various risk factors – demographic, treatment, country, etc. The radiation dosimetry estimates from WP2 will be incorporated into case-control analyses to determine estimates of risk of cardiac disease – who is at risk and who is not.
Conclusion
In this largest study of childhood cancer survivors carried out so far we will show estimates of risk for each of five different types of symptomatic cardiac disease among survivors of childhood cancer. PCSF is a very large pan-European study, and shows how it is possible to obtain information on heart disease, not routinely collected in cancer registries, in many different settings. The advantages of PCSF lie in the way that the cardiac events are all defined in a similar way, and the large size of the study enables us to provide more precise risk estimates than previously. These data will be of the utmost importance when designing new treatment protocols, and in safeguarding the long-term health of survivors.

Work Package 4: Second malignant neoplasms: cohort and nested case-control studies
Introduction
Individuals diagnosed with cancer in childhood experience serious premature morbidity and mortality. In particular, by 50 years from diagnosis, 30% of those who survive for at least 5-years have died compared to 6% expected based on death rates in the general population. Among survivors who reach mature adulthood after childhood cancer second or further malignant neoplasms account for about half of the excess deaths. The development of further new primary cancers is one of the most serious adverse consequences of being treated for childhood cancer. By combining data from across Europe new insights into the long-term risks of further new primary cancers may be obtained because of the long history of cancer registration in many European countries. PanCareSurFup’s pooled studies allow us to assess risks for further new primary cancers, particularly among survivors aged over 40 years. As the largest study of childhood cancer survivors PanCareSurFup will provide new information concerning subsequent cancers, including more precise estimates of risk, possible new risk factors, and show how the occurrence of new cancers is stable, or has increased or decreased during the many decades of follow-up possible in PCSF.
There are particular concerns relating to survivors of childhood cancer because:
• exposure to treatment occurs when the body and its organs are not fully developed;
• genetic factors related to the occurrence of childhood cancer could influence the risk of development of further new primary cancers either independently or through interaction with elements of treatment;
• unlike most survivors of adult cancer (diagnosed over 50 years of age) childhood cancer survivors have their entire adult life ahead of them;
• the smaller anatomic volume of children means that radiotherapy is likely to affect more healthy organs potentially leading to greater toxicity.
Further new primary bone cancers and soft tissue sarcomas are among the most frequent new cancers observed in the initial decades after childhood cancer and the prognosis is poor. As survivors reach 50 years of age the common cancers of mature adulthood in the general population become the most frequently observed new primary cancers including digestive and genitourinary carcinomas.
Methods
PanCareSurFup has pooled individual patient data from 13 cohorts from 12 European countries for which there was complete ascertainment of further new primary cancers. Cohorts were contributed by both population-based cancer registries and major treatment centres. The countries involved were Denmark, Finland, France, Hungary, Iceland, Italy, the Netherlands, Norway, Slovenia, Sweden, Switzerland and the United Kingdom.
When the cohorts were combined there were 69,460 individuals who survived at least 5 years. Among these, 4,200 further new primary cancers developed. For the purposes of PanCareSurFup we concentrated on new primary bone cancers, soft tissue sarcomas, digestive and genitourinary cancers as they are among those more frequently observed . For each of these four cancers we have undertaken a cohort study and nested case-control study.
Each cohort study will produce estimates of the percentage of 5-year survivors who develop a new primary cancer according to time elapsed since 5-year survival. These estimates will be compared to the same data from the general population in order to develop risk estimates.
Each nested case-control study will focus on the risk arising from survivors’ treatments. For instance, we can investigate variation in the risk of each one of the new cancers, listed above, depending on the cumulative dose of radiation received and the cumulative dose of specific types of cancer chemotherapy received. So the cohort study will enable us to understand the extent to which survivors develop further new primary cancers, and in particular how this compares with the expected risk. The case-control studies will help us identify the factors which cause further new primary cancers, and, in particular, the extent to which aspects of treatment for the childhood cancer are associated with the development of further new primary cancers. Whenever possible cases and controls provided a saliva sample to enable future investigation of links between particular genes and the risk of specific further cancers.
Numbers available for specific studies
We now consider the numbers of the different types of further new primary cancers which are available for the cohort and case-control studies:
• For cohort analyses there were 235, 301, 311 and 297 bone cancers, soft tissue sarcomas, digestive cancers and genitourinary cancers observed, respectively, among the total of 69,460 5-year survivors;
• It was possible to select a control matched to the following number of cases of specified types: 220 (bone cancer), 247 (soft tissue sarcoma), 301 (digestive cancer) and 287 (genitourinary cancer).
First and second cancers
The 235 further new primary bone cancers were most frequently observed among survivors of retinoblastoma (n=73), bone sarcoma (n=37) and soft tissue sarcoma (n=37). The 301 further new primary soft tissue sarcomas were most frequently observed among survivors of retinoblastoma (n=64), central nervous system tumours (n=42) and Wilms tumour (n=34).
Location of second cancers
The 311 further new primary digestive cancers were most commonly located in bowel (n=154), liver (n=48), stomach (n=37) and pancreas (n=31). The 297 further new primary genitourinary cancers were most frequently observed in the kidney (n=74), bladder (n=48), ovary (n=43) and testis (n=39).

Likely impacts
Practical benefits to survivors and their health care professionals of the evidence produced from large-scale studies such as PanCareSurFup include providing information for:
counselling, educating and empowering survivors;
developing clinical follow-up guidelines;
preparing survivorship care plans;
providing educational material for health-care professionals;
evaluating risks as well as benefits of proposals for future treatment protocols;
advising national health authorities in relation to groups at sufficiently high risk to consider recall for counselling, screening or other interventions;
identifying low risk groups for whom self-management may be more appropriate;
providing risk stratification evidence to national health authorities to inform decisions regarding intensity of clinical follow-up for different groups of survivors.

Work Package 5: Late mortality
Introduction
Traditionally, survival beyond 5 years from diagnosis has been the standard for „cure“. However, the risk of cancer recurrence and cancer-related deaths extends well beyond this arbitrary point. Late, or premature, mortality among survivors of childhood and adolescent cancer, defined as deaths occurring more than 5 years after diagnosis, are the subject of WP5 in PanCareSurFup. However, this is not an easy task in a pan-European project where national legislation concerning data protection and logistics set up significant barriers. WP5 set out to collect data on approximately 12,000 late deaths occurring to 5-year survivors.
Methods
The collaboration of 12 data providers from 11 different European countries resulted in the establishment of the PanCareSurFup data base regarding largest in the world cohort of 5-year survivors of childhood cancer in whom vital status was assessed and the cause of death in deceased persons was investigated. WP5 was concerned with documenting the deaths that occurred after a survivor had lived at least five years from diagnosis (“late mortality”).
The data for the study come partly from population-based registries including incident cases from the date of diagnosis (Italy-pop., Denmark, Finland, Iceland, Sweden, and Slovenia), partly from registries of 5-year survivors of childhood cancer (France, Hungary, the Netherlands, Swiss, and UK) and partly from end of the therapy register (Italy-hosp.). Totally there were 120,552 cases classified according to different versions of ICD and ICD-O classifications. After extensive work, including feedback from the data providers, the primary cancer diagnosis could be classified according to the ICD-O classification, 3rd revision in 111,768 cases.
Results
Our most important finding was the decreasing late mortality with every decade of diagnosis i.e. the patients diagnosed with childhood cancer more recently had better long-term survival. At the same time, we found that the improvement depended mainly on results achieved by patients with leukemia or Hodgkin’s lymphoma.
The most interesting finding was that the magnitude of late mortality and the pattern of causes of death was dependent on the primary diagnosis, chronological period of the diagnosis and the length of follow-up.
For analysis of late mortality the 5-year survivor cohort included 79,293 individuals. Out of these, in 77,279 cases the diagnosis of the primary tumor could be put into one of the 13 categories (Figure 5). As can be seen, leukemia, central nervous system tumors and Hodgkin’s lymphoma are most frequent. It is reassuring that these are also the most frequent cancers occurring during childhood in population-based cancer registries.

FIGURE 5. Proportion of diagnostic categories of the primary cancer
In this PanCareSurFup series, cancer had been diagnosed between 1940 and 2008, with 58.2% of cases diagnosed in the eighties and nineties. The last years of follow-up were between 2006 and 2015. Survivors were followed for an average of 23 years from diagnosis.
By the end of follow-up, 9,080 (11.7%) of the 5-year survivors had died. The next step in the analysis was to determine the causes of death in 5-year survivors. These are shown in the figure below.

FIGURE 6. Causes of late deaths
The primary cancer remains the leading cause of death up to 20 years after diagnosis. After that deaths from a second cancer and deaths from other causes predominate. The good news is that both cancer and non-cancer deaths fall steeply with every decade of diagnosis up to the present. That is, late mortality was more likely after childhood cancer diagnosed a long time ago; late mortality dropped significantly in every decade since the beginning of our study. When we look at the specific causes of death different patterns occur: we find that the decrease in total mortality depends almost entirely on diminishing mortality due to primary cancer and to infections. Nevertheless, late mortality exceeds the mortality expected from the general population throughout the whole observation period. The results are being prepared for publication.
Potential impact
Results of the study will hopefully influence future treatment of childhood cancer in the direction of continuing improvements in survivors, while becoming even less toxic. At the same time, follow up of the childhood cancer survivors must be improved in order to further diminish late deaths, especially those due to secondary neoplasms and circulatory causes. Incorporation of these results into the guidelines produced by WP6 in PanCareSurFup will help to reduce late mortality even further.

Work Package 6: Guidelines, long-term follow-up and transition
Introduction
Though the current survival rate in Europe of children and adolescents treated for cancer is approximately 80%, about 60-75% of survivors have one or more, and 30-40% two or more, chronic medical problems. Many of these medical problems are serious and life-threatening, increasing both the risk of premature mortality and the logistic and financial burden on healthcare systems. Long-term follow-up (LTFU) of childhood cancer survivors (CCS) aims to facilitate timely detection of these problems in the expectation that this will reduce chronic morbidity and premature mortality. However, several strategies for the delivery of LTFU exist, with considerable variability in the health professionals involved as well as how, where and when LTFU occurs.
Effective implementation of evidence-based clinical practice guidelines can lead to significant improvements in healthcare delivery, with potential to improve health outcomes and reduce healthcare costs by facilitating rational allocation of resources to those most at risk and most likely to benefit from intervention. Although some European countries have developed guidelines to inform the content of LTFU, these have been developed independently of each other, resulting in some discordant recommendations. Furthermore, many European countries do not have any access to LTFU guidelines.
Overall Objectives
PanCareSurFup WP6 aims to provide an opportunity for equal access to long-term follow-up (LTFU) care across Europe by the development of guidelines for:
1) Clinical practice, based on the previous treatment received, for the prevention, early detection and treatment of physical and psychosocial late adverse effects (LAEs) after childhood and adolescent cancer.
2) Organisation of LTFU that will facilitate incorporation of the recommendations for follow-up in the above clinical practice guidelines.
3) Transition care practices to optimise age-appropriate LTFU healthcare for those survivors who are approaching or have already reached adult age.
4) Survivors and their families to promote a healthy lifestyle, including specific advice to address individual patient issues.

Part A. Questionnaire survey of current LTFU practice and use of guidelines in Europe
As a first step in this WP an online questionnaire survey to identify current LTFU practice, and particularly the use of LTFU guidelines, in Europe was circulated to one appropriate LTFU contact individual in each of the 44 European countries treating children with malignancy (6 small countries send their patients to neighbouring countries for treatment). The overarching aim of the survey was to inform the development, dissemination and implementation of the pan-European LTFU guidelines that WP6 would be developing later in the PanCareSurFup project. The objectives of Part A were to:
1). Document whether LTFU guidelines are used in each country, and if so which guidelines and what topics they cover;
2). Determine how LTFU is provided;
3). Seek views on the potential need for pan-European LTFU guidelines.
Methods
The questionnaire asked about the respondent, about delivery of LTFU in the respondent’s centre and country, use of LTFU guidelines and respondent’s views on the value of developing pan-European LTFU guidelines. Responses were received from 31 countries (overall response rate 70%) including 24 of 26 EU countries contacted (92%).
Results
The results showed that the use of LTFU guidelines varies considerably between and often within countries. Guidelines in use include recommendations regarding physical LAEs (late adverse effects) for which surveillance should be performed (n=22, 96%), the specific groups of survivors at risk of the specified LAEs, and also the frequency at which surveillance of these LEAs should be carried out (both n=23, 100%). Many guidelines include recommendations for surveillance of psychosocial LEAs (n=16, 70%) and promotion of a healthy lifestyle to survivors and their families (n=15, 65%). However, few guidelines include recommendations for who should perform LTFU of survivors (n=7, 30%), where this should be carried out (n=5, 22%), or transition to age-appropriate LTFU services for those survivors approaching or of adult age (n=5, 22%). Over half of the respondents (n=13, 54%) stated that important aspects of recommendations are missing from the guidelines currently in use in their centre or country.
Nearly all respondents (n=28, 93%) agreed or strongly agreed that there is a need for pan-European LTFU guidelines to be developed, making recommendations about specific physical LAEs for which surveillance should be performed (n=29, 97%). Most respondents agreed or strongly agreed that recommendations should be made about further action to be taken if a specific LAE is detected (n=27, 90%), as well as for strategic issues including minimum LTFU requirements that should be performed in all European countries (n=27 of 29 responses, 93%), transition to age-appropriate LTFU services in childhood cancer survivors (CCS) approaching or already of adult age and promotion of a healthy lifestyle (both n=26, 87%). Although most respondents (n=23, 77%) agreed or strongly agreed that recommendations should be made about who should perform LTFU of CCS and where, there was a noticeably higher rate of disagreement for these questions. Most respondents (n=27, 90%) stated they would use pan- European guidelines in their centre to improve the LTFU care given, while 20 (67%) stated that these guidelines would be used to establish a new LTFU service.
This was the first detailed study to assess the availability, content and use of guidelines for LTFU of CCS in Europe. It highlighted the absence of recommendations in existing guidelines for particular aspects of LTFU and revealed widespread recognition of the need for pan-European LTFU guidelines that include aspects of service delivery as well as the actual content of LTFU care.
Overall there was strong consensus that guidelines and recommendations are needed for many aspects of LTFU care. The results have been published (→ Brown. Pediatr Blood Cancer 2015;62:322-328).

FIGURE 7. Results from survey concerning follow-up practices

Part B. Guideline development
WP6 has undertaken two strands of guideline development, one for late effects surveillance and one for transition practice. A great deal has been achieved with several guidelines already published and many under development. Recruitment of expert members for each topic is a crucial but time-consuming aspect of guideline development work which is therefore ongoing and likely to continue for at least another 2-3 years.
Results
Guidelines for surveillance of LAEs during LTFU. These guidelines have been developed using evidence-based methodology developed by members of WP6 in collaboration with international colleagues, as part of the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). This methodology has been published (→ Kremer Paediatr Blood Cancer 2013; 60: 543-549). Many of the guidelines have been (or are still being) developed by an active ongoing collaboration between WP6 and IGHG (many WP6 members have active and senior roles within). The other guidelines are being developed by WP6 alone using methodology adapted from the published IGHG approach. In collaboration with IGHG, 4 guidelines have been published so far, concerning breast cancer surveillance (→Mulder LancOncol 2013;14:621-629), cardiomyopathy surveillance (→ Armenian LancOncol 2015;16:e123-136), premature ovarian insufficiency (→ vanDorp J Clin Oncol. 2016 Oct 1;34(28):3440-50), and guidelines for male gonadotoxicity surveillance (→ Skinner, Lancet Oncol. 2017 Feb;18(2):e75-e90. The guideline for thyroid cancer surveillance has been submitted for publication (→Clements 2017). Below are listed the guidelines that are being developed under the collaboration with IGHG (Table 5).

TABLE 5. Guidelines being developed in collaboration with IGHG
Guidelines in progress

a) Secondary CNS neoplasms surveillance guidelines
Mental health surveillance guidelines
b) Metabolic syndrome surveillance guidelines
c) Hypothalamic / pituitary dysfunction surveillance guidelines
d) Pulmonary dysfunction surveillance guidelines
e) Ototoxicity surveillance guidelines
f) Coronary artery disease surveillance guidelines Guidelines to commence during 2017/18

a) Renal dysfunction surveillance guidelines
b) Bone toxicity surveillance guidelines
c) Secondary GIT malignancies surveillance guidelines
d) Neurocognitive dysfunction surveillance guidelines

In addition, a number of guidelines are under development by PCSF WP6 alone (Table 6)

TABLE 6. Guidelines being developed by PanCareSurFup WP6 alone
Completed Guidelines

a) Hepatic surveillance recommendations (→ Bardi manuscript in preparation)
Guidelines to commence during 2017/18

a) Lower urinary tract surveillance recommendations
b) Craniofacial / dental surveillance recommendations
c) Gastrointestinal surveillance recommendations
d) Secondary AML surveillance recommendations
e) Skin / alopecia surveillance recommendations
f) Spine / scoliosis surveillance recommendations
g) Spleen / immunological surveillance recommendations
h) Visual surveillance recommendations

Overall Objective 3: Transition care practices
Guidelines for delivery of long-term Follow-up care are being developed by WP6 alone using methodology based on the published IGHG approach. The guidelines completed or in progress are listed below
Completed
Transition definition (→Mulder: Eur J Cancer 2016; 54: 64-68)
In progress
Transition recommendations
Models of LTFU care recommendations
Health promotion recommendations

Additional work to continue in 2017/8
Development of the above guidelines has been accompanied by many other achievements
Multinational and multidisciplinary team continue their work on guideline development, including planning topic selection, oversight of progress, implementation and related issues.
Two training web conferences during June 2012 (one each covering the characteristics of evidence-based guidelines, and the detailed guideline development methodology).
These training web conferences informed the development of a guideline development handbook.
A joint WP6/WP7 Implementation and Feasibility sub-group was convened to identify barriers to implementation of guidelines in European regions/individual countries and consider strategies to help with these issues at the stage of guidelines development.
A joint WP6/WP7 PLAIN Information sub-group was convened to ensure that the guidelines are made available in lay terms for survivors, and non-specialist health professionals and consider issues of presentation, translation and dissemination. This has been undertaken done in collaboration with another EU-FP7 funded project (ENCCA, WP13) which developed the "Survivorship Passport".
Performance measures for evaluation of implementation of the most important recommendations in the published LTFU surveillance guidelines are under development (scheduled completion date spring 2017).
Potential Impact
The results of the survey highlighted the need for pan-European guidelines to inform clinicians, survivors / families and healthcare systems about LTFU care should be delivered (models of care, transition) and what it should include (surveillance for late adverse effects, health promotion). They have also provided an important baseline to inform subsequent dissemination and implementation of the guidelines across Europe. Clinical practice guidelines for late adverse effects have identified gaps in knowledge of late effects on which to base guidelines. This work will continue and is intended to become the standard for countries to base their surveillance and counselling for late effects. Organisation of LTFU, transition care practices, healthy lifestyle promotion, together with the guidelines offer the opportunity to improve equity of access to LTFU in all European countries.

➢ We still have a long way to go
➢ The hard part is now
➢ Cure is definitely not enough
➢ Use survivor experiences and keep survivors engaged from an early stage
➢ We earn from each other
➢ Don´t underestimate yourself
➢ Continue to inform all along the way from the beginning of treatment
➢ Treatment summaries/Passport to empower survivors
➢ Risk stratification which identify those at risk (few) and those with a small or no increased risk (many)
➢ Update professionals (e.g. GPs) on social media and other novel means of keeping contact with their patients
➢ Implement new technologies where possible, e.g. apps to remind/alert survivors about follow-up
➢ Impart new information to survivors as gently as possible – don’t scare the survivors unnecessarily
➢ Lobby important stakeholders such as MPs, MEPs, and Health Authorities etc.

Potential Impact:
Management and Coordination
Results
WP8 has continued to lead the Consortium through multiple web conferences of the Executive Board on a regular basis as well as through physical meetings (General Assemblies) at least twice yearly. WP8 has also been present in most other web conferences related to WP2-5 and WP6 respectively. The web site (www.pancaresurfup.eu) has been constantly updated with new information and new publications.
Work with other EU projects such as ENCCA (ended Dec 31, 2015), PanCareLIFE and ExPO-r-Net has been ongoing with the Coordinator from ULUND being present at several if not most of their meetings. This means that common ground between these European projects has gone forward, with significant advances made by all stakeholders.
IMPACT
The work of the PanCareSurFup consortium has had significant benefits for European research and for the continued development of the PanCare Network (www.pancare.eu). PanCare has, together with SIOP-Europe, continued to develop the field of survivorship after childhood cancers, with, again, the work being done for the benefit of stakeholders. This is obvious not least in the new Joint Action on Rare Cancers where SIOP-Europe is leading Work package 9 on Childhood cancers and PanCare is task leader for task 9.4 “To make recommendations on models of healthcare for survivors of childhood cancers, including long-term follow-up, transition to adult medicine, and the use of a Survivorship Passport”. Another joint venture between SIOP-Europe and PanCare is the Strategic Plan for Childhood Cancer in Europe where the Coordinator for PanCareSurFup is leading objective number 6, “Quality of Survivorship”.
As a follow-up to ExPO-r-Net (a pilot European reference Network), the European Commission launched a call for new European reference Networks (ERNs) and ERN PaedCan was approved and will be launched in Vilnius on March 9-10, 2017. Several of the institutions involved in PanCareSurFup are partners in ERN PaedCan. The PanCareLIFE consortium also derived significant benefit from the prior development of PCSF, in development of its own procedures and research questions, establishing synergies between and beyond these research projects.
1. Potential Impact
A. Improved international competitiveness
PanCareSurFup has collected the largest database of information on the health of long-term survivors of childhood and adolescent cancer, exceeding by a factor of approximately four the next largest series (the US-based Childhood Cancer Survivors Study). Its quality is based on the fact that it is largely population-based, meaning that all survivors are included, thus reducing biases, and also on the extensive data checking and harmonization done at source and centrally. PanCareSurFup contains a number of world-renowned experts in their fields; interactions between strong and weaker partners will help to raise the standards of the outputs of PCSF, and thus the competitiveness of Europe and the participating institutions.
B. Impacts on European competitiveness in the area of science and technology
The difficulties encountered and overcome in establishing the PCSF cohort of long-term survivors should not be overlooked. Collecting and harmonising data from many different countries with differing standards and cultures has been achieved despite considerable obstacles. These included different disease coding practices, lack of collaboration among some colleagues outside PCSF, mis-communication, language difficulties, etc. Nonetheless the project is successful. The present project in which the largest number of survivors of childhood cancer are assembled is unprecedented in its impact both for individual countries and for Europe as a whole. Nor is its impact limited to Europe, but will be incorporated world-wide into current practice.
The linking of different researchers and register sources from all over Europe will enhance European scientific competitiveness by sharing mutual strengths and experiences in the production of unique data. It will also encourage countries in the development of their own national population-based cancer registries, and lead to increased cooperation.
To set-up these case-control studies is also an exceptional opportunity to integrate European Scientific Excellence in common large scale structured research projects, and to reach scientific objectives which could not be attained at a national level due to the large numbers required for accurate estimates.
Radiation dosimetry, as described in WP2 at the Institut Gustav Roussy in Paris, will produce standardized tables of radiation dose received during radiotherapy to all main organs at risk of late effects. They will be a unique production of this project, and provide information that is presently lacking. The tables can be used to help guide radiotherapists to give a more precisely focussed dose of radiation to the target organ and avoid healthy tissue.
The production and implementation of guidelines in all aspects of long-term follow-up of survivors, including clinical practice recommendations appropriate for the many diverse European countries, models of LTFU care, transition from paediatric to adult care and health promotion will offer an unparalleled opportunity to develop coherent but state of the art healthcare provision for a highly vulnerable group of individuals. No previous guidelines have attempted to address the healthcare needs of childhood cancer survivors (CCS, in the document childhood is understood to include adolescence) in such a diverse but linked group of countries, but the use and refinement of standardised methodology for guideline development and production of evidence summaries will provide a template for similar future projects both within and without Europe.
On a day to day basis, the introduction and implementation of harmonised clinical practice guidelines in all European countries will improve standards of long-term follow-up care for survivors with respect to surveillance to facilitate early assessment for late adverse effects, and the provision of interventions including both overall health promotion and the appropriate initial management of complications identified by surveillance. The guidelines will provide recommendations about appropriate levels of care, which will facilitate access to, and maximise the number of survivors in care, thereby improving their clinical management and optimising their present and future health.
C. Creating high value jobs
A number of young people from different PCSF beneficiaries (Netherlands, Switzerland, UK) have obtained their doctoral degrees based on PCSF data and expertise. These young scientists have been exposed to the best research and the most extensive research networks that they can then use to further their own careers, and land high value jobs in academia, industry and public service.
D. Better informed public
The media events described below, run by PCSF beneficiaries, have been largely successful in raising awareness about the health consequences of treatment for childhood cancer. PCSF participants were on radio, TV, YouTube, and made personal appearances to describe the work of the consortium.
E. More and successful research applications, consortia and funding.
The success of PanCareSurFup spurred on the PanCare network to apply to the Commission for a second consortium. This application was successful, and in November 2013 PanCareLIFE (Grant no. 602030) was funded to almost €6 million through the European Union’s FP7 funding mechanism. PanCareLIFE is a 5-year project that focuses on late effects in survivors of cancer diagnosed during childhood or adolescence, specifically, on hearing loss, on loss of fertility and on quality of life. In addition to these data-intensive projects, PanCareLIFE also includes a subproject that seeks to improve knowledge and use of measures to preserve fertility, a work package focusing on guidelines for fertility preservation, and work packages dealing with dissemination and management (www.pancarelife.eu). To help with the costs of PCSF, many participants applied for extra funding to agencies such as local/national cancer charities.
PanCare also made an application for a third consortium, to be called PanCareAll Outcomes, in April 2016, but was unsuccessful.
F. Increasing the effectiveness of public services and policy
PCSF is in the process of developing absolute, relative and excess risks for cardiac disease and second malignancies in order to provide a reliable and unbiased evidence base for concentrating health services resources on those most at risk and most likely to benefit from intervention. This risk stratification is badly needed by public health authorities in order to discriminate between survivors who do not need specific interventions and those whose lives can be saved by specific interventions. The ability to properly target health resources will save the tax-payers money in the long run. Input from PCSF participant into the development of the Irish national cancer control plans has meant that the new plan pays attention to issues of survivorship, from adult as well as childhood cancer, and includes a section on childhood cancer for the first time.

G. Enhancing health and quality of life of long-term survivors of childhood cancer:
PanCareSurFup collected, harmonised and is in the process of analysing data on issues relating to risk factors for life-threatening late adverse effects which, after being fed back to the development of clinical trials, will suggest preventive measures, intervention and clinical trials, to reduce late toxicity, allowing continued good survival and ultimately leading to improved care and quality-of-life, and possibly reduced mortality.
In addition, the information gained through work on guidelines, models of follow-up care and transition will empower and enable survivors and their care-givers to make the best possible decisions regarding their health.
H. Developing the country’s international reputation
Besides world leaders in their fields PCSF participants include some from countries that have less-well developed scientific establishments. Their involvement in PCSF at all levels (setting policies and procedures, developing study protocols, data collection and transmission, and data analysis and publication) will raise the reputation of each country for excellent science, medical care and research.
I. Setting standards and improving standards
The results of the PCSF projects, especially the guidelines, will be used to create standards of care in some countries and to improve standards of care in other countries. In addition, the process of collecting data and the standards set through the Study Protocol have enabled clinical collaborators and cancer registries to improve their own internal standards, by establishing databases with proper security protocols and documentation. Even during the course of the project PCSF leaders received requests for the variable list that can be used as a guide for future data collection. PCSF deliverables can help countries to the process of national data collection. Harmonised guidelines for long-term follow-up procedures will encourage countries to collect and register data more harmoniously across Europe. In turn, this will enable establishment of new clinical trials for treatment of children with cancer.
J. Solving major national and global problems and challenges, including an ageing population
PCSF has created and continues its work of creation and updating of standardised clinical follow-up guidelines. These are intended to guide treatment and to empower survivors. PCSF will produce risk estimates, especially targeted to older survivors for whom little information is currently available. These will enable more accurate risk prediction, and assist in planning intervention studies to prevent or diagnose late adverse effects as early as possible among those most at risk. Results from PCSF will provide a basis for training health care professionals and engaging them in further late effects studies.
2. Socioeconomic impact
Over the last 40 years, treatment for childhood and adolescent cancer has improved greatly; 5- year survival after childhood cancer now reaches and exceeds 80% for some cancers in developed countries. Approximately 1 in 750 of young adults is now a childhood cancer survivor. Estimates place the number of long-term survivors in Europe at between 300,000 and 500,000. However, significant differences in both survival and services for long-term follow-up exist across Europe. The frequency of late complications continues to rise as the length of follow-up increases with, so far, no evidence of a plateau of incidence. Some late complications of treatment lead to chronic ill health or disability, and thereby constitute a significant burden both on individuals and families, and on health services and society
However, there is considerable opportunity for early identification and appropriate management of complications to improve the survivors’ health and quality of life, and to maximise efficient and cost-effective use of health services. The PanCareSurFup consortium has created an integrated group of research and service projects to meet these needs.
PanCareSurFup has assembled a strong pan-European consortium that links researchers, service providers and families and survivors into a unit that has focussed attention on this emerging problem of late effects in Europe.
Research based on this cohort has centered on cardiac toxicity, second cancers and late mortality, with service projects based on a study of models of follow-up and transition to adult care. PanCareSurFup is preparing for publication articles that will describe risks of complications of treatment received. Risk prediction and guidelines for care and education will be based on our research and existing evidence, and tailored for each country. The expected benefit is to provide every European childhood cancer survivor with better access to care and better long-term health.
3. Wider societal implications of the project so far
A. Economic impact of the General Assemblies held twice yearly in cities across Europe was estimated as the amount of money spent at the most recent GA. In a survey of PCSF participants respondents estimated that each spent €660 for travel and expenses. Many respondents brought family members or colleagues and also spent time as tourists.
B. Impact on Survivor/Parent organizations
In Ireland, participant Boyne was instrumental in bringing together the parents of two men who had survived brain tumours. These parents, together with Boyne, founded the Irish national organization for survivors and parents – CanCare4Living (www.cancare4living.ie). CC4L has established relationships with PanCare, with the Irish Cancer Society, with the Northern Ireland Childhood Cancer Fund, and is working with the Irish government to put in place multidisciplinary services for survivors. PCSF has active participation from CCR (Childhood Cancer International, representing survivors and families world-wide)
4. Main dissemination activities
PanCareSurFup in Work Package (WP) 7 has created a Publication Committee to monitor and encourage presentations and publications of methods and results arising from PCSF’s activities. WP7 comprises all PCSF participants and has sponsored a number of activities for and about survivors in order to alert them to the work of PCSF and also to encourage them to proactively manage their own health.
A. Publication Committee. Chaired by UBERN, with members from ULUND (Coordinator), UBHAM, Boyne, INSERM, UNEW and AMC. The committee has developed a publication policy that includes statements about authorship and use of PCSF foreground. The following list of publications has arisen from the PCSF consortium to date:
Brown MC, Levitt GA, Frey E, Bárdi E, Haupt R, Hjorth L, Kremer L, Kuehni CE, Lettner C, Mulder RL, Michel G, Skinner R; PanCareSurFup Consortium. The views of European clinicians on guidelines for long-term follow-up of childhood cancer survivors. Pediatric Blood and Cancer. 2015 Feb;62(2):322-328. doi: 10.1002/pbc.25310.
Schwartz B, Benadjaoud MA, Clero E, et al. Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment. Radiation and Environmental Biophysics 2014:53(2):381-390.

Frey E, van der Pal H. Transitional care of a childhood cancer survivor to adult services: facilitating the process of individual access to different models. Current Opinion in Supportive and Palliative care 2013:7(3):309-313.

Skinner R, Oeffinger KC. Developing international consensus for late effects screening and guidance. Current Opinion in Supportive and Palliative care 2013:7(3):303-308.

Mulder RL, Hudson MM, Skinner R, et al. Health problems in survivors of childhood cancer: the need for international collaboration in long-term follow-up care. Future Oncology 2013:9(11):1667-1670.

Kremer LC, Mulder RL, Oeffinger KC, et al. A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatric Blood & Cancer 2013:60(4):543-549.

Mulder RL, Kremer LC, Hudson MM, et al. Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. The Lancet Oncology 2013:14(13):e621-629.

Kuehni CE, Rueegg CS, Michel G, et al. Cohort profile: The Swiss Childhood Cancer Survivor Study. International Journal of Epidemiology 2012:41(6):1553-1564.

Armenian, S.H., et al., Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. The Lancet Oncology, 2015. 16(3): p. e123-e136.

Hjorth, L., et al., Survivorship after childhood cancer: PanCare: A European Network to promote optimal long-term care. European Journal of Cancer, 2015. 51(10): p. 1203-1211.

Skinner R, Haupt R, Hjorth L, Kremer LC & MulderRL.. The European Experience of Establishing Guidelines for Surveillance of the Childhood Cancer Survivor. In: Mucci GA, Torno LR, editors. Handbook of Long Term Care of the Childhood Cancer Survivor: Spring

Handbook for guideline development; collaboration between International Guideline Harmonization Group, PanCareSurFup and Cochrane Childhood Cancer Group
Feijen Elizabeth (Lieke) A. M., Helena J. van der Pal, Elvira C. van Dalen, Renee L. Mulder, Edit Bardi, Claudia Kuehni, Wim J. E. Tissing, Leontine C. M. Kremer. A New Method to Facilitate Valid and Consistent Grading Cardiac Events in Childhood Cancer Survivors Using Medical Records. PLOS one, 2014, 9(7)
Feijen EAM, Font-Gonzales A, van Dalen EC, van der Pal HJH, Reulen RC, Winter DL, Kuehni CE, Haupt R, Alessi D, Byrne J, Bardi E, Jakab Z, Grabow D, Garwicz S, Jankovic M, Levitt GA, Skinner F, Zaletel LZ, Hjorth L, Tissing WJE, de Vathaire F, Hawkins MM, Kremer KCM, PanCareSurFup consortium. Late cardiac events after childhood cancer: methodological aspects of the pan-European study PanCareSurFup. PLOSOne, September 19, 2016.
van Dorp W, Mulder RL, Kremer LC, Hudson MM, van den Heuvel-Eibrink MM, van den Berg MH, Levine JM, van Dulmen-den Broeder E, di Iorgi N, Albanese A, Armenian SH, Bhatia S, Constine LS, Corrias A, Deans R, Dirksen U, Gracia CR, Hjorth L, Kroon L, Lambalk CB, Landier W, Levitt G, Leiper A, Meacham L, Mussa A, Neggers SJ, Oeffinger KC, Revelli A, van Santen HM, Skinner R, Toogood A, Wallace WH, Haupt R. Recommendations for Premature Ovarian Insufficiency Surveillance for Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Report From the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration With the PanCareSurFup Consortium. Journal of Clinical Oncology 2016;34:3440-3450.
In addition, PCSF authors have presented both platform and poster presentations at national and international meetings, including the following:
• European Symposium on Late Complications after Childhood Cancer (ESLCCC 09) in Edinburgh, Scotland, October 2009.
• 14th International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer, Arlington, VA, June 2014
• European Symposium on Late Complications after Childhood Cancer (ESLCCC14), Edinburgh, Scotland, October 2014
• European Symposium on Late Complications after Childhood Cancer (ESLCCC16), Copenhagen, Denmark, September 2016
The Publication Committee reviews all applications of intent to write a paper, and also reviews the final paper pre-publication. The goal is to strive for excellence at all times, and to achieve publication in journals with the highest impact factor. The institutions of each author are encouraged to prepare a press release with photo concerning the papers published by their scientists.
B. Website
The PanCareSurFup website (www.pancaresurfup.eu) carries information about the project, the work packages, their objectives and dissemination activities. The top of each page shows a group of survivors participating in the ”Race of Brave Bikers” at Marostica, Italy, in June 2013 (more below). The opening page shown above carries the logo and announcement for the PanCare SurFup conference in Brussels, 23-24 May 2016, and links to the conference programme and registration information (more below)
C. PCSF Brochures
To carry the message of PCSF to a wide audience WP7 developed, first, a large brochure describing the project in some detail in English, and then a series of smaller, tri-fold brochures describing the project in simpler languages. These smaller brochures were translated and printed in 9 European languages, English, Italian, German, French, Romanian, Polish, Slovenian, Czech and Hungarian. The brochures are available here http://boyneresearch.ie/brochures.html.
All brochures were available and handed out at national and international conferences, such as SIOP, ESLCCC, the International Conference on Complications (above), PanCare meetings from 2012 onwards, the PCSF Conference in Brussels in May 2016, meetings of the Irish Cancer Society, of CanCare4Living, of Childhood Cancer International (CCI),
D. Race of Brave Bikers
The first 'Race of Brave Bikers' took place in May 2012, sponsored by PanCareSurFup. Other sponsors included Italian bicycle manufacturers, Italian charities and food producing companies. Up to two survivors each from a number of European countries, including Ireland, Sweden, Austria and Italy, were invited to an all-expenses paid trip to cycle around Marostica, a medieval city in Italy, in conjunction with the professional race GranFondo Fizik. A Round Table discussion was held with professionals and survivors participating. The purpose was to empower survivors and to spread the word about survivorship.
The second Race of Brave Bikers occurred in Marostica in April 2013, with the same format, that is, a bicycle in conjunction with the annual GranFondo Fizik, and included a Round Table discussion. This event is part of the dissemination work package for PanCareSurFup. To view some photos and to read more about this, and other events, see (http://boyneresearch.ie/resources/Newsletter_08_August_2012.pdf). Photos are also available on our Facebook page.
E. MSC Cruise
PanCare and PanCareSurFup were delighted to be part of the fundraising event -“Cruise towards Life” which was held in Genoa, Italy on 24th/25thOctober 2013. The event was run by MSC Cruises with the support of other Italian sponsors. The aim was to inform people not directly involved in childhood cancer about the success in Europe of treating children and adolescents affected by cancer, the importance of the cooperative work of a European group like PanCare, and the goal of achieving a complete cure in childhood cancer, which is today a reality, as well as the task of caring about the health status of long-term survivors (role of PanCareSurFup). The evening aboard MSC Opera included a cocktail reception, dinner, speeches, entertainment and an auction. The evening was a great success with 1,200 guests in attendance. A press conference and round table was arranged for the following day. It involved scientific experts from Italy (AIEOP), Europe (PanCare), and the U.S., who discussed results, problems, and projects on childhood cancer.
F. Conferences
a) The Irish Conference on Survivorship after Cancer during Childhood and Adolescence, in association with the Irish Cancer Society, took place in the Croke Park Conference Centre in Dublin in November 2011. It was sponsored by PanCareSurFup and participant Boyne, and highlighted the work of PCSF in second cancers and cardiac disease, as well as guidelines. It featured a series of panels of professionals and survivors to address issues of concern to survivors. It was attended by over 100 parents and survivors, health-care professionals and policy-makers.
b) PanCareSurFup for Childhood Cancer Survivors European Conference Acting Now! was held in the Thon Hotel EU in Brussels from 23-24 May 2016. The objectives of the conference were to highlight the work of PCSF, to address current challenges in ensuring the quality of survivorship, and to empower survivors to play an active role in maintaining their own health and well-being with specific tools, such as the ‘Survivorship Passport’. Over 130 people attended the conference which was addressed by MEP Aloiz Peterle, who is a member of the interest group – MEPs against cancer (MAC). The programme was moderated most ably by Vivienne Parry OBE from the UK. It can be viewed on the PCSF website (http://www.pancaresurfup.eu/pancaresurfup/pancaresurfup-is-hosting-a-european-conference/).
Take Home Messages from the Conference by Survivors

➢ We still have a long way to go
➢ The hard part is now
➢ Cure is definitely not enough
➢ Use survivor experiences and keep survivors engaged from an early stage
➢ We earn from each other
➢ Don´t underestimate yourself
➢ Continue to inform all along the way from the beginning of treatment
➢ Treatment summaries/Passport to empower survivors
➢ Risk stratification which identify those at risk (few) and those with a small or no increased risk (many)
➢ Update professionals (e.g. GPs) on social media and other novel means of keeping contact with their patients
➢ Implement new technologies where possible, e.g. apps to remind/alert survivors about follow-up
➢ Impart new information to survivors as gently as possible – don’t scare the survivors unnecessarily
➢ Lobby important stakeholders such as MPs, MEPs, and Health Authorities etc.

FIGURE PARTICIPANTS

SARAH QUIGLEY FROM IRELAND DR. CLAIRE BERGER (FRANCE) HAS A QUESTION

G. PCSF Bulletin
In conjunction with SIOPE PanCareSurFup prepared a series of 12 Bulletins, intended to highlight the work of PCSF, and to tell the public something about the people behind PCSF. Each bulletin carries a letter from the Coordinator, a list of events involving PCSF participants and an in-depth interview with one of the PCSF participants. The bulletins can be found here: http://www.pancaresurfup.eu/press/pancaresurfup-bulletins/
4. Exploitation of results
PCSF has exploited the considerable resources that the EU has invested in strengthening European cancer registries, via EUROCOURSE, etc, by extracting data in order to create a new European structure to assess the health of long-term survivors of childhood cancer. The list of publications in the scientific literature is provided above. In addition, the PCSF list of first-level publications (those that address the hypotheses in the Description of Work) comes to about 30 papers at present. These will be given top priority for analysis and publication, ahead of the also lengthy list of second-level publications (those not foreseen in the Description of Work). Foreground generated by PCSF will lead to development and investigation of new hypotheses.
PCSF authors will continue to attend the major national and international conferences to present the results of the study. One of the dissemination goals is for junior scientists at each institution to be encouraged to be first authors, and to learn about late effect studies.
The Sustainability Plan, below, outlines how the consortium will maintain its core publication activities into the future. Publications and presentations will be encouraged for relevant international meetings.
5. Sustainability Plan
At the final General Assembly in Erice, Sicily in November 2016, PanCareSurFup agreed that the Publication Committee would be expanded and renamed in order to be the body primarily responsible for carrying the PCSF activities forward. The committee will be responsible for maintaining the database of presentations and publications arising from the consortium and for organising the PanCareSurFup Symposium as part of each semiannual PanCare meeting. These Symposia will be the forum for PCSF investigators to present analyses in progress, and concluded, to get valuable feed-back and suggestions from the PanCare membership, and to allow new ideas to emerge that would take advantage of the rich trove of data represented by PCSF. Two PCSF Symposia each year will serve to maintain the momentum to present and to publish the methods and results of PCSF until all the hypotheses of PCSF have been addressed in publications.

List of Websites:
www.pancaresurfup.eu
Lars Hjorth, Consultant, Lund University
Tel: + 46 46 17 82 73
Fax: + 46 46 13 05 73
E-mail: lars.hjorth@med.lu.se

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LUNDS UNIVERSITET
Sweden
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