Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008 First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28 March 2008 Participants Name Centre / Country Discipline / Interests e-mail Edit Bardi (EB) Budapest, Hungary Paediatric Oncologist, [email protected] nephro & cardiotoxicity Joern-Dirk Beck (JBe) Erlangen, Germany Paediatric Oncologist, [email protected] LESS Julianne Byrne (JBy) Drogheda, Ireland Epidemiology, Boyne [email protected] Research Institute Jos PM Bokkerink (JBo) Nijmegan, Paediatric Oncologist, [email protected] Netherlands long-term follow-up Desiree Debling (DD) Mainz, Germany Epidemiology, German [email protected] Childhood Cancer Registry Eva Frey (EF) Vienna, Austria Paediatric Oncologist [email protected] Stanislaw Garwicz (SG) Lund, Sweden Paediatric Oncologist, [email protected] SMNs, late mortality, ANCR / NOPHO Heidi Glosli (HG) Oslo, Norway Paediatric Oncologist [email protected] Riccardo Haupt (RH) Genoa, Italy Paediatric Oncologist, [email protected] ELTEC, OTR Ann-Marie Jacobsson Lund, Sweden Research coordinator [email protected] (AMJ) Lars Hjorth (LH) Lund, Sweden Paediatric Oncologist, [email protected] nephrotoxicity, Chair Swedish Late Effects Gp Zsuzsanna Jakab (JZ) Budapest, Hungary Hungarian Paediatric [email protected] Cancer Registry Momcilo Jankovic (MJ) Monza, Italy Paediatric Oncologist, [email protected] ELTEC, OTR Bernarda Kazanowska Wroclaw, Poland Paediatric Oncologist, [email protected] (BK) chair of Polish Paediatric Solid Tumour Group Leontien Kremer (LK) Amsterdam, Paediatric Oncologist, [email protected] Netherlands LATER, Cochrane CCC Herwig Lackner (HL) Graz, Austria Paediatric Oncologist [email protected] Gill Levitt (GL) Great Ormond St, Paediatric Oncologist, [email protected] UK cardiotoxicity, models of care, past chair CCLG Late Effects Gp (LEGp) Jon Havard Loge (JL) Oslo, Norway Clinical psychologist [email protected] Andrea Moser (AM) Graz, Austria Paediatric Oncologist [email protected] Guido Pastore (GP) Novara, Italy Paediatric Oncologist, [email protected] Epidemiologist, Piedmont Registry Catherine Rechnitzer Copenhagen, Paediatric Oncologist, [email protected] (CR) Denmark late effects Rod Skinner (RS) Newcastle, UK Paediatric Oncologist, [email protected] BMT, nephrotoxicity, member of CCLG LEGp Elaine Sugden (ES) Oxford, UK Paediatric [email protected] Radiotherapist, chair of CLLG LEGp Florent de Vathaire IGR, France Epidemiologist [email protected] (FdV) Eva Widing (EW) Oslo, Norway Paediatric Oncologist, [email protected] Norwegian Late Effects Gp Lorna Zadravec Zaletel Lubljana, Slovenia Radiotherapist [email protected] (LZ) 1 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008 Apologies Mike Hawkins Birmingham, UK Epidemiologist, member [email protected] of CCLG LEGp, BCCSS, ELTEC

27th March 2008

Introductions

LH described the aim of the meeting and outlined the proposed agenda / timetable, including:  The Erice Statement as a possible working-tool for the collaboration  Research, e.g. late mortality, perhaps genetic polymorphisms, identify questions/issues that only can be answered by a multinational approach  Lobbying/advocacy and application versus the EU for funding  Facilitation of optimal long-term follow-up (LTFU), try to define early and late endpoints of LTFU  Equal access to care across Europe  Education on all levels; survivors, parents, health care systems, society  How to include survivors and parents in the collaboration  Core groups for various topics within the collaboration  Common database with common variables  Working with Cancer Registries  How to reach/include those not present at this meeting; other groups or individuals  A name for our collaboration  Next meeting RH summarised the previous discussions held in Budapest (30 November 2007), including a reminder about the constitution and mission of ELTEC. He also described the development of the Erice Statement. Points relevant to the aims of the current meeting included:  Much variation in current systems for registration of long-term survivors and delivery of LTFU  Funding needed to increase the profile of LTFU / survivorship  EU funding is desirable, but needs a research question which would be better answered by a Pan- European Network (conceivable that an “education” question might be feasible in addition to or instead of a “research” question)  Any Network should be inclusive of new EU members  First project must be visible and successful in a relatively short timeframe  Possible projects could include one or more of: . Evidence based guidelines . Re-institution of ACCIS Network (probably difficult since this is now closed) . Gene-Rad-Risk (GRR) model . Borrowing from the LCH model (education, common database) . Other proposals such as a study involving one of  genetic polymorphisms (?premature ovarian failure)  anthracycline pharmacokinetics (again perhaps including polymorphism study)  second malignant neoplasm (SMNs) – perhaps a comparison of data from hospital and population registries JBe described 4 relevant strands of activities of the GPOH including:  LESS (ongoing study group looking at several aspects of late toxicity including endocrinopathy in CNS tumours, CNS toxicity, late effects in sarcomas)  Quality of life (Gaby Calaminus)  Radiotherapy toxicity (RiSK)

2 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008  DKKR (German Childhood Cancer Registry) This work broadly aims to look at: . Detection . Prevention . Research

RS presented a brief summary of the constitution, aims and activities of the CCLG (Children’s Cancer and Leukaemia Group) Late Effects Group. One important aim of the group is to collaborate with international groups.

Other salient points discussed at this stage:  SG – can this Network help to ensure that LTFU is actually being carried out?  LK – production of evidence-based guidelines is a potentially important aim.  JBe – important to make Governments aware of the existence of long-term survivors and the importance of their issues. Parents’ Associations have an important role. Important to separate research proposals from structural developments. May be wise to only look at significant major toxicities (ie those causing “clinical problems”, such as cardiotoxicity, nephrotoxicity, endocrine toxicity).  EB – in many countries survivors who are ≥18 years of age are routinely transferred to adult services (as a result of health care system policies).  RH – current Italian OTR project is demonstrating increased risk of late death in survivors of childhood malignancy, and raising concern that this may only represent the “tip of the iceberg”.  GL – information derived from LTFU needs to be fed back to those individuals / groups responsible for designing new treatment protocols.  This Network may have a role in exploring systems that bypass barriers to funding. For example, when health service providers state that “this test will not help this patient, and therefore we will not fund it” – yet for the sake of future survivors it would be important to investigate it. Maybe this group can find methods of funding or implementing such studies (RS, ES, LK).

Discussion about how to continue the meeting in smaller groups  Agreement that the meeting participants preferred to initiate and continue overall discussion in the whole group format at least on the 27th March, breaking up into smaller sub-groups on the 28th (i.e. giving more time to “whole group” discussion).  In Budapest, SMNs was chosen as a major topic for early research questions. RH sought assurance that this was the correct decision. General agreement that it was best to select one topic to maximise chances of obtaining EU funding, but also acknowledgement from the wider group that we would wish to address a broader range of issues in due course.  SG – premature death is the “ultimate toxicity”. When considering late deaths after treatment for childhood cancer, more than 95% is excess. Surely this is an important message for dissemination. However, this fact does not preclude the ability to then focus on specific issues such as SMNs, cardiotoxicity etc. Nevertheless it indicates that important aspects including primary and secondary prevention and lifestyle issues need to be considered.  GL – in some patients survivorship is very much like a “chronic disease”.  LK – this then raises considerable study design issues, notably identifying the correct cohorts of survivors to study.  ES – important to know the “size of the problem” in order to facilitate lobbying of Governments. Again late deaths is the most important fact.  SG suggested that an initial “umbrella” late mortality study could then facilitate subsequent detailed studies, e.g. of polymorphisms. It might also allow opportunities for education.  RH – feels that the EU will probably be very interested in differences between countries, in terms of provision of and access to care.

3 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008  JL – speculated whether an audit of services, perhaps looking at the gap between what is provided and what units / countries would like to provide. However, SG felt that it was important not to take too much time over this and thereby delay an EU funding application.  Several participants discussed the difficulties of obtaining treatment data, and suggested that registries could be audited concerning this issue. RH raised (again) the issue of data collection in survivors >18 years of age, and commented on the impact of European legislation regarding this.  In this context, several participants raised concern about the remit of our group, and specifically whether there might be conflict or competition with frontline treatment groups (obviously desirable to avoid this).  SG – suggested that the group should be called a “Network”, implying that it is inclusive (open to everyone, and is not intending to compete with existing groups.  Several participants (JBe, EF, CR, RS) felt that it was important to involve front-line treatment groups from the start to make them feel involved, emphasising that we wish to take a generic approach, i.e. not to focus on any particular disease group.  RH questioned whether we could set up a European cohort of survivors, whilst LH and EB thought that EU funding might be facilitated by making an application that ensured some resources for all, especially if this led to data production. In contrast, JBe wondered whether it was wiser to restrict involvement initially to those centres able to provide “high quality” data.  LK – reiterated importance of obtaining money to facilitate the development of European guidelines.

“Whiteboard” Discussion Participant contributed areas that they wish to see addressed by the Network. Initial suggestions were:  LK - patient care, guidelines, education  GL – audit, centre/country issues, Registries, research Network  JBe – late mortality “Round the table responses” included:  HL – difficult to obtain agreement on what to do.  DD – large group discussion could lead to 2 or 3 ideas which could then be worked up for funding applications.  JBe – we need to decide which idea is the priority, and also decide very quickly whether it is “fundable” before committing much time to working a proposal up.  MJ – many ideas will not be workable, but ideally we need to seek innovative yet specific, simple and workable ideas, affecting survivors and parents.  ZJ – data collection, minimum LTFU requirements, SMNs would be her priorities.  EB – developing guidelines is very hard, but developing minimum LTFU requirements may be more feasible (and could be used to influence Governments and / or the EU).  EF – could seek to develop a framework, using different kinds of Registries, including some limited centre / Registry studies tailored according to the needs of the question; do need guidelines and criteria for minimum LTFU requirements. Ultimately, education is cost saving, and could be focused on specific risk groups.  HG – re-emphasised the need for early results. Our “strength in numbers” could help. Important areas are interventions, late deaths, SMNs.  JL – use existing Registries for specific purposes.  FdV – case control studies.  LK – need to decide priorities. A longer preparation period may be necessary.  JBo – minimum LTFU guidelines are very important, although several already exist.  GL – the name of the group / Network will be very important. A research database could be achievable through good will of the participants.

4 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008  CR – as a starting point, we need to know who and where the survivors are. If we wish to develop guidelines, we probably need to “put all the writers in a Convent for a week”! We will also need to define an update mechanism.  ES – guidelines are very important. Would also like to look at models of care.  JBy – there are clearly national disparities, and we need to try and remove inequalities of access to care. This should be our mantra.  RH – should develop a Network. Suggested the possible name PENACCS (Pan-European Network on Awareness of Childhood Cancer Survivorship). Then, we need to define a cohort for an easy study, such as late mortality, which will demonstrate inequalities, for example in access to care. Guidelines could be written alongside this, emphasising risk factors based on previous treatment. We need to remember families and survivors (emphasised by MJ), and question whether they might be more interested in current active chronic disability rather than the risk of second malignancy in the future. However, to be sure, we need to ask them (i.e. survivors and families).  CR – suggested an alternative name EUROLECT (EUROpean Late Effects of Cancer Therapy).  LH – emphasised the importance of including parents and survivors, and also of contacting centres and countries not represented in Lund at this meeting.

28th March 2008

Development of sub-groups 1) Framework/Network (led by LH) . JBe, JBy, DD, HG, ZJ, LK, GL, 2) Survivor care (led by RS) . EB, JBo, EF, MJ, BK, AM, CR, EW, LZ 3) Research (led by RH) . SG, HL, JL, GP, ES, FdV

Sub-group reports

1) Framework/Network PANCARE – Pan-European Network for care of survivors after childhood and adolescent cancer Mission statement – Pan-Care is a European network of professionals, survivors and their families established to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. The objectives of today are to establish the structure of the Network, including naming a chairperson and a steering committee. Within the Network, working groups need to be established.  Collaboration among all relevant registries and databases, to establish a common database for all survivors, ultimately resulting in a European survivor cohort (DD, MH, LK, ZJ). First a nationwide inventory of existing registries and databases through a questionnaire.  To identify and contact groups or activities that share our stated intent, in order to stimulate collaboration (JBy, LH, GL). A similar nationwide inventory as above.  To identify a variety of funding sources on different level, e.g. charities, EU, government (HG, LH, GL). A similar nationwide inventory as above.  To inventory laws, regulations and ethical issues relevant to each working group.  To establish a web page, possibly through SIOP-E or a university (JBe, JBy, HG, LK).

2) Survivor Care Guidelines  For every country in Network (Europe)  Guidelines (where feasible – dependent on evidence base) or “suggestions”  Ideally, derived from evidence-based critical appraisal 5 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008  Need to include cost effectiveness  Should be developed by evidence-based critical appraisal process – need to apply for funding  Should be developed by a working group – with individuals focusing on specific topics  Implementation may vary according to local factors Equal access to survivor care / education / empowerment  Centres / countries – how to ensure all survivors have access (i.e. avoiding loss to FU)  Pan-European context – ascertain differences between countries, discuss how to address these . guidelines, website / educational documents (for professionals and families / survivors) . equal access to education . with the aim of empowerment . involve all treating professionals, e.g. especially radiation oncologists  Communication (particularly with families / survivors)  Audit (CR) – of infrastructure (?should this be a later aim) Survivor / family representation  Strengthen / enhance development of existing parent and especially survivor groups  Via ICCPHO  Survivor groups with professional input (multidisciplinary, e.g. doctors, psychologists) . activities (e.g. meetings, camps) . mutual support . education  Ascertain what survivors / families want . How to meet their variable needs/desires  Written / internet resources Transition  Referral routes / pathways to care – more than one way of achieving transition  Questionnaire (EF) – what do you understand by transition, how / where / who do you do it?  Describing models of transition  Group statement / recommendation → internet resource

Feedback from the wider group raised the following issue with respect to guideline production.  Who would the guidelines be for – everybody?  What would the guidelines be for? How should they be described? How should they be written?

3) Research a) We believe that it is very important to start this network with several audits on: i) Registries, ii) Legislation iii) Availability of care, iv) Funding b) We are interested on health status of LTS, and believe we need a standardized approach across Europe. We propose a study on late mortality as a first marker of morbidity of CCS. These data may be used is a first step to prevention and education programs. We believe that this approach is strategic for the documentation of prevalence of clinical relevant conditions that might be addressed in the future with Ad hoc studies. We recognize that the primary end point is not very competitive under the “scientific” point of view, but could be used as a tool for homogeneous approach across different countries i) We will use both Population as Hospital based registries, and analyze them separately. The inclusion criteria will be to be a 5 year survivor. We will use the official cause of death to calculate SMR (even if we know that there is about 10% misclassification error. ii) Causes of death will be anyway validated (in a parallel study) either as a whole or on a sample (funding!)

6 Minutes of First Pan-European Meeting on Childhood Cancer Survivorship Lund, Sweden, 27-28th March, 2008 iii) Organize a nested case-control study within each cohort iv) Incidence of second cancers, if possible, will also be pursued (in selected registries) c) Data base of publication related to late effects from the network (either published in English or other national languages) Notes: i) New treatments might increase survival, but at the same time also late mortality because of very aggressive treatment used to “cure” the original cancer. ii) Consider difficulties in collecting data from survivors diagnosed many years ago. We might use type of diagnosis and era as surrogate marker of exposure. iii) The medical community believes that fight against childhood cancer has been a success, but we should cautiously recognize that cure has some cost. iv) This study could be beneficial for survivals v) Reduce costs of follow-up?

Final Discussions  When considering the development or modification of databases, we need to decide whether these are research databases or registry databases. There are huge differences between these.  Name of the Network – different options suggested included: . PENACCS . PENOCCS (Pan-European Network on Childhood Cancer Survivorship) . EUROLECT . PANCARE (Pan-European Network for CARE of Survivors after Childhood and Adolescent Cancers) . EUROCCSS . PEGS (Pan-European Group on Survivors)  Need to decide our aims. Agreed that important to elect a Chairperson, or at least initially a Steering Committee. Ultimately, this may need to include one representative per country or perhaps a smaller core group (with appropriate transparency of election). Initial step taken to set- up a Steering Committee of LH, RH and RS, who will enlist further help as needed.  Priorities – as set in the above working sub-groups.  Funding – need to submit a proposal to the EU Health Committee. Initial proposal (on which further lobbying can be based) is very brief (10 lines maximum).  Affiliation – should construct an inventory of like-minded groups, and discuss whether we should seek affiliation with one of them.  Involvement of those countries and centres not represented at this meeting. . Need names . Individuals could be invited for specific topics, and may need to be “head-hunted” . Specific suggestions for who should seek other participants:  Baltic countries, Finland – LH  Belgium - LK  Bulgaria / Romania – EB  Czech Republic, Slovakia etc – BK  Greece – MJ  Spain/Portugal – RH  Switzerland – HL  Smaller countries – SIOP list

Next meeting Graz, Austria (HL has very kindly agreed to host) 13-14th November 2008

RS, 13th July 2008 7