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					PanCareSurFup Research Protocol (WP1-5)                                                                                          Page 1




                                                     PANCARESURFUP

  PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies
                           Comments by Eva Steliarova-Foucher of 21 April 2011, revised on 6 May 2011




                           Study Protocol             Version 4.0, 2 March 2011




                                                                          th
PanCareSurFup is a medium-sized collaborative project funded by the 7 Framework Programme of the EU; grant agreement no.:
25705

Start date:                                       1 February 2011

End date:                                         31 January 2016

Work programme topic addressed:                   HEALTH.2010.2.4.1-7, Predicting long-term side effects to cancer therapy




Scope of this document

PanCareSurfup comprises 8 “Work Packages” (WPs). This Study Protocol is principally concerned with those WPs which will collect
new epidemicological data, specifically WP1,.….WP5. However, there is occasional reference to WP6 (Clinical Follow-up Guidelines),
WP7 (Dissemination of Knowledge gained) and WP8 (Management of the entire project).




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PanCareSurFup Research Protocol (WP1-5)                                                                                                                                                         Page 2




Table of Contents

Table of Contents ........................................................................................................................................................................................... 2

1.       Overview ........................................................................................................................................................................................... 423

1.1      Objectives ......................................................................................................................................................................................... 423

1.2      Participants ....................................................................................................................................................................................... 523

1.3      Potential Impact................................................................................................................................................................................ 523

2.       Background ....................................................................................................................................................................................... 623

3.       List of Work Packages ....................................................................................................................................................................... 723

4.       Work Package Specific – Background, Objectives and Methods ...................................................................................................... 823

4.1      WP1. Data collection and harmonisation ......................................................................................................................................... 823

4.1.1 Background ....................................................................................................................................................................................... 823

4.1.2 Objectives ......................................................................................................................................................................................... 923

4.1.3 Methods............................................................................................................................................................................................ 923

4.2      WP2. Radiation Dosimetry .............................................................................................................................................................. 1223

4.2.1 Background ..................................................................................................................................................................................... 1223

4.2.2 Objectives ....................................................................................................................................................................................... 1223

4.2.3 Methods.......................................................................................................................................................................................... 1323

4.3      Work Package 3: Cardiovascular disease: cohort and nested case-control studies ........................................................................ 1423

4.3.1 Background ..................................................................................................................................................................................... 1423

4.3.2 Objectives ....................................................................................................................................................................................... 1523

4.3.3 Methods.......................................................................................................................................................................................... 1523

4.4      Work Package 4: Second malignant neoplasms: cohort and nested case-control studies ............................................................. 1723

4.4.1 Background ..................................................................................................................................................................................... 1723

4.4.2 Objectives ....................................................................................................................................................................................... 1923

4.4.3 Methods.......................................................................................................................................................................................... 2023

4.5      Work Package 5: Late Mortality ..................................................................................................................................................... 2023

4.5.1 Background ..................................................................................................................................................................................... 2023

4.5.2 Objectives ....................................................................................................................................................................................... 2223

4.5.3 Methods.......................................................................................................................................................................................... 2223
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8.       Timeline .......................................................................................................................................................................................... 2523

9.       References ...................................................................................................................................................................................... 2523

APPENDICES.............................................................................................................................................................................................. 2723

1.   Need to provide underlying cohorts within which late deaths, subsequent primary neoplasms and cardiac conditions have
been ascertained. ..................................................................................................................................................................................... 2723

2.       Cohorts for late deaths, subsequent primary neoplasms and cardiac conditions – lists of essential variables.............................. 2723

3.       Cohort analyses of the risk of subsequent primary neoplasms (SPNs) ........................................................................................... 3023

4.       Inclusion/exclusion of retinoblastoma survivors ............................................................................................................................ 3023

5.       Is there any restriction on age at late death, SPN or cardiac condition .......................................................................................... 3023

6.       Definition of “cases” for the case-control studies of SPNs ............................................................................................................. 3023

7.       Validation of cases of SPN within the nested case-control studies................................................................................................. 3823

8.       Selection of controls matched to SPN cases ................................................................................................................................... 3823

9.       Radiotherapy records collection for the case-control studies ........................................................................................................ 3923

10.      Chemotherapy records collection for the case-control studies ...................................................................................................... 4023

11.      Questionnaires................................................................................................................................................................................ 4123

12.      DNA Collection for case-control studies ......................................................................................................................................... 4823

13.      PanCareSurFup International Data Collection Systems for the SPN case-control studies .............................................................. 5023

14.      Consent Forms and Information Sheets ......................................................................................................................................... 5223

15.      Schedule of Deliverables................................................................................................................................................................. 5623

16.      Schedule of Milestones ................................................................................................................................................................... 5723




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1.          Overview

1.1         Objectives

     1.   Establish three adverse health outcome specific and retrospectively ascertained pan-European cohorts of survivors of
          childhood cancer within which the occurrence of late mortality, second malignant sarcomas and carcinomas, and cardiac
          events have been (or may be) systematically ascertained and validated. Focusing on carcinomas which are common in the
          general population after age 40 years and which are frequent among survivors: specifically cancers of digestive and
          genitourinary sites.

     1.2. Undertake individual patient radiation dosimetry for individuals included within the nested case-control studies to obtain      Formatted: Bullets and Numbering
          estimates of dose to the site of development of the adverse event and the corresponding site in the matched controls.

     3.   Estimate the absolute risk of each of these adverse health outcomes within the relevant cohort and compare observed and
          expected numbers of events where general population rates are available to enable the calculation of expected numbers. Of
          particular interest will be the comparison of observed and expected numbers among those aged over 40 years.

     4.   Execute three nested case-control studies of cardiac disease, second malignant sarcoma and second malignant carcinoma,
          respectively, and one cohort study of late mortality, occurring among survivors to determine the aspects of radiotherapy
          and type and dose of chemotherapy associated with increased risk.

     5.   Produce clinical follow-up guidelines for health care professionals, survivors and their families based on existing evidence
          and the results from this study in terms of the absolute risk available from the cohort studies and the relative risks in
          relation to risk factors from the case-control studies, as they become available. This includes issues related to transition
          from a paediatric to adult environment for on-going follow-up.

     5.6. Establish partnerships between providers and survivor/parent groups to disseminate information about PanCareSurFup to           Formatted: Bullets and Numbering
          the general public, to health professionals and survivor/parent groups; train health care professionals through conferences,
          workshops, booklets and web based information; empower and educate survivors to be as informed as possible concerning
          their long-term risks, and about general and specific health promotion measures that they can use to optimise their future
          well-being.




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1.2       Participants



 Participant        Name of principal investigator     Organisation legal name                     Abbreviation       Country
 no.
 1                  Lars Hjorth (Coordinator)          Lunds universitet                           ULUND              Sweden
 2                  Roderick Skinner                   University of Newcastle                     UNEW               UK
 3                  Riccardo Haupt                     Istituto Giannna Gaslini                    IGG                Italy
 4                  Desiree Grabow                     Universitätsmedizin Mainz                   UMC                Germany
 5                  Julianne Byrne                     Boyne Research Institute                    Boyne              Ireland
 6                  Eva Frey                           Children’s Cancer Research Institute        CCRI               Austria
 7                  Leontien Kremer                    Academisch Medisch Centrum                  AMC                Netherlands
 8                  Edit Bárdi                         Markusovszky Kórház                         HSZOMB             Hungary
 9                  Paola Pisani                       Università di Torino                        UNITO              Italy
 10                 Gill Levitt                        Great Ormond Street Children’s              GOSH               UK
                                                       Hospital
 11                 Claudia Kűhni                      Universität Bern                            UBERN              Switzerland
 12                 Florent de Vathaire                Institut Gustave Roussy                     IGR                France
 13                 Mike Hawkins                       University of Birmingham                    BHAM               UK
 14                 Momcilo Jankovic                   Fondazione MBBM                             MBBM               Italy
 15                 Ruth Ladenstein                    SIOPE                                       SIOPE              Belgium
 16                 Eva Steliarova-Foucher             IARC                                        IARC               France



1.3       Potential Impact

PanCareSurFup presents a proposal that tightly integrates a number of quite diverse elements, all working together to improve the
lives of European children and adolescents who have survived cancer. The participants represent all elements within the European
research and clinical communities, thus providing strong links to existing European bodies and projects, such as IARC, ENCCA, ENCR,
EUROCOURSE, SIOPE and others. This will enable the establishment of smooth collaborations between PanCareSurFup and relevant
European groups. The diversity of this proposal lies in its reach, from radiation dosimetry constructing phantoms to simulate dose
and scatter radiotherapy to different organs, a variety of studies from second malignancies, to cardiovascular outcomes to late
mortality, none of which has been satisfactorily addressed in the past, yielding information that will be translated into guidelines
and disseminated to the research communities, to survivors and their families and to the general public. This pan-European study
will pool patients from large national registries thus becoming the largest study of childhood cancers in the world. The benefits are     Comment [ESF1]: This is questionnable!
that for the first time, we can develop accurate estimates of the risks arising from very specific therapies for life-threatening late
effects. For instance, there is very little known of the ways in which the aging process, normal to all of us, may be accelerated or
altered in survivors of childhood and adolescent cancer. Existing data suggests that cardiovascular diseases and second
malignancies may occur at higher rates than expected for older survivors. But detailed information is lacking. PanCareSurFup will be
able to provide a great deal of detailed information on precise risks for cardiovascular diseases, for second malignancies and for
late mortality among the oldest groups of survivors.




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2.        Background

Survival after childhood cancer has improved substantially over recent decades and currently up to 80% of children diagnosed in
developed countries survive to at least 5 years. Such improvements in survival mean that 1 in 750 of the young adults in the general
population of such countries is a survivor of childhood cancer. Furthermore, unlike survivors of cancer diagnosed in of adult
agecancer, mostly diagnosed after 60 years of age (in Europe almost 70% of them after the age of 60 years), survivors of childhood
cancer have all of their adult life ahead of them. Cancer in childhood is rare: for every child who contracts cancer, more than 100
adults get cancer; the overall age-standardised incidence rate in Europe is 140.0 cases per million children aged 0-14 [1, 2]. Data are
not available, but it is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe, and this
number will rise rapidly due to continued improvements in treatment. Such good survival prospects raise important questions
relating to late adverse effects of treatment for cancer. The most serious adverse effects are fatal and considerable insights into
treatment toxicity may be gained from detailed investigations of causes of death occurring beyond 5-year survival (so called late
mortality). Experience in previous studies has identified second malignant neoplasms and cardiotoxicity as two of the most serious
and frequent adverse health outcomes which are related to previous doses of exposure to chemotherapy and radiotherapy given to
treat the childhood cancer. As childhood cancer is rare, and the adverse health outcomes rarer still, much of the previous work
addressing the risks of specific adverse health outcomes in relation to aspects of previous anti-cancer treatment has failed to
include adequate numbers of survivors, particularly when addressing multi-drug chemotherapies with or without radiotherapy, and
when addressing issues concerning the interaction between aspects of treatment and genotype. Studies addressing interactions
between separate risk factors cannot be performed satisfactorily without pan-European collaboration. Moreover, the estimation of
the nature of dose-response relationships would be achieved with much greater precision within a pan-European setting. Some of
the applicants in PanCareSurFup have previously undertaken an investigation of the risk of second primary breast cancer in relation
to genetic susceptibility and radiation dose to breast tissue in the GENE-RAD-RISK study funded under EURATOM call of FP-6.

Perhaps the most serious outstanding questions relating to survivors of childhood cancer concern their risk for the common
diseases of mature adulthood in developed countries as they reach those decades of life, beyond 40 years of age, when cancer and
cardiovascular disease begin to exponentially increase in risk in the general population. The uncertainty and concern is reinforced
because exposure to cancer therapy took place in childhood whilst organs and bodily systems were still immature and developing.
However, Europe is well positioned to address these questions because of its history of cancer registration going back to the 1940s.
The number of survivors who are aged beyond 40 years in individual countries is insufficient to satisfactorily estimate such risks,
but combining data across Europe will provide an outstanding opportunity to address these questions. Currently the strengths of
PanCareSurFup in terms of the number of cases registered, record linkage, enrichment with detailed treatment data and radiation
dosimetry, cannot easily be matched in the world.

Our objectives will provide unbiased and reliable measures of incidence, risk and risk factors (potential treatment related causes) of
the most serious and frequent adverse health outcomes, including late mortality experienced by survivors of childhood cancer. A
DNA bank will lay the foundation for future genotypic analyses. Variation by sex and country will be investigated. PanCareSurFup
will provide an unrivalled opportunity to: update existing standardised clinical follow-up guidelines, provide evidence-based risk
prediction, identify high risk groups for possible intervention studies to prevent or diagnose as early as possible adverse health
outcomes, provide an evidence base for training health care professionals, to focus health service resources on those most at risk
and most likely to benefit from intervention, and to investigate health promotion initiatives. The health of long-term survivors of
childhood cancer is both physical and psychosocial, and is best achieved through active partnerships between health-care providers
and survivors and their families. The results obtained in PanCareSurFup’s research projects will be included with existing evidence-
based outcomes in the dissemination and training activities of this project. PanCareSurFup will use current and emerging
communication tools to reach the communities of interest, including conferences and workshops, for training and dissemination of
these results, aiming for the widest possible involvement of existing EU childhood cancer bodies and survivor/parent groups, lay
and professional, to ensure that health professionals receive appropriate training and information, that late complications are
anticipated, prevented and treated optimally to ensure the best quality of life for survivors and their families.

Many published studies have established the risk of adverse health outcomes experienced by survivors of childhood cancer.
However, no international pooled study is planned on cardiac disease, secondary sarcoma or adult type carcinoma after childhood
and adolescent cancer. Recent research from the United States has shown 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. Some poorly understood late
complications of treatment lead to chronic ill health, disability or late mortality, and thereby constitute a significant burden on
individuals and their families, as well as on health services and society. It has been clearly established that large scale investigations
have particular advantages because of the rarity of childhood cancer and the even greater rarity of the adverse health outcomes.
However, there are two principal questions which remain to be addressed concerning the long-term health of survivors. Firstly,
what is the magnitude of the long-term excess risk of morbidity and mortality to survivors of diseases which are common in the
general population among middle aged and older adults, particularly cancer and cardiac disease? Europe has a history of
population-based cancer registries that are in a position to provide unique insight into these questions because of the substantial
number of survivors aged beyond 40 years which are accessible to a pan-European collaborative approach. Secondly, with the new
tools available to probe the human genome it is important to address the question of genetic susceptibility to the adverse effects of
radiotherapy and chemotherapy, particularly in relation to carcinogenesis and cardio-toxicity because of the frequency and gravity           Formatted: Font: 8 pt, Italic, Do not check
of these adverse health outcomes. It is well established that to satisfactorily address the issue of interaction between such                spelling or grammar


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environmental factors and genetic susceptibility requires at least several hundreds of matched sets and these numbers are only
achievable on a pan-European basis (Table 1). Therefore, DNA will be collected, but not analysed, during the life-time of
PanCareSurFup.

3.        List of Work Packages




           Work package (No)                                                      Work package title

 Work Package 1 (WP1)                           Data collection and harmonisation

 Work Package 2 (WP2)                           Radiation dosimetry

 Work Package 3 (WP3)                           Cardiovascular disease: cohort and nested case-control study

 Work Package 4 (WP4)                           Second malignant neoplasms: cohort and nested case-control studies

 Work Package 5 (WP5)                           Late mortality

 Work Package 6 (WP6)                           Guidelines, long-term follow-up and transition

 Work package 7 (WP7)                           Dissemination and Training

 Work Package 8 (WP8)                           Management and coordination




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4.        Work Package Specific – Background, Objectives and Methods

4.1       WP1. Data collection and harmonisation

4.1.1     Background


                                                 Figure 1. Schematic of data flow




Figure 1 shows how the data will flow into and within PanCareSurFup. First, data providers (DP) send the core variables on each
case to WP1. Then follows a period of data cleaning and quality control procedures (see…..) to be applied to each dataset from
each DP. Once this process has completed WP1 sends the cohort data to each of WP3 – 5. The final step is the assembly of the
Virtual Cohort. This means that the analytic teams feed back to WP1 on the feasibility and quality of the detailed variables, and
identifies their location and the means of obtaining the information.

Population-based cancer registries systematically collect official data on cancer incidence and follow-up, mortality and survival.
These registries have developed a reliable infrastructure for data collection and reasonable standardisation of information. They
are well organised and are associated within the European Network of Cancer Registries (ENCR, www.encr.com.fr). The structure
and data standardisation developed within ENCR allowed establishment of several pan-European projects, such as CAMON [Bray F,
Guerra Yi M, Parkin DM. The comprehensive cancer monitoring programme in Europe. Eur J Public Health. 2003 Sep;13(3 Suppl):61-
6.], EUROCARE [3] (EUROpean CAncer REgistry-based study on survival and CARE of cancer patients, www.eurocare.it) , ACCIS
(Automated Childhood Cancer Registration System [4], and EUROCOURSE (FP7 ERA-NET; Optimisation of the Use of Registries for
Scientific Excellence in research www.eurocourse.org). Data quality assurance processes and harmonization of prospective
databases over Europe are on-going within the ENCR (e.g. ref. [5]). In contrast, hospital-based registries are strong on treatment
and risk factor information on patients. These two approaches will contribute to PanCareSurFup. A core database to be set up in
Mainz, Germany, in order to collect baseline data for the PanCareSurFup-studies of WP2-5.




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4.1.2     Objectives

The primary goal of WP1 is to ensure the availability of information on late health sequelae in cancer patients first diagnosed
before the age of 20 years across Europe. This WP aims to avoid a multiplicity of data requests to registries by being the single
focus within PanCareSurFup that seeks information from the registries. Our goals will be achieved through the following specific
objectives:

          4.1.1.1   Production of a benchmark overview of the occurrence of subsequent primary tumours and survival in the
                    population of five-year survivors of childhood or adolescent cancer, based on data collected in European
                    population-based cancer registries.
          4.1.1.2   Establish three retrospectively ascertained pan-European cohorts of survivors of childhood cancer (Work
                    Package 1) within which the occurrence of late mortality, relevant second malignant neoplasms and cardiac
                    events has been (or may be) systematically ascertained and validated.
          4.1.1.3   Set up specialised databases of long-term survivors to study:
                    a) Cardiac diseases in WP3
                    a)b) Second primary sarcomas and carcinomas in WP4                                                                     Formatted: Bullets and Numbering
                    a)c) Causes of late mortality in WP5
          4.1.1.4   Preparation of a virtual prospective pan-European database of long-term survivors to improve the availability of
                    information on long-term survivors. This work will be performed in collaboration with all the other work
                    packages to ensure that all relevant information is taken into account. The virtual database will consist of rules
                    for collection, coding, storing and exchange of information relevant for studies of specified adverse health
                    outcomes. It will also include a dynamic database of all available data sources.
          4.1.1.5   All potential data sources (clinical and population-based) will be considered for construction of the relevant
                    retrospective cohorts. The collected data will then be analysed in the respective WPs. The central statistical
                    core group formed by the leadership of WP1-5 will be chaired by the UBHAM representative to facilitate and
                    coordinate the statistical work performed in each WP. The data collected will be analysed within the respective
                    WPs.

In conclusion, the contribution of WP1 to PanCareSurFup will be three-fold: (1) to identify the existing data sources and intensify
the use of relevant data already collected across Europe; (2) to encourage improvement of quality and completeness of these data
and (3) to prepare for the potential collection of high quality data needed for future studies.

WP1 will work with WP8 and national databases in obtaining ethics approval in relevant countries for data collection. It is the
responsibility of WP1 to ensure protection and security of data in the central database and nondisclosure of personal data, in
compliance with European ethical guidelines.

4.1.3     Methods

Task 1    Analysis of routine data from the existing population-based cancer registries across Europe to benchmark selected late
          effects in long term survivors, in collaboration with IARC and ENCR:

     a)   In collaboration with ENCR, overview of the relevant cancer registration practices will be conducted and analysed using
          an on-line questionnaire facility developed in the framework of other European projects of the ENCR. All members of
          ENCR (www.encr.iarc.fr) will be invited to participate.
     a)b) The ensuing results will include (1) overview of available information for use in the other work packages and (2) prospects      Formatted: Bullets and Numbering
          for expanding the range of variables collected and identifiable adverse health outcomes.
     a)c) Relevant data will be collected and a report will be prepared in collaboration with the ACCIS project to benchmark
          information on the long-term survivors of childhood/adolescent cancer in European population with respect to the
          occurrence of second primary tumours (by first and second tumour, age and period and location at diagnosis) and survival
          beyond 5-years after the diagnosis (in detailed categories of survivors)


Task 1 will be coordinated by the IARC, due to the accumulated expertise in working with European cancer registries through ENCR,
EUROCOURSE and ACCIS, and a possible link with ENCCA (SIOPE application for Health.2010.2.4.1-3 “European Network for cancer
research in children and adolescents. The output will be used to relate the results from clinical studies to the general European
population. Tasks 2-6 will be coordinated by UMC.



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Task 2    Analysis of existing clinical databases across Europe to benchmark selected late effects in long term survivors

     a)   Within the PanCare network a survey of existing databases of long-term survivors and follow-up practices will be
          conducted and analysed to provide an overview of the existing information and its variability.
     a)b) Collection and analysis of available clinical data will be undertaken in those centres where data definitions and standards     Formatted: Bullets and Numbering
          allow this. The results will be interpreted in collaboration with SIOPE.
     a)c) A report will be prepared summarising the findings from all sources and outlining the possible ways of standardisation of
          data definition, collection and coding.

Task 3    Mapping of data sources for establishment of study cohorts for WP3-5. Task 3 will be coordinated by UMC in
          collaboration with WP2,…,5, with participation of all data providers.

     a) Identify those countries centres who can contribute to the study questions of WP 3, 4, 5
     a)b) Establish three pan-European cohorts of survivors of childhood cancer for which the occurrence of each specific outcome:        Formatted: Bullets and Numbering
          cardiac disease, relevant second primary neoplasms, and late mortality has been systematically ascertained.
     a)c) Based on the PanCare network and on previous surveys, data sources identified as “keyplayers” will be considered for
          inclusion in each cohort for analysis in WP 2-5 (data sources from France, Hungary, Italy, the Netherlands, the Nordic
          countries, Slovenia, Switzerland, UK).
     a)d) In collaboration with WP2, WP3, WP4 and WP5, inclusion and exclusion criteria will be defined for each of the three
          cohorts. The core set of variables to be collected for each registered case in order to contribute to WPs 3-5 will be
          described. Variables will be defined and common coding rules established in order to enhance data comparability and
          ultimately the harmonization of information. A database structure will be designed that reflects the protocol.
     a)e) Questionnaires will be developed and administered to selected data providers. The results of the questionnaires will be
          used to invite data holders into this collaboration.
     a)f) A structure for a common database will be developed and populated with data collected in those countries listed above.
     a)g) Identify cohorts within individual countries for WP 3, 4, 5 based on the protocols of WP 3, 4, and 5 for which relevant
          cardiac adverse outcomes, second malignant neoplasms (SMNs), and/or late mortality have been (may be) systematically
          ascertained.
          i.     Help in developing the protocol for mortality (WP5)
          i.ii. Help in developing the protocol of nested case-control study for cardiac disease (WP3)                                    Formatted: Bullets and Numbering
          i.iii. Help in developing the protocol of nested case-control study for secondary tumours (WP4)
     h) Prepare and coordinate the communication, exchange and harmonization between several individual countries and WP 2,
          3, 4, and 5.
     h)i) To ease data collection from many providers for use in four different studies (cohort study on late mortality, two case-        Formatted: Bullets and Numbering
          control studies about SMN, and case-control-study about cardiac adverse outcome) limit contact with providers to only
          one channel (WP1).

Task 4    Data collection and harmonization, coordinated by UMC in collaboration with WP1,…,5, with participation of all data
          providers.

All data provided to the central database will be anonymous. A mechanism of data collection will be developed, including a
database of collaborators, eligibility criteria and instructions for data coding and submission. These include

     a) Development of procedures to systematically check formal validity of the data (with respect to the protocol),
     a)b) Recode data according to the common classification systems adopted,                                                             Formatted: Bullets and Numbering
     c) Format data for inclusion in the common database. This is necessary since at present population-based and clinical
          registries, for example, use different classification systems for tumours and causes of death. They will have to adopt a
          common system (e.g. ICD-O-3) or at least consistent systems. WP1 will perform systematic conversions when necessary
          and will maintain documentation of all data manipulations performed.
     c)d) Call for data to be circulated among potential data providers by approximately month 6 of year 1.                               Formatted: Bullets and Numbering
     c)e) Sequence of data reception, sorting, processing, validation, storage, analysis and provision: WP1 will interact with data
          providers for data corrections following the procedures developed in a). For this purpose each (anonymized) record will
          be assigned an identification number unique to this project composed of an ID number provided by the participating
          centre plus a code for the centre. It will be the centres’ responsibility to ensure that they can return to the case’s
          information they hold if necessary. The project ID number will not allow identification of individuals. Nevertheless, WP1
          will ensure that the data collected will be used only for the purposes described in this project and agreed with data
          providers. Where several centres in one country contribute data, it will be the responsibility of local PIs to identify
          overlaps of the local cohorts and to eliminate duplicates. Duplicates will be identified by record linkage according to local
          practices and regulations. Cases in the merged file will be labelled as registered by both data sources, or only in one of
          them and which. Files of anonymised records containing no duplicates will then be submitted to WP1.
     c)f) Validation of the data by sorting out errors via correspondence with data providers in consultation with relevant WPs.
     c)g) Datasets covering partially overlapping populations (e.g. sub-national population-based cancer registries versus national       Formatted: Font: 8 pt, Italic, Do not check
          networks of paediatric oncology) will be submitted from both sources, after having identified the registrations in the          spelling or grammar


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          other partially overlapping dataset. The submitted partially overlapping datasets will be linked in the central database
          and the presumed duplicates will be resolved in collaboration with both providers. The final file of anonymous records
          will contain no duplicates.
     c)h) Data validation procedures will be developed, including:
          i.     Automatic check routines of individual records;
          i.ii. Matching data from various sources to identify duplicate records                                                          Formatted: Bullets and Numbering
          i.iii. Efficient communication with data providers
          i.iv. Data quality standards

Task 5    Provision of the databases for other work packages

     a)   WP1 will provide the relevant subsets of the common file with respect to the endpoints to be evaluated, to WP 3 and 4 as
          soon as all checks on the data are complete. This process should be complete by approximately mid-year 2. It will also
          provide WP5 with data to plan the validation study as well as the whole subset of the cohort suitable for the analysis of
          late mortality.

This task includes the following sub-tasks:

     b) Construction of a database of long term survivors for a study of cardiac diseases;
     b)c) Construction of a database of long term survivors for a study of second primary tumours;                                        Formatted: Bullets and Numbering
     b)d) Construction of a database of long term survivors for a study of late mortality;

Task 6    Establishment of a virtual pan-European database of late effects in long-term survivors of cancer in childhood and
          adolescence

Based on the collected data and the knowledge generated within this project, a proposal for establishment of a virtual database of
late-effects in long term survivors will be prepared. This virtual database will describe necessary characteristics of a database to
facilitate future data collection based on the networks established during PanCareSurFup. This task will be coordinated by UMC,
with participation of all data providers and WP2, 3, 4 and 5. This task will comprise the following sub-tasks:

     a)   Hold a workshop to define necessary characteristics of a database and establish a virtual pan-European database of late
          effects.
     a)b) The establishment of the network and identify the following characteristics:                                                    Formatted: Bullets and Numbering
          i.      Eligibility criteria
          i.ii. The content of each long term survivor’s record, including minimum requirements, separately for each end-point of         Formatted: Bullets and Numbering
                  interest
          i.iii. Recommended coding of all listed variables
          i.iv. Validation routines
          i.v. Quality standards
          i.vi. Database structure
          i.vii. Data extraction filters based on purpose of use
          i.viii. Location and administration of the virtual database
          i.ix. Data protection and security measures
          i.x. Classification of data providers
          i.xi. List and link to the data providers
     c) In collaboration with the other work packages, a detailed report will provide an overview of the current needs and
          tailored recommendations for improvement of data availability through routine data collection mechanisms.




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4.2       WP2. Radiation Dosimetry

4.2.1     Background

Radiation therapy, even more than chemotherapy, carries significant and life-threatening long term organ toxicities, affecting the
heart, the lungs, the gonads and multiple endocrine systems. These toxicities depend on many parameters, including the total dose
delivered to the organ at risk, the volume of organ exposed to a given dose level [6], and the fractionation of the dose [7, 8]. To
these can be added host factors that contribute to overall risk include age at treatment, gender, chemotherapy, life style related
factors, co-morbidities and genetic predisposition.

Late iatrogenic events are not only due to high radiation doses delivered to the target organ, or to the organs located within the
radiation therapy fields, but also to lower doses received near or even far from the target organ because of scatter radiation [9, 10].
It is a matter of considerable concern that, in spite of progress in radiotherapy techniques and treatment protocols, a large part of
the body may receive doses capable of inducing late iatrogenic effects. With the introduction of new treatment techniques, this
problem may even increase. In particular, Intensity-Modulated Radiation Treatment, which results in increased beam-on time and
therefore in more stray radiation to a larger volume of the body, has led to speculation that it may result in an even higher
frequency of second cancers than after conventional radiation therapy [11].

Radiation therapy in paediatric oncology is a highly individualized treatment which is adapted to each patient in order to deliver
exactly the prescribed dose to the volume of the tumor, while minimizing the irradiation of healthy organs. Nevertheless, the
current Treatment Planning System software considers only organs located at a few centimeters from the radiation fields, whereas
scatter radiation delivers significant (more than one hundred mGy) doses to organs located at a longer distance from the radiation
therapy field. Scatter radiation is a special problem for children: their smaller bodies mean that uninvolved organs are closer, and
minimizing the dose to these organs is more difficult to achieve. Therefore, because radiation therapy has played a major role
during several decades in pediatric oncology, and still plays an important role, reconstructing the radiation therapy treatment in
order to determine the radiation doses received to each organ is crucial to establishing the causes of side effects.

In the last several decades MD Anderson hospital in Houston, TX, has become the leader in radiation therapy reconstruction and
dose estimation, and has provided data used in most of the published cohort or case-control studies aiming at establishing the dose
response relationship between the radiation dose received to an organ during radiotherapy and the risk of second cancer to this
organ [12]. More recently, since the end of the eighties, INSERM has also developed experience in radiation treatment
reconstruction for epidemiological studies [13, 14]. Up to now, the retrospective dosimetry of most published studies on dose-
response between radiation dose to healthy organs during cancer radiotherapy and later cancer or cardiac disease risk has been
performed by one or other of these two groups.

A recently identified concern relates to the sources of uncertainty in retrospective dosimetry and their consequences on dose-
response estimation [15]. The sources of uncertainty arise from a number of factors. For instance, the position, the location and the
volume of the heart vary greatly with age, gender, anthropometric parameters, treatment position, and also because of the heart’s
own continuous motion. Also, there are now more realistic whole body anthropomorphic phantoms which are an improvement
compared to those used up to now by MD Anderson and INSERM. Such phantoms are in development at the University of Florida
[16] and at IGR [17]. These considerations will be incorporated into the procedures for radiation dosimetry in this project.

4.2.2     Objectives

4.2.2.1   To perform radiation therapy reconstruction and whole body dosimetry for the subjects included in WP3 and WP4 who
          received radiotherapy
4.2.2.2   To estimate radiation dose received to the various structures of the heart during radiotherapy, as well as uncertainties in
          this estimate for WP3 patients.
4.2.2.3   To estimate radiation dose received to the specific site of the second malignant neoplasm during radiotherapy, as well as
          uncertainties in this estimate for WP4 patients.
4.2.2.4   To estimate radiation dose received to other organs (integral dose, active bone marrow, carotid arteria, thymus…) which
          could play a role in the risk of events considered in WP3 and WP4, in addition to the dose received to the target organs.
4.2.2.5   To produce a table of standardized dose estimation for organs at risk, for the main types of childhood cancer, for W3 and
          W4 subjects for whom technical radiation therapy records are lost or unavailable, as well as uncertainties around these
          estimates.




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4.2.3     Methods

4.2.3.1  Patients and treatment data input needed for reconstruction of treatment and dose calculation will be extracted from
         copies of technical and medical records sent by WP3 and WP4 participants. This process is independent from the other
         parts of the dose estimation process. Indeed, once these data in the software, algorithms of dose estimation and
         positions of the organs or of the anatomical sites of interest may be changed, in need, without having to entry once
         again. Because the data entry step needs a highly trained dosimetrist with radiotherapy experience, it has to be planned
         very strictly. In particular, WP2 needs a steady flow of copies of the technical and medical records of WP3, WP4 patients.
4.2.3.2 The identification of the sources of uncertainty in the dose estimation process will be carried out in collaboration with
         Mark Little (NCI, Bethesda), who has had long experience of assessment of uncertainty in radiation dosimetry and of their
         consequencies on dose-response estimation.
4.2.3.3 Because the variations of volume and position of the heart is a specific issue in WP3 dosimetry, these variations,
         according to age, sex, anthropometric parameters and treatment position and of their consequences in dose estimation
         will be thoroughly investigated.
4.2.3.4 Retrospective dose estimations will be performed using software developed by partner 12 (INSERM). This software is
         particularly adapted to the present task because it may simulate child in treatment position. This software is in course of
         improvement by including more realistic anthropomorphic human phantoms based on CT scan slides.
4.2.3.5 Although this software had been adapted for 68 treatment machines and energies, there are other machines for which
         the software is not yet suitable. A preliminary step will be to modifythe software as necessary and validate the results.
         These procedures will be carried out by an independent Quality Assessment company for Therapeutic Radiology and
         Oncology, called EqualEstro.
4.2.3.6 Whole body dose distribution estimation (more than 1 million voxel in the human body) will be estimated for each case
         and control of WP3 and WP4 who had received raidotherapy
4.2.3.7 Assessment, in collaboration with the WP4 participants, radiologists and radiotherapists, of the most probable position of
         the SMN at time of SMN diagnosis and of the most probable position of these sites at time of first childhood cancer
         treatment, will be done using all radiological documents available.
4.2.3.8 Dose-volume histogram within the heart and in the areas or organs with SMN will be produced for each case and control
         who received radiotherapy.
4.2.3.9 Standardized dose estimates will be produce for cases and controls of WP4 and WP5 for whose radiation therapy
         reconstruction would be impossible because technical records of radiotherapy lost or too many missing parameters.
4.2.3.10 Comparison of dose estimates will be accomplished by comparing the dose estimates obtained from the INSERM
         software with those estimated using other software, for instance, the software of Marilyn Stovall in Texas, and with those
         estimated using the mixed anthropomorphic phantoms developed by the National Cancer Institute of NIH and the
         University of Florida. In case of signficant differences, the reason will be identified and, ifneeded, software will corrected,
         and doses re-estimated. Because the processes of data entry and of dose estimation are separate, doses can be re-
         estimated in 1 or 2 weeks.
4.2.3.11 Uncertainties around dose estimates will be provided.
4.2.3.12 Participants IGG, UMC, AMC, HZSOMB, UBERN, UBHAM, ULUND will assist with supplying radiation records,
         interpretation and trouble-shooting as needed, validation of dose estimates based on professional knowledge




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4.3       Work Package 3: Cardiovascular disease: cohort and nested case-control studies

4.3.1     Background

Cardiovascular diseases are among the most lethal long-term adverse effects of childhood cancer treatment. Overall, the mortality
due to cardiovascular disease in long-term survivors of childhood cancers is 5 to 7 fold higher than expected compared to the
general population [18-20]. In addition, the excess risk continues to increase with increasing follow-up and attained age, even 35
years or more after childhood cancer treatment [20].

Anthracyclines and cardiac irradiation are the two main known treatment-related risk factors for cardiovascular diseases [21-26].
Anthracyclines, e.g., doxorubicin, daunorubicin and epirubicin, are known risk factors of long-term cardiotoxicity, which can
become manifest as either clinical heart failure [21, 26] or as asymptomatic cardiac dysfunction [22, 24, 27]. Up till now, the
published studies do not have the ability to predict the long term cardiotoxicity associated with a specific dose of anthracyclines,
because their results are extremely variable due to small study size, variations in follow-up time, attained age, populations studied,
lack of common definitions for cardiac outcomes and lack of common methods of investigation.

Heart irradiation is also an established risk factor for cardiovascular disease, including atherosclerosis, pericarditis, myocardial
infarction and valvular defects [23]. The frequency of radiation-induced clinical cardiovascular diseases after childhood cancer
increases with increasing follow-up time [22, 23]. The available useful information on radiation-induced cardiac diseases following
childhood cancer is nevertheless quite limited. Nothing is known about the role of the fractionation of the dose and about the
influence of heterogeneity of the radiation dose to the heart, nor about the risk of association between radiotherapy,
anthracyclines and/or other drugs. Due to this lack of information, it is still not possible to accurately anticipate the long term
consequences of radiotherapy, including those arising from newer radiotherapy techniques.

In addition to these two well identified but not well quantified risk factors, recent studies suggest that other drugs, such as
alkylating agents and vinca alkaloids, may also increase the risk of cardiovascular disease [20]. However, these associations remain
to be confirmed and the magnitude of the individual risks to be estimated.

A recent large cohort study evaluated the incidence and risk factors for cardiovascular disease among childhood cancer survivors.
The results were based on self reported questionnaires, but validation of the cases was impossible and a precise estimation of the
role of treatment schedules and doses could not be performed [26].

Many studies have been performed relating DNA polymorphisms to cardiac diseases and their potential interactions with
environmental cardiac risk factors [28]. But there still is no consensus for genetic markers of genetic susceptibility to cardiac
diseases that have any usefulness in clinical practice [28]. In childhood cancer survivors, the situation could notably differ. First,
because the risk associated with anthracyclines and radiation is very high and therefore their modifiers are easier to identify.
Secondly, for the numerous enzymes linked to anthracycline metabolism, DNA polymorphisms could modulate the variation in
enzymes activity or increase susceptibility to toxic metabolites, and therefore modulate the risk of cardiotoxicity. Until now, only a
few studies have been published on genetic susceptibility to anthracyclines and none have appeared on radiation-induced
cardiotoxicity [29, 30].

Only a large-scale Pan-European nested case-control study will be able to provide the information needed to predict the long term
risks to which children treated now or in the past will be exposed in the coming years. This information will also help us to
anticipate the long-term risks associated with new treatment protocols and provide information to reduce cardiovascular disease
when developing new protocols, and therefore to better evaluate their risk/benefit ratio.

4.3.1.1   Power calculation of the study

We expect to assemble a total of approximately 600 cases and 600 controls of all cardiac diseases combined (defined below in
WP3) from the sources mentioned below in WP3. This will enable us to address most of the questions of clinical interest in
subgroups of patients. The power calculations performed for second malignant neoplasms (SMNs) in WP4 below apply equally to
cardiac diseases overall and indicate that our study has ample statistical power to detect meaningful effects. The power
calculations pertaining to genetic alleles similarly apply. It is therefore reassuring that our study can detect associations with both
clinical and statistical significance.




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4.3.2      Objectives

4.3.2.1    Establish a pan-European cohort of survivors of childhood cancer for whom the occurrence of cardiovascular disease has
           been systematically ascertained and validated.
4.3.2.2    Determine the incidence and absolute risk of cardiovascular disease among 5 years survivors in the cohort
4.3.2.3    Undertake a nested case-control study of cardiovascular disease developing within the cohort to determine aspects of
           radiotherapy and chemotherapy most strongly associated with increased risk. Investigate the nature of the dose-
           response relationship between cumulative dose of radiation from radiotherapy, cumulative dose of specific anti-cancer
           drugs and the risk of cardiac disease.
4.3.2.4    Collect and store biological material (blood or saliva) of cases and controls for future DNA studies.
4.3.2.5    Provide reliable and unbiased evidence for:
           a) counselling, educating and empowering survivors;
           b) educating health care professionals;
           c) reviewing and updating standardised guidelines for the clinical follow-up of survivors;
           d) evaluating alternative proposals for future treatment protocols from a risk as well as benefit perspective;
           e) assessing proposals for screening tests among particular groups;
           f) evaluating potential intervention studies aimed at reducing the risk of specific adverse outcomes.

4.3.3      Methods

4.3.3.1    Develop a protocol for the nested case-control study for WP 3. Participants UMC, BOYNE, UNITO, UCL, UBERN, IGR,
           UBHAM.
4.3.3.2    Identify cohorts within individual countries for which relevant cardiovascular disease have been (may be) systematically
           ascertained, in collaboration with WP 1, 2, 4 and participants UMC, UBERN, IGR, UBHAM
4.3.3.3    Contribute to developing the questionnaires and analysing responses in collaboration with WP1and participants UMC,
           UBERN, IGR, UBHAM
4.3.3.4    Ascertain all potential occurrences of the relevant cardiovascular disease within these cohorts in collaboration with WP1.
           More than 5-year childhood cancer survivors who developed a cardiac disease after diagnosis of their primary tumour will
           be identified from the registries in the United Kingdom, France, Switzerland, Netherlands, Hungary, and Italy, with
           participants UMC, UBERN, IGR, UBHAM.
4.3.3.5    Definition of cases: Only the following diseases, graded according the CTCAE v3 criteria (http://ctep.cancer.gov) in more
           than 5 years childhood cancer survivors will be included:


Heart failure
Grade 3: Symptomatic congestive heart failure responsive to intervention, or ejection fraction < 40%-20%, or shortening fraction <15%
Grade 4: Poorly controlled congestive heart failure, intervention such as device or heart transplantation indicated
Grade 5: Death due heart failure
Cardiac ischemia/infarction
Grade 3: Symptomatic and testing consistent with ischemia or unstable angina or intervention needed
Grade 4: Acute myocardial infarction (troponin or ECG)
Grade 5: Death due myocardial infarction
Pericarditis
Grade 3: With physiological consequences
Grade 4: With life threatening consequences
Grade 5: Death due to pericarditis
Valvular disease
Grade 3: Symptoms of severe regurgitation or stenosis, symptoms controlled with interventions
Grade 4: Life threatening or intervention (valve replacement or valvuloplasty) indicated
Grade 5: Death due to valvular disease
Cardiac arrhythmia
Grade 3: Medically controlled or controlled with device (e.g. pacemaker)
Grade 4: Life threatening (e.g. arrhythmia associated with congestive heart failure, hypotension, syncope, shock)
Grade 5: Death due to cardiac arrhythmia



4.3.3.6    Validate the potential occurrences of cardiovascular disease for each possible case, principally through obtaining copies
           of original records or by contacting physicians. Once case selection is complete, every case of cardiac disease and every
           death from cardiac disease will be included, whatever the quality of the data available for the patient in collaboration
           with WP1, and participants UMC, UBERN, UBHAM.
4.3.3.7    Identify cohorts for possible inclusion in the analysis to estimate the absolute risk of cardiac diseases in childhood cancer
           survivors. All cohorts of childhood cancer survivors with complete follow-up of cardiac disease will be identified in
           collaboration with WP1, and participant UMC.                                                                                           Formatted: Font: 8 pt, Italic, Do not check
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4.3.3.8    Undertake the pan-European cohort analyses of the absolute risks for cardiovascular disease when the cohort is received
           from WP1. This would include estimation of proportion of different groups of survivors developing specific types of
           cardiovascular disease by specified ages and periods of follow-up. The groups of survivors would be defined in terms of
           type of childhood cancer, types of treatment age at treatment and calendar period of treatment. To be done in
           collaboration with participant UMC, UBERN.
4.3.3.9    Select controls matched to confirmed cases. The identified cases will be matched 1:1 with controls, who will be drawn
           from among childhood cancer survivors who did not develop a cardiac disease by matching on country of treatment, sex,
           age at first cancer diagnosis, date of first cancer diagnosis, length of follow-up. If this is not possible, the closest matches
           available will be selected in collaboration with WP 1 and the national registries and in collaboration with participants
           UMC, UBERN, IGR, UBHAM.
4.3.3.10   Collect details of radiotherapy received by cases and controls during the relevant period at risk from the original
           treatment centres in collaboration with participant UMC.
4.3.3.11   Collect details of chemotherapy received by cases and controls during the relevant period at risk from the original
           treatment centres in collaboration with participant UMC.
4.3.3.12   Collect radiation records of cases and controls for WP 5 in collaboration with WP 1 and WP 4 in collaboration with
           participant UMC, UBERN.
4.3.3.13   Collect biological material (blood or saliva) of cases and controls to investigate the role of DNA polymorphisms. This
           material will be stored in the countries and these analyses will be not part of this grant. In collaboration with WP 4, and
           participants UMC, UBHAM.
4.3.3.14   Implement a questionnaire about family history and other risk factors for cardiac disease to all survivors and controls
           included in the case control study in collaboration with WP 4, and participant UBHAM.
4.3.3.15   Establish the pan-European case-control study data file to enable future case-control analyses. In collaboration with WP1
           and participants UMC, UBERN, IGR, UBHAM.
4.3.3.16   Receive the results, the estimates of radiation doses received to the heart in cases and controls, as well as uncertainties
           affecting these estimates from WP 2, participant IGR.
4.3.3.17   Undertake the case-control analyses investigating the risk of overall cardiovascular disease and for the different types of
           cardiac disease in relation to: cumulative exposure to radiation, as a result of radiotherapy, cumulative dose specific
           chemotherapeutic drugs and relevant factors collected by the records or existing national questionnaires.
4.3.3.18   To identify cohorts which could be included in the analysis to estimate the absolute risk of cardiac diseases in childhood
           cancer survivors all cohorts of childhood cancer survivors with a complete follow-up of cardiac disease will be identified in
           collaboration with participants UMC, UBERN, IGR, UBHAM.




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4.4       Work Package 4: Second primary neoplasms: cohort and nested case-control studies

4.4.1     Background

Second primary neoplasms (SPNs) are internationally acknowledged to be one of the most serious consequences of treatment for
childhood cancer and the importance of investigating both aspects of treatment and genetic susceptibility has been emphasised in
a recent National Cancer Institute (NIH) Workshop report [31]. Considerable uncertainties remain concerning the risks and causal
factors, particularly among survivors aged over 40 years when cancer incidence in the general population begins its inexorable
increase. By combining data from across Europe insights into such long-term risks and potential interactions between elements of
treatment and genotype may be meaningfully undertaken.

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 SMN risk 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;
        because of the smaller anatomic volume during childhood, radiotherapy is likely to involve a greater proportion of this
         volume than in adulthood, potentially leading to greater toxicity.


4.4.1.1   Bone and soft tissue sarcoma

Second malignant sarcomas are among the most frequent solid SMNs observed after childhood cancer and their prognosis is
relatively poor [32]. There are 7 previous studies which investigated the role of chemotherapy and radiotherapy in the risk of
second sarcoma [33-39]. Applicants on the present grant application were principal investigators in 4 of these published studies.
The maximum number of cases available to each of these previous investigations was about 100. This seriously limited the extent
to which treatment-related risk factors and their interaction could be studied. No meaningful analysis of genotypic factors was
possible with such limited numbers.

4.4.1.2   Adult-type carcinomas

The average age within most cohorts of survivors of childhood cancer worldwide is still relatively young and only a small proportion
have been followed-up beyond 40 years of age. The Nordic and British childhood cancer registries were established sufficiently
long ago that they contain some of the largest numbers of long-term survivors available globally. As a consequence, for example,
about 200 digestive carcinomas and 200 genitourinary carcinomas have been observed among survivors within these 2 registries.
Such carcinomas, which are relatively common within the general population after age 40 years, are rare in cohorts with limited
follow-up. Several of the applicants on the current application were principal investigators on the EURATOM FP-6-funded
investigation GENE-RAD-RISK which involved a pan-European case-control study of second primary breast cancer after childhood
cancer. This was also designed to explore treatment related factors and genotypic factors, and their interaction, in relation to the
risk of breast cancer.

4.4.1.3   Anticipated contribution/achievements

The first deliverables will be reports (ultimately leading to publications) on the absolute risks of bone and soft tissue sarcoma; also
digestive and genitourinary carcinomas. This will include the proportion of survivors affected by increasing attained ages and
periods of follow-up and how this varies in relation to type of childhood cancer and its treatment. In addition, the observed
number of SMNs of a particular type will be compared with that expected across increasing attained ages and periods of follow-up
– overall and for specific types of childhood cancer and treatment groups.

We estimate about 600 cases of second sarcoma following childhood cancer which would be matched to the same number of
controls (Table 1). We estimate 600 cases of adult type carcinoma (300 digestive and 300 genitourinary) which would be matched
to 600 controls. Such numbers will provide the best current opportunity available worldwide to investigate the effect of
radiotherapy, chemotherapy and genotype and their interactions on the risk of these SMNs. This would include:
         Investigation of the shape of the dose-response between both the cumulative dose of radiation (from radiotherapy) and
          dose of specific chemotherapeutic drugs, and the risk of specific types of SMN. Factors modifying this dose-response
          would also be explored including age at exposure and duration of follow-up.
         Interaction between different elements of treatment on the risk of specific types of SMN would be investigated.


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4.4.1.4     Statistical analysis

Standard methods for the analysis of cohort and case-control studies will be used [40, 41]. However, within the case-control studies
it will be important to explore models which are linear, quadratic, cubic, quartic and exponential in dose of radiation and
chemotherapeutic drug. Interaction between specific elements of therapy will be explored as well as potential modifiers such as
age at exposure and duration of follow-up. Confounding information collected by interview will also be taken into account. The
statistical power of this study is addressed below.

The number anticipated from different countries/regions are given in the Table below.

                                                               NUMBER OF CASES OF:
 Country / Region                                                                                                  Total
                                                                                                                              Total cases
                                                                                                                  Number
                                    Bone         Soft tissue       Sarcoma      Digestive       Genitourinary                 & controls
                                                                                                                  of cases
                                   sarcoma        sarcoma           NOS        carcinoma         carcinoma
 UK                                  97              96               0              80              77             350          700
 Nordic countries                    39              53               0              123            131             346          692
 France                              81              36               0              60              33             210          420
 Netherlands*                        0               0               120*            35*             35*            190*         380*
 Italy, exclusive of Torino          17              13              23              21              4               78          156
 Torino                              0               0               15              3               2               20           40
 Slovenia                            2               6                0              0               4               12           24
 Hungary                             0               0                5              2               2               9            18
 Switzerland                         0               0               19              23              13              55          110
 TOTAL                              236             204              182             347            301            1270          2540
            NOS: Not otherwise specified

  *Total number of cases from Netherlands is 135, at least.

4.4.1.5     Statistical power of the study

A total of 300 cases and an equal number of controls will permit us to have a higher than 80% statistical power to detect a relative
risk of 2.5 or more due to a risk factor present in 5% of the controls (chosen to reflect this frequency in the general population of
patients treated for a childhood cancer). If this risk factor is more frequent, say 20% of the population, this minimal relative risk will
be 1.7 (Figure 1.left). For 400 cases and 400 controls, these relative risks will be, respectively, 2.2 and 1.6 (Figure 1. right) and 1.9
and 1.5 for an analysis of 600 cases and 600 controls. Given the expected magnitudes of risk we are looking for, this lower limit is
entirely acceptable.




Figure1. Statistical power




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Genetic risk factor.

The following table indicates the minimum odds-ratio that the various analyses, including those for cardiac disease, will enable us
to detect, with a power of 80% and alpha set at 5%, according to the frequency of a dominant allele.


                                              Odds-ratio

                 Allele frequency             300 cases              400 cases             600 cases

                 0.01                         3.42                   3.00                  2.65

                 0.05                         1.98                   1.82                  1.65

                 0.10                         1.72                   1.61                  1.48

                 0.20                         1.60                   1.50                  1.40




This table shows that our studies have good statistical power to detect the association of alleles occurring at frequencies as low as
1%.

Interaction

As an example, if the genetic factor is relatively rare (allele frequency = 5%) and is associated with a moderate increase in risk (OR =
2.5) and if the treatment factor occurs in 10% of controls and increases the risk of cardiac disease by a factor of 2 (OR = 2.5), the
study (600 cases and 600 controls) will have a power of 80% to detect an interaction of a factor of 3, compared to a multiplicative
model, i.e. an OR of 15 for the exposed subjects carrying the predisposing allele. Using the same hypotheses, a study of 300 cases
and 300 controls will be able to detect an interaction between radiation and allele occurring at a magnitude of 4.8 or higher. These
considerations apply equally to the analysis of cardiac disease and to SMNs, to be done outside the workscope of this application.

4.4.2     Objectives

4.4.2.1   Establish a pan-European cohort of survivors of childhood cancer for whom the occurrence of second primary sarcomas
          and second primary “adult-type” carcinomas has been systematically ascertained and validated.
4.4.2.2   Within the cohort compare observed and expected numbers of second primary cancers (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.
4.4.2.3   Undertake 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. Investigate the nature 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.
4.4.2.4   Undertake a nested case-control 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.
          Investigate the nature 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 adult-type carcinoma.
4.4.2.5   Provide a reliable and unbiased evidence base useful for:
          a) counselling, educating and empowering survivors;
          b) educating health care professionals;
          c) reviewing and updating standardised guidelines for the clinical follow-up of survivors;
          d) evaluating alternative proposals for future treatment protocols from a risk as well as benefit perspective;
          e) assessing proposals for screening tests among particular groups;
          f) evaluating potential intervention studies aimed at reducing the risk of specific adverse outcomes.




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4.4.3     Methods

4.4.2.1  Identify cohorts within individual countries for which relevant second malignant neoplasms (SMNs) have been (may be)
         systematically ascertained.
4.4.2.2 Ascertain all potential occurrences of the relevant SMNs within these cohorts.
4.4.2.3 Within each individual cohort validate the potential occurrences of SMN, principally through obtaining copies of
         pathology reports. (See Appendix – ‘Validation of cases within case-control studies’).
4.4.3.4 Select controls matched to confirmed SMNs. (See Appendix – ‘Selection of Controls’).
4.4.3.5 Establish the pan-European cohort study data file to enable cohort analysis of absolute risks.
4.4.3.6 Undertake the pan-European cohort analyses of the absolute risks of SMN. This would include estimation of proportion of
         different groups of survivors developing specific types of SMN by specified ages and periods of follow-up; also
         comparisons of observed number with those expected from the general population. The groups of survivors would be
         defined in terms of type of childhood cancer, types of treatment, age at treatment and calendar period of treatment.
4.4.3.7 Collect details of radiotherapy received by cases and controls during the relevant period at risk from the original
         treatment centres. (See Appendix – ‘Radiotherapy records collection for case-control studies’).
4.4.3.8 Collect details of chemotherapy received by cases and controls during the relevant period at risk from the original
         treatment centres. (See Appendix – ‘Chemotherapy records collection for case-control studies’).
4.4.3.9 Execute telephone questionnaire interview with cases and controls. (See Appendix – ‘Questionnaires’).
4.4.3.10 Obtain a sample of DNA from those cases and controls who consent to provide it as part of the interview. (See Appendix –
         ‘DNA collection for case-control studies’).
4.4.3.11 Establish the pan-European case-control study data file to enable case-control analysis.
4.4.3.12 Undertake the case-control analyses investigating the risk of SPC in relation to: cumulative exposure to radiation, as a
         result of radiotherapy, cumulative dose specific chemotherapeutic drugs and relevant factors collected by questionnaire.

4.5       Work Package 5: Late Mortality

4.5.1     Background

Traditionally, clinicians have used 5-year survival from the time of diagnosis as a generalized benchmark for cure. However, the risk
of cancer and cancer therapy-related death extends well beyond this arbitrary point. Late mortality among survivors of childhood
and adolescent cancer, defined as death occurring more than 5 years after diagnosis, can be regarded as the ultimate adverse
effect of the cancer disease and/or its treatment.

                                                                       Unfortunately, most therapeutic protocols are not designed to
                  Figure 2. From Armstrong et al, 2009                 monitor patients beyond the time point for assessing clinical
                                                                       efficacy (typically 5 to at most 10 years from diagnosis).
                                                                       Moreover, most paediatric oncology programs are not
                                                                       structured to systematically follow patients as long-term
                                                                       survivors into adulthood. For these reasons, assessment of
                                                                       late mortality is generally dependent on epidemiologic studies
                                                                       to investigate the risk of late, but premature, death and its
                                                                       determinants.
                                                                       In the United States, the most recent report of late mortality
                                                                       from the Childhood Cancer Survivor Study (CCSS) [42] included
                                                                       a total of 2,821 deaths that have occurred among the 20,483
                                                                       eligible 5-year survivors aged 0-20 years at diagnosis. When
                                                                       their all-cause mortality rates were compared with those for
                                                                       the United States population, adjusted for age, sex and
                                                                       calendar year, the standardised mortality ratio (SMR) showed
                                                                       a substantially increased risk of dying that persisted 30 years
                                                                       after diagnosis: the SMR was 20.7 in the first 5 to 9 years after
                                                                       the paediatric tumour and 6.9 for more than 30 years follow-
                                                                       up. Since the risk of death due to the paediatric malignancy
                                                                       decreases with time passing, these persisting elevated rates of
                                                                       mortality suggest that other causes for late mortality become
                                                                       increasingly important with time.


Surprisingly little is known about late mortality in most of the European countries. Data from the United Kingdom [43] reporting
3,049 late deaths, and the Nordic countries [18] concerning 1,422 late deaths, indicate that approximately 10 to 17% of 5-year
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to the background population. Overall, long-term survivors of childhood cancer experience about 11-fold greater risk of death than
the background population.

There are only a few other, smaller studies on late mortality in other European countries. Cardous-Ubbink et al. [44] reported on
122 late deaths from a single Amsterdam hospital, Dama et al. [45] analyzed 144 fatalities from the population-based Childhood
Cancer Registry of Piedmont region in Italy, and Trombert-Paviot [46] presented 42 late deaths observed in the Rhone-Alpes region
cancer registry in France. There is no information available regarding late mortality from most of the European countries, including
countries as densely populated as Germany, Spain or Poland.

This very limited number of epidemiological studies shows that within 5 – 10 years after diagnosis the main cause of death is
relapse of the primary tumour, while later on second primary tumours and cardiac and pulmonary causes become more important.
While cancer treatments remain the main cause of excess mortality after very long follow-up (more than 15 years after diagnosis),
a number of aspects of this relationship have not been satisfactorily investigated yet. Recently, Tukenova et al [47] analysed 603
late fatalities from British and French cohort of 5-year survivors and could for the first time establish a relationship between the
radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality. This study also
confirmed a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.

Another aspect that needs to be documented is the experience of survivors in many European countries where such studies have
not been conducted as yet. Heterogeneity in treatment practices and protocols over time and across countries may well have
varying impact on late mortality. This assumption is based on the investigation performed in the Nordic countries, known for their
seemingly uniform standard of living and well-developed health care system [48]. Overall late mortality was significantly higher in
Denmark and Finland than in Norway and Sweden for cohorts of survivors diagnosed in the 1960s. This could not be explained by
inverse differences in 5-year survival. These differences diminished over time and had disappeared for patients diagnosed and
treated in 1980-1989, the last period studied. The pattern was similar for both genders. The convergence of mortality rates was
most probably the effect of a closer collaboration among Nordic paediatric oncologists that led to the development and
implementation of common protocols for treatment and follow-up of childhood cancers in all countries.

To study the long-term risk of severe and lethal conditions in survivors as a direct consequence of the cancer treatment earlier in
their lives is in their best interest, but in many European countries such studies have been impeded by legislation on data
protection and logistics barriers. Most European registries regularly follow-up incident cases for vital status in order to measure
survival probability after diagnosis, but few systematically collect and code the actual cause of death. We will promote the
expansion of routine procedures to include causes of death to as many European cancer registries as possible in order to document
the experience of childhood cancer survivors throughout Europe. This will also favour introduction of health promotion measures,
both by primary and by secondary prevention.

From information obtained as part of a PanCare survey in 2009, we estimate that the participants of the WP will be able to analyse
about 12,000 late deaths that occurred among 5-year survivors of childhood and adolescent cancer in 16 countries, thus ensuring
by far the largest material in the word, with an accompanying ability to obtain precise measurements of small effects.




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4.5.2     Objectives

4.5.2.1   To establish a pan-European cohort of survivors for which all deaths occurring at least five years from diagnosis have
          been (or can be) ascertained and for which an official cause of death is available.
4.5.2.2   To analyse total, gender-specific and cause-specific mortality in this cohort, including survivors from various European
          countries with different health systems over extended period of time.
4.5.2.3   To relate absolute and excess risk (compared to background population) of death from specific causes to gender, type of
          childhood cancer, age at diagnosis, period of cancer diagnosis and, in a subset of patients, type of treatment.
4.5.2.4   To validate the official causes of death through accessing death certificates, hospital records and autopsy reports in a
          sample of patients.
4.5.2.5   To assess the comparability and quality of causes of death recorded in different countries.
4.5.2.6   To clarify, in those countries where mortality data and/or causes of death are not readily available, the reasons for the
          lack of information.

4.5.3     Methods

4.5.3.1   In collaboration with WP1 we will develop the protocol to participate in the late mortality study (Participants ULUND,
          UNITO, UMC and IARC). This will describe requirements to participate in the study and definitions for the information to
          be collected: size of the cohort of paediatric tumours, incidence period, most up-to-date follow-up; variables describing
          the paediatric tumour including stage, variables describing treatments; variables describing vital status and causes of
          death; availability of suitable population statistics to compute expected events. We will also help developing a set of
          validity checks that will be performed by WP1 systematically on causes of death (Participants ULUND and UNITO).
4.5.3.2   Where data from multiple centres/registries within a country are contributed, it will be the responsibility of data
          providers to ensure the elimination of duplicate case registrations before submission of anonymised records. Participant
          ULUND will be responsible for the data from the Nordic countries (Denmark, Finland, Iceland, Norway, Sweden) and from
          Slovenia, UNITO and IGG will provide data from the Italian population-based and hospital-based Italian registries, AMC
          will be responsible for the Dutch data, HSZOMB for the Hungarian cohort, UBERN for the data from Switzerland, IGR for
          the French cohort, UBHAM for the data from British cohort and IARC for the data from population-based registries from
          countries not covered by other participants.
4.5.3.3   As most registries maintain their data as coded at the time of registration, we will provide WP1 with rules to convert and
          group disease codes from different ICD revisions introduced over time, in order to have a consistent definition of the
          cause of death (participants ULUND, UNITO, UMC and IARC). We will refer to WHO recommendations to guide this work.
4.5.3.4   The cohorts of survivors will be compared with the background population with respect to cause-specific mortality, years
          of life lost and overall survival. Differences will be measured by means of Standardized Mortality Ratios (SMR) and
          Absolute Excess Risks (AER) for broad and detailed categories of causes of death as defined by the International
          Classification of Diseases (10th revision), adjusting for age and calendar year of diagnosis of the primary tumour, age at
          death and gender. We will also estimate cause-specific cumulative risk of dying allowing for competitive causes of death.
          All analyses will be repeated in subgroups, e.g. diagnostic group and age at incidence of the paediatric tumour (ICCC-3
          classification), gender, and treatment modality and prognostic factors, where available. Analyses will be performed by
          participants ULUND and UNITO.
4.5.3.5   Where detailed information on treatment, prognostic factors and other host characteristics are available we will also
          carry out internal comparisons by treatment modality using Cox multivariable regression modelling with attained age as
          the time scale. As above, separate analyses will be repeated for different diagnostic groups of the paediatric tumour
          (participants ULUND and UNITO).
4.5.3.6   We will develop the protocol of a study on the validity of coded underlying causes of death as obtained from routine
          mortality registries (participants ULUND, UNITO, UMC, IARC and BOYNE). The study will entail the verification of the
          reported cause of death by reviewing the original death certificate and obtaining confirmatory information from hospital
          records and pathology registries and will be based on a representative samples of deaths recorded among survivors as
          well as in the general population. The study will also evaluate consistency of data quality across participating countries.
          Similar studies on newly identified causes of deaths that are found in excess may be required to confirm the validity of
          the new findings.




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                                                                                  Ruth Ladenstein, SIOPE                                  Formatted   ...
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                                                                                  Leontien Kremer, AMC                                    Formatted   ...
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                                                                                  Julianne Byrne, BOYNE                                   Formatted   ...
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                                                                                  Julianne Byrne, BOYNE                                   Formatted   ...
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4             Second malignant              Mike Hawkins (chair)                  Desiree Grabow, UMC                                     Formatted   ...
              neoplasms: cohort and                                               Florent de Vathaire, IGR                                Formatted   ...
              nested case-control studies                                         Leontien Kremer, AMC
                                                                                  Mike Hawkins, UBHAM                                     Formatted   ...
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                                                                                  Julianne Byrne, BOYNE                                   Formatted   ...
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                                                                                  Desiree Grabow, UMC                                     Formatted   ...
                                                                                  Florent de Vathaire, IGR
                                                                                  Mike Hawkins, UBHAM                                     Formatted   ...
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                                                                                  Julianne Byrne, BOYNE                                   Formatted   ...
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                                                                                  Eva Steliarova-Foucher, IARC                            Formatted   ...
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5.        Publications from PanCareSurFup

          5.1       Location of analyses

Analyses of the current PCSF hypotheses will be undertaken in various locations. Details to come

          5.2       List of primary publications

Lead author, lead analyst and list of co-authors for each paper. Details to come

          5.3       List of secondary publications

Lead author, lead analyst and list of co-authors for each paper. Details to come

          5.2       Analytic plans

Outline of the statistical analysis plan for each paper, or each group of papers. Details to come

6.        Ethics considerations

Each data provider who needs an ethics review may already have their own consent forms and information sheets in their own
languages and in conformance to the requirements of the local ethics boards. Templates are provided in the Appendix for the
Information Sheet, the Adult Consent Form and a Proxy Consent Form, in case these are useful. They can be altered to suit local
needs.

PanCareSurFup will seek to interview and to obtain biospecimens (mouth (buccal) swabs only, not blood samples) from all
survivors identified in the three case-control studies. Other survivors who contribute only to the cohort studies will not be
interviewed. Nor will they be asked to give a biospecimen. Eligibility criteria for these studies are included in the Appendix (page
xx).

Besides adults, minors will also be asked for an interview covering correlates for cardiac events and for SPNs. (Appendix xx) Minors
participating in case-control studies will also be asked for biospecimens (buccal swabs). There may not be a lower limit in age for
                                               th
minors. However, all minors (before their 18 birthday on the day of the study) must/should sign an Assent Form. The Information
Sheet should be modified locally for better understanding. In addition, the parent/guardian should sign a Consent Form for a Minor
Child. Thus, each participating child must/should have two consent forms, one signed in person, and the other signed by an adult.

PCSF will seek a proxy respondent for all participants in the case-control studies who meet the criteria outlined in the Appendix.
There may be different ethics rules regarding proxy respondents. For instance, in the UK, the BCCSS cannot obtain permission from
their ethics boards for proxy respondents. However, this situation may not obtain elsewhere. To avoid survival bias, it is important
that each data provider seek permission to interview proxy respondents. The definition of who can serve as a proxy respondent is
also outlined in the Appendix.

The uses of the DNA obtained for the case-control studies has not been settled at this time. For the ethics board, it may be possible
to obtain a blanket permission for genetic studies (not further specified) in the future. The template consent form (Appendix xx) is
phrased in this way. Local standards may vary.

6.1       Ethics reviews

Each data provider must obtain their own ethics reviews from the local ethics board. Once approval for the study has been
obtained, each data provider must send a copy of the signed certificate from the ethics board to the Study Coordinator (Lars
Hjorth), or his study manager, Ingela Bystrom. Ingela will see that the certificate is forwarded to the relevant EC authority.

7.        End of study issues

7.1       Ownership of data

         Each data provider retains ownership of the data that they provided to PCSF. The data will be stored at the University of
Birmingham until all analyses outlined in this document have been completed and the results of these analyses have been
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agreement. For instance, a new consortium may propose to add data to PCSF for a new, prospective, study. In cases like this, PCSF
consortium will discuss the proposal and agree on the way forward.

The question of ownership of the results of Radiation Dosimetry (WP2) remains to be resolved.

7.2       Procedures to store data

All data will be stored at UMC-Mainz, or at the University of Birmingham during the course of the study. Upon study completion
the data will be archived and stored at the same location, or elsewhere (to be discussed). Additional studies involving DNA linked to
characteristics of subjects may be undertaken at a later date. It is important that all data, including genetic data, be stored in a
suitable manner, in order that it may be used for future studies (Appendix xx). Since genetic analysis will not be done under PCSF,
blood samples/genetic material will be stored in each country. The exact procedures for storage and retrieval of genetic material
will be discussed and finalized before the end of the study.

8.        Timeline

          See Appendices: Schedule of Deliverables & Schedule of Milestones

9.        References

1.        Steliarova-Foucher, E., et al., Geographical patterns and time trends of cancer incidence and survival among children and
          adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study. Lancet, 2004. 364(9451): p. 2097-
          105.
2.        Kaatsch, P., et al., Time trends of cancer incidence in European children (1978-1997): report from the Automated
          Childhood Cancer Information System project. Eur J Cancer, 2006. 42(13): p. 1961-71.
3.        Gatta, G., et al., Survival of European children and young adults with cancer diagnosed 1995-2002. Eur J Cancer, 2009.
          45(6): p. 992-1005.
4.        Steliarova-Foucher, E., et al., Quality, comparability and methods of analysis of data on childhood cancer in Europe (1978-
          1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer, 2006. 42(13): p. 1915-51.
5.        Schmidtmann, I. and M. Blettner, How do cancer registries in Europe estimate completeness of registration? Methods Inf
          Med, 2009. 48(3): p. 267-71.
6.        Gagliardi, G., I. Lax, and L.E. Rutqvist, Partial irradiation of the heart. Semin Radiat Oncol, 2001. 11(3): p. 224-33.
7.        Kong, F.M., et al., Physical models and simpler dosimetric descriptors of radiation late toxicity. Semin Radiat Oncol, 2007.
          17(2): p. 108-20.
8.        Yorke, E.D., Modeling the effects of inhomogeneous dose distributions in normal tissues. Semin Radiat Oncol, 2001. 11(3):
          p. 197-209.
9.        Yang, Y., et al., A three-source model for the calculation of head scatter factors. Med Phys, 2002. 29(9): p. 2024-33.
10.       Zhu, T.C. and B.E. Bjarngard, Head scatter off-axis for megavoltage x rays. Med Phys, 2003. 30(4): p. 533-43.
11.       Hall, E.J. and C.S. Wuu, Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys,
          2003. 56(1): p. 83-8.
12.       Stovall, M. and R.J. Shalek, A review of computer techniques for dosimetry of interstitial and intracavitary radiotherapy.
          Comput Programs Biomed, 1972. 2(3): p. 125-36.
13.       Francois, P., et al., A mathematical child phantom for the calculation of dose to the organs at risk. Med Phys, 1988. 15(3):
          p. 328-33.
14.       Diallo, I., et al., Frequency distribution of second solid cancer locations in relation to the irradiated volume among 115
          patients treated for childhood cancer. Int J Radiat Oncol Biol Phys, 2009. 74(3): p. 876-83.
15.       Little, M.P., et al., New models for evaluation of radiation-induced lifetime cancer risk and its uncertainty employed in the
          UNSCEAR 2006 report. Radiat Res, 2008. 169(6): p. 660-76.
16.       Bolch, W., et al., Hybrid computational phantoms for medical dose reconstruction. Radiat Environ Biophys, 2009.
17.       Alziar, I., et al., Individual radiation therapy patient whole-body phantoms for peripheral dose evaluations: method and
          specific software. Phys Med Biol, 2009. 54(17): p. N375-83.
18.       Möller, T.R., et al., Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a
          population-based study in the Nordic countries. J Clin Oncol, 2001. 19(13): p. 3173-81.
19.       Mertens, A.C., et al., Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer
          Survivor Study. J Natl Cancer Inst, 2008. 100(19): p. 1368-79.
20.       Tukenova, M., et al., Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood
          Cancer. J Clin Oncol, 2010. Epub ahead of print(Feb 8).
21.       Kremer, L.C., et al., Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic
          review. Ann Oncol, 2002. 13(4): p. 503-12.
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                                                                                                                                          spelling or grammar


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22.       Pein, F., et al., Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid
          tumour at the Institut Gustave Roussy. Br J Cancer, 2004. 91(1): p. 37-44.
23.       van der Pal, H.J., et al., Risk of morbidity and mortality from cardiovascular disease following radiotherapy for childhood
          cancer: a systematic review. Cancer Treat Rev, 2005. 31(3): p. 173-85.
24.       Lipshultz, S.E., et al., Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute
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25.       van Dalen, E.C., et al., Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up
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26.       Mulrooney, D.A., et al., Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective
          analysis of the Childhood Cancer Survivor Study cohort. Bmj, 2009. 339: p. b4606.
27.       Kremer, L.C., et al., Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a
          systematic review. Ann Oncol, 2002. 13(6): p. 819-29.
28.       Cambien, F. and L. Tiret, Genetics of cardiovascular diseases: from single mutations to the whole genome. Circulation,
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29.       Wojnowski, L., et al., NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with
          doxorubicin-induced cardiotoxicity. Circulation, 2005. 112(24): p. 3754-62.
30.       Blanco, J.G., et al., Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone
          oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood
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32.       Jenkinson, H.C., et al., Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain.
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33.       Hawkins, M.M., et al., Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst,
          1996. 88(5): p. 270-8.
34.       Le Vu, B., et al., Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J
          Cancer, 1998. 77(3): p. 370-7.
35.       Menu-Branthomme, A., et al., Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during
          childhood. Int J Cancer, 2004. 110(1): p. 87-93.
36.       Jenkinson, H.C., et al., A study of soft tissue sarcomas after childhood cancer in Britain. Br J Cancer, 2007. 97(5): p. 695-9.
37.       Henderson, T.O., et al., Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor
          Study. J Natl Cancer Inst, 2007. 99(4): p. 300-8.
38.       Wong, F.L., et al., Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA, 1997. 278(15): p. 1262-
          7.
39.       Tucker, M.A., et al., Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med, 1987. 317(10): p.
          588-93.
40.       Breslow, N.E. and N.E. Day, The analysis of case-control studies. Statistical methods in cancer research. Vol. 1. 1980, Lyon:
          International Agency for Research on Cancer.
41.       Breslow, N.E. and N.E. Day, The design and analysis of cohort studies. Statistical methods in cancer research. Vol. 2. 1987,
          Lyon: International Agency for Research on Cancer.
42.       Armstrong, G.T., et al., Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer
          Survivor Study. J Clin Oncol, 2009. 27(14): p. 2328-38.
43.       Reulen, R., et al., Long-term Cause Specific Mortality Among Survivors of Childhood Cancer. JAMA, 2010. 304 (2): p. 172-
          179.
44.       Cardous-Ubbink, M.C., et al., Long-term cause-specific mortality among five-year survivors of childhood cancer. Pediatr
          Blood Cancer, 2004. 42(7): p. 563-73.
45.       Dama, E., et al., Late deaths among five-year survivors of childhood cancer. A population-based study in Piedmont
          Region, Italy. Haematologica, 2006. 91(8): p. 1084-91.
46.       Trombert-Paviot, B., et al., Mortalite tardive apres cancer des enfants survivants a cinq ans dans la region Rhone-Alpes.         Formatted: French (France)
          Rev Epidemiol Sante Publique, 2008. 56(6): p. 383-90.
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47.       Tukenova, M., et al., Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood
          Cancer. J Clin Oncol, 2010. 28(8):p.1308-15.
48.       Möller, T.R., et al., Late mortality among five-year survivors of cancer in childhood and adolescence: Differences between
          the Nordic countries. Acta Oncol, 2004. 43(8): p. 711-8.




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APPENDICES

1.         Need to provide underlying cohorts within which late deaths, subsequent primary neoplasms and
           cardiac conditions have been ascertained.
Both to undertake cohort analyses as stated in the application to the EC and to enable central selection of controls for the case-
control studies it is essential that data providers supply a list of essential variables characterising their cohorts.

2.         Cohorts for late deaths, subsequent primary neoplasms and cardiac conditions – lists of essential
           variables.

                                                      Cohort Baseline Variables:

There should be records added and not fields to add subsequent events (SNM, Cardiac…): See the detailed                                            Formatted: Left
comments of 21 April 2011 sent to Desiree on the Baseline variables list.                                                                          Formatted: Font: 9 pt, Not Bold, English
                                                                                                                                                   (United States)
Number of Variable                Variables name                 Variable          Characteristics              Comment                            Comment [d2]: Will be numbered as soon as
                                                                 Acronym           Format                                                          variables and order of variables is clear
Late Mortality Cohort Variables
                                  Country code                   CCode             XXX
                                  National unique ID-            ID                XXXXXXXXXX….                 ID number used in the
                                  Number                                                                        individual country amended by
                                                                                                                country-code
                                  PCSF unique ID-Number          PCSFID            XXXXXXXXXX……
                                  Gender                         Sex               1 = male
                                                                                   2 = female
                                                                                   9 = not known, missing
                                  Year/Month of Birth            Birth             YYYYMM                       Four digits for year, two digits
                                                                                                                for month (01-12)
                                  Date of first Cancer           DxDate            YYYYMM                       Four digits for year, two digits
                                  diagnosis                                                                     for month (01-12)
                                  Site of first Cancer (ICD-     DxICDOT           C XX.X                       Tumour site, ICD-O-T or ICD
                                  O-3 Topography)                                                               number and edition                 Comment [d3]: What if other coding than ICD-
                                  Type of first Cancer (ICD-     DxICDOM           M XXXX                       Tumour type; Snomed/ICD-O-M        O-3 or ICCC-3?; Ask countries to use coding
                                  O-3 Morphology)                                                               or SNOMED number and               programmes from IARC for ICD-O?
                                                                                                                edition
                                  Type of first Cancer (ICD-     DxICDOB           0, 1, 2, 3, 6, 9
                                  O-3 Behaviour)
                                  Basis of diagnosis             DxBasis           (ICD-O-3, page 38)           “most valid basis of diagnosis”;   Formatted: Portuguese (Brazil)
                                                                                   0 = DCO                      Criteria are described in ICD-O-
                                                                                   1 = clinical                 3, p. 38;                          Formatted: Portuguese (Brazil)
                                                                                   2 = Clinical investigation   (3 and 8 not assigned)             Formatted: Portuguese (Brazil)
                                                                                   4 = specific tumour
                                                                                   markers                                                         Formatted: Portuguese (Brazil)
                                                                                   5 = cytology
                                                                                                                                                   Formatted: Portuguese (Brazil)
                                                                                   6 = histology of a
                                                                                   metastasis                                                      Formatted: Portuguese (Brazil)
                                                                                   7 = histology of a primary
                                                                                   tumour                                                          Formatted: Portuguese (Brazil)
                                                                                   9 = unknown
                                  Involvement in Clinical        DxTrial           1 = yes; 0 = no
                                  Trial
                                  Name of Clinical Trial first   DxTrialName       Code-list
                                  diagnosis                                        (to be defined)
                                  Name of protocol arm           DxTrialArm        Code-list
                                                                                   (to be defined)
                                  Major protocol violation       DxTrialViol       1 = yes; 0 = no
                                  Type of major protocol         DxTrailViolType   1 = relapse,
                                  violation                                        2 = …..
                                                                                                                                                   Comment [d4]: How much information do we
                                  Surgery first Dx               DxSurg            1 = yes; 0 = no
                                                                                                                                                   want? E.g. ovaries = both sides, only one side,
                                  Date of first surgery          DxSurgDate        YYYYMM                       Four digits for year, two digits   laterlity, with regard to fertility????
                                                                                                                for month (01-12); not Biopsy
                                  Chemotherapy first Dx          DxChemo           1 = yes; 0 = no                                                 Comment [d5]: Do we mean the first cicle?
                                  Date of Chemotherapy at        DxChemoDate       YYYYMM                       Four digits for year, two digits
                                                                                                                                                   Formatted: Font: 8 pt, Italic, Do not check
                                  first Dx                                                                      for month (01-12)
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                                     RT (external beam) first     DxRText         1 = yes; 0 = no
                                     Dx
                                     Date of RT (external         DxRTextDate     YYYYMM                       Four digits for year, two digits
                                     beam) at first Dx                                                         for month (01-12)
                                     RT (implanted) first Dx      DxRTimp         1 = yes; 0 = no
                                     Date of RT (implanted) at    DxRTimpDate     YYYYMM                       Four digits for year, two digits
                                     first Dx                                                                  for month (01-12)
                                     BMT (bone marrow             DxBMT           1 = yes; 0 = no
                                     transplant) first Dx
                                     Date of BMT (bone            DxBMTDate       YYYYMM
                                     marrow transplant) first
                                     Dx

Outcome Death
                                     Year/Month of last           DeathFUP        YYYYMM                       Four digits for year, two digits
                                     follow-up with respect to                                                 for month (01-12)
                                     death
                                     Outcome of last follow-      DeathFUPOutc    1=alive, 2=dead, 3=lost to
                                     up with respect to death                     follow-up
                                     Source of this FUP Death     DeathSource     e.g. Cancer registry = 1;
                                                                                  Clinical visit = 2;
                                                                                  Questionnaire to survivor
                                                                                  =3
                                     Year/Month of death          DeathDate       YYYYMM                       Four digits for year, two digits
                                                                                                               for month (01-12)
                                     Underlying Cause of          DeathCause      ICD 10
                                     Death ICD Code
                                     Contributing Cause of        DeathContrib1   ICD 10
                                     Death 1 ICD Code
                                     Contributing Cause of        DeathContrib2   ICD 10
                                     Death 2 ICD Code
                                     Contributing Cause of        DeathContrib3   ICD 10
                                     Death 3 ICD Code

SMN Cohort Variables
Repeat all variables above besides
specific death variables
                                     Year/Month last FUP with     SMNFUP          YYYYMM
                                     respect to SMN
                                     Outcome of last follow-      SMNFUPOutc      1=alive, 2=dead, 3=lost to
                                     up with respect to SMN                       follow-up
                                     Source of this FUP SMN       SMNSource       e.g. Cancer registry = 1;
                                                                                  Clinical visit = 2;
                                                                                  Questionnaire to survivor
                                                                                  =3
                                     Total number of              SMNDxNo         X
                                     subsequent primary
                                     cancers
                                     Date of diagnosis with       SMN1Date        YYYYMM                       Four digits for year, two digits
                                     SMN 1 (Second                                                             for month (01-12)
                                     Neoplasms)
                                     Site of first Cancer (ICD-   SMN1ICDOT       C XX.X                       Tumour site, ICD-O-T or ICD
                                     O-3 Topography)                                                           number and edition
                                     Type of first Cancer (ICD-   SMN1ICDOM       M XXXX                       Tumour type; Snomed/ICD-O-M
                                     O-3 Morphology)                                                           or SNOMED number and
                                                                                                               edition
                                     Type of first Cancer (ICD-   SMN1ICDOB       0, 1, 2, 3, 6, 9
                                     O-3 Behaviour)

                                     Basis of diagnosis SMN1      SMN1Basis       (ICD-O-3, page 38)           “most valid basis of diagnosis”;
                                                                                  0 = DCO                      Criteria are described in ICD-O-
                                                                                  1 = clinical                 3, p. 38;
                                                                                  2 = Clinical investigation   (3 and 8 not assigned)
                                                                                  4 = specific tumour
                                                                                  markers
                                                                                  5 = cytology
                                                                                  6 = histology of a
                                                                                  metatstasis
                                                                                  7 = histology of a primary                                      Formatted: Font: 8 pt, Italic, Do not check
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                                                                                tumour
                                                                                9 = unknown

Repeat all SMN1 cohort variables   Date of diagnosis with       SMN2Date        YYYYMM
for SMN2, 3, 4, 5                  SMN 2 (Second
                                   Neoplasms)
“                                  Date of diagnosis with       SMN3Date        YYYYMM
                                   SMN 3 (Second
                                   Neoplasms)
“                                  Date of diagnosis with       SMN4Date        YYYYMM
                                   SMN 4 (Second
                                   Neoplasms)
“                                  Date of diagnosis with       SMN5Date        YYYYMM
                                   SMN 5 (Second
                                   Neoplasms)

Cardiac Cohort Variables
Repeat all mortality cohort
variables above besides specific
death event variables
                                   Year/Month last FUP with     CardioD         YYYYMM
                                   respect to cardiac
                                   conditions
                                   Outcome of last follow-      CardioFUPOutc   1=alive, 2=dead, 3=lost to
                                   up with respect to cardiac                   follow-up
                                   conditions
                                   Source of this FUP cardiac   CardioSource    e.g. Cardiac registry = 1;
                                   conditions                                   Clinical visit = 2;
                                                                                Questionnaire to survivor
                                                                                =3
                                   Total number of diagnosis    CardioNo        X
                                   with cardiac events
                                   Date of Dx Cardiac           Cardio1Date     YYYYMM
                                   Condition 1
                                   Validation of Cardiac        Cardio1Val      1 = yes; 0 = no
                                   Condition 1
                                   Source of Validation         Cardio1Cond     e.g. ECG = 1, angiogram
                                   Cardiac Condition 1                          report = 2, cardiac
                                                                                enzymes = 3, echo report
                                                                                = 4, hospital discharge
                                                                                letter = 5, GP = 6
Repeat these specific variables
Cardio1 for conditions 2,3,4,5……




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3.        Cohort analyses of the risk of subsequent primary neoplasms (SPNs)

The case-control studies of SPNs will be restricted to subsequent primary digestive and genitourinary carcinomas, together with
bone and soft tissue sarcomas. However, most of the larger data providers have already ascertained and validated all SPNs
irrespective of site/type. Therefore PanCareSurFup presents an opportunity to undertake the largest ever cohort study of all types
of SPNs after childhood cancer. Furthermore as the Nordic and UK data are based on population-based registries established over
50 years ago, an unrivalled opportunity exists to investigate long-term risk with unprecedented accuracy. Consequently, in addition
to cohort analyses relating to the SPNs included within the case-control studies, analysis of the risk of all types of SPNs will also be
undertaken.

4.        Inclusion/exclusion of retinoblastoma survivors

For satisfactory investigation of the risk of SPNs after retinoblastoma it is essential to distinguish between heritable and non-
heritable cases. The former being defined as those cases which are either bilateral or have a positive family history of the disease.
For satisfactory cohort analysis, stratification by heritability is essential. For satisfactory case-control design it is essential to match
cases and controls on heritability.

Therefore only those data providers who are in a position to separate heritable and non-heritable cases of retinoblastoma should
provide retinoblastoma survivors to PanCareSurFup.

5.        Is there any restriction on age at late death, SPN or cardiac condition

None whatever.

6.        Definition of “cases” for the case-control studies of SPNs

Digestive cases

Any primary neoplasm occurring subsequent to the index childhood cancer which has an:
ICD-0(3) Topography C15 to C26 inclusive
and
ICD-0(3) Morphology which includes “carcinoma” or “adenocarcinoma” with a behavior code ≥3.
An exhaustive list of such “carcinoma” and “adenocarcinoma” conditions follows below.


Genitourinary cases

Any primary neoplasm occurring subsequent to the index childhood cancer which has an:
ICD-0(3) Topography C51 to C58 inclusive or C60 to C68 inclusive
and
ICD-0(3) Morphology which includes “carcinoma” or “adenocarcinoma” with a behaviour code ≥3, except for bladder for which all
behavior codes are acceptable.
An exhaustive list of such “carcinomas” and “adenocarcinoma” conditions follow below. However, bladder lesions are included
irrespective of whether they are classified as malignant, benign, in-situ or of uncertain behavior.


Bone and soft tissue sarcomas

Any primary neoplasm occurring subsequent to the index childhood cancer which has an ICD-0(3) Morphology code comprising one
of the following:




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ICD-0(3) = “Sarcoma” Citation should be provided

   Histology       Behavior                               Description
    87103           8710/3      Glomangiosarcoma
     88003          8800/3      Sarcoma, NOS
     88013          8801/3      Spindle cell sarcoma
     88023          8802/3      Giant cell sarcoma
     88033          8803/3      Small cell sarcoma
     88043          8804/3      Epithelioid sarcoma
     88053          8805/3      Undifferentiated sarcoma
     88103          8810/3      Fibrosarcoma, NOS
     88113          8811/3      Fibromyxosarcoma
     88123          8812/3      Periosteal fibrosarcoma
     88133          8813/3      Fascial fibrosarcoma
     88143          8814/3      Infantile fibrosarcoma
     88323          8832/3      Dermatofibrosarcoma, NOS
     88333          8833/3      Pigmented dermatofibrosarcoma protuberans
     88403          8840/3      Myxosarcoma
     88503          8850/3      Liposarcoma, NOS
     88513          8851/3      Liposarcoma, well differentiated
     88523          8852/3      Myxoid liposarcoma
     88533          8853/3      Round cell liposarcoma
     88543          8854/3      Pleomorphic liposarcoma
     88553          8855/3      Mixed type liposarcoma
     88573          8857/3      Fibroblastic liposarcoma
     88583          8858/3      Dedifferentiated liposarcoma
     88903          8890/3      Leiomyosarcoma, NOS
     88913          8891/3      Epithelioid leiomyosarcoma
     88943          8894/3      Angiomyosarcoma
     88953          8895/3      Myosarcoma
     88963          8896/3      Myxoid leiomyosarcoma
     89003          8900/3      Rhabdomyosarcoma, NOS
     89013          8901/3      Pleomorphic rhabdomyosarcoma, adult type
     89023          8902/3      Mixed type rhabdomyosarcoma
     89103          8910/3      Embryonal rhabdomyosarcoma
     89123          8912/3      Spindle cell rhabdomyosarcoma
     89203          8920/3      Alveolar rhabdomyosarcoma
     89213          8921/3      Rhabdomyosarcoma with ganglionic differentiation
     89303          8930/3      Endometrial stromal sarcoma
     89313          8931/3      Endometrial stromal sarcoma, low grade
     89333          8933/3      Adenosarcoma
     89353          8935/3      Stromal sarcoma, NOS
     89363          8936/3      Gastrointestinal stromal sarcoma
     89643          8964/3      Clear cell sarcoma of kidney
     89803          8980/3      Carcinosarcoma, NOS
     89813          8981/3      Carcinosarcoma, embryonal type
     89913          8991/3      Embryonal sarcoma
     90403          9040/3      Synovial sarcoma, NOS
     90413          9041/3      Synovial sarcoma, spindle cell
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     90423          9042/3      Synovial sarcoma, epithelioid cell
     90433          9043/3      Synovial sarcoma, biphasic
     90443          9044/3      Clear cell sarcoma NOS
     91203          9120/3      Hemangiosarcoma
     91243          9124/3      Kupffer cell sarcoma
     91403          9140/3      Kaposi sarcoma
     91703          9170/3      Lymphangiosarcoma
     91803          9180/3      Osteosarcoma, NOS
     91813          9181/3      Chondroblastic osteosarcoma
     91823          9182/3      Fibroblastic osteosarcoma
     91833          9183/3      Telangiectatic osteosarcoma
     91843          9184/3      Osteosarcoma in Paget disease
     91853          9185/3      Small cell osteosarcoma
     91863          9186/3      Central osteosarcoma
     91873          9187/3      Instrosseous well differentiated osteosarcoma
     91923          9192/3      Parosteal osteosarcoma
     91933          9193/3      Periosteal osteosarcoma
     91943          9194/3      High grade surface osteosarcoma
     91953          9195/3      Intracortical osteosarcoma
     92203          9220/3      Chondrosarcoma, NOS
     92213          9221/3      Juxtacortical chondrosarcoma
     92313          9231/3      Myxoid chondrosarcoma
     92403          9240/3      Mesenchymal chondrosarcoma
     92423          9242/3      Clear cell chondrosarcoma
     92433          9243/3      Dedifferentiated chondrosarcoma
     92603          9260/3      Ewing sarcoma
     92903          9290/3      Ameloblastic odontosarcoma
     93303          9330/3      Ameloblastic fibrosarcoma
     93423          9342/3      Odontogenic carcinosarcoma
     94423          9442/3      Gliosarcoma
     94803          9480/3      Cerebellar sarcoma, NOS
     95393          9539/3      Meningeal sarcomatosis
     95813          9581/3      Alveolar soft part sarcoma
     97403          9740/3      Mast cell sarcoma
     97553          9755/3      Histiocytic sarcoma
     97563          9756/3      Langerhans cell sarcoma
     97573          9757/3      Interdigitating dendritic cell sarcoma
     97583          9758/3      Follicular dendritic cell sarcoma
     99303          9930/3      Myeloid sarcoma
     88906          8890/6      Metastatic leiomyosarcoma




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ICD-0(3) = “Carcinoma” or “adenocarcinoma”

 Morphology      Behavior                                      Description
   80102          8010/2    Carcinoma in situ, NOS
    80103         8010/3    Carcinoma, NOS
    80106         8010/6    Metastatic carcinoma
    80123         8012/3    Large cell carcinoma, NOS
    80133         8013/3    Large cell neuroendocrine carcinoma
    80143         8014/3    Large cell carcinoma with rhabdoid phenotype
    80153         8015/3    Glassy cell carcinoma
    80203         8020/3    Carcinoma, undifferentiated type, NOS
    80213         8021/3    Carcinoma, anaplastic type, NOS
    80223         8022/3    Pleomorphic carcinoma
    80303         8030/3    Giant cell and spindle cell carcinoma
    80313         8031/3    Giant cell carcinoma
    80323         8032/3    Spindle cell carcinoma
    80333         8033/3    Pseudosarcomatous carcinoma
    80343         8034/3    Polygonal cell carcinoma
    80353         8035/3    Carcinoma with osteoclast-like giant cells
    80413         8041/3    Small cell carcinoma, NOS
    80423         8042/3    Oat cell carcinoma
    80433         8043/3    Small cell carcinoma, fusiform cell
    80443         8044/3    Small cell carcinoma, intermediate cell
    80453         8045/3    Combined small cell carcinoma
    80463         8046/3    Non-small cell carcinoma
    80502         8050/2    Papillary carcinoma in situ
    80503         8050/3    Papillary carcinoma, NOS
    80513         8051/3    Verrucous carcinoma, NOS
    80522         8052/2    Papillary squamous cell carcinoma, non-invasive
    80523         8052/3    Papillary squamous cell carcinoma
    80702         8070/2    Squamous cell carcinoma in situ, NOS
    80703         8070/3    Squamous cell carcinoma, NOS
    80713         8071/3    Sq. cell carcinoma, keratinizing, NOS                                                                         Formatted: Italian (Italy)
    80723         8072/3    Sq. cell carcinoma, lg. cell, non-ker.                                                                        Formatted: Italian (Italy)
    80733         8073/3    Sq. cell carcinoma, sm. cell, non-ker.
                                                                                                                                          Formatted: Italian (Italy)
    80743         8074/3    Sq. cell carcinoma, spindle cell
                                                                                                                                          Formatted: Italian (Italy)
    80753         8075/3    Squamous cell carcinoma, adenoid
                                                                                                                                          Formatted: Italian (Italy)
    80763         8076/3    Sq. cell carcinoma, micro-invasive
                                                                                                                                          Formatted: Italian (Italy)
    80783         8078/3    Squamous cell carcinoma with horn formation
                                                                                                                                          Formatted: Italian (Italy)
    80823         8082/3    Lymphoepithelial carcinoma
                                                                                                                                          Formatted: Italian (Italy)
    80833         8083/3    Basaloid squamous cell carcinoma
    80843         8084/3    Squamous cell carcinoma, clear cell type                                                                      Formatted: Italian (Italy)

    80903         8090/3    Basal cell carcinoma, NOS                                                                                     Formatted: Italian (Italy)

    80913         8091/3    Multifocal superficial basal cell carcinoma
    80923         8092/3    Infiltrating basal cell carcinoma, NOS
    80933         8093/3    Basal cell carcinoma, fibroepithelial
    80943         8094/3    Basosquamous carcinoma
    80953         8095/3    Metatypical carcinoma
    80973         8097/3    Basal cell carcinoma, nodular
                                                                                                                                          Formatted: Font: 8 pt, Italic, Do not check
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    80983         8098/3    Adenoid basal cell carcinoma
    81023         8102/3    Trichilemmocarcinoma
    81103         8110/3    Pilomatrix carcinoma
    81202         8120/2    Transitional cell carcinoma in situ                                                                           Formatted: Italian (Italy)
    81203         8120/3    Transitional cell carcinoma, NOS                                                                              Formatted: Italian (Italy)
    81213         8121/3    Schneiderian carcinoma
    81223         8122/3    Trans. cell carcinoma, spindle cell
    81233         8123/3    Basaloid carcinoma
    81243         8124/3    Cloacogenic carcinoma
    81302         8130/2    Papillary trans. cell carcinoma, non-invasive
    81303         8130/3    Papillary trans. cell carcinoma
    81313         8131/3    Transitional cell carcinoma, micropapillary
    81402         8140/2    Adenocarcinoma in situ
    81403         8140/3    Adenocarcinoma, NOS
    81406         8140/6    Metastatic carcinoma
    81413         8141/3    Scirrhous adenocarcinoma
    81433         8143/3    Superficial spreading adenocarcinoma
    81443         8144/3    Adenocarcinoma, intestinal type
    81453         8145/3    Carcinoma, diffuse type
    81473         8147/3    Basal cell adenocarcinoma
    81503         8150/3    Islet cell carcinoma
    81543         8154/3    Mixed islet cell & exocrine adenocarcinoma
    81603         8160/3    Cholangiocarcinoma
    81613         8161/3    Bile duct cystadenocarcinoma
    81703         8170/3    Hepatocellular carcinoma, NOS
    81713         8171/3    Hepatocellular carcinoma, fibrolamellar
    81723         8172/3    Hepatocellular carcinoma, scirrhous
    81733         8173/3    Hepatocellular carcinoma, spindle cell variant                                                                Formatted: Italian (Italy)
    81743         8174/3    Hepatocellular carcinoma, clear cell type                                                                     Formatted: Italian (Italy)
    81753         8175/3    Hepatocellular carcinoma, pleomorphic type
    81803         8180/3    Comb. hepatocel. carcinoma & cholangiocarcinoma
    81903         8190/3    Trabecular adenocarcinoma
    82003         8200/3    Adenoid cystic carcinoma
    82012         8201/2    Cribriform carcinoma in situ
    82013         8201/3    Cribriform carcinoma
    82102         8210/2    Adenocarcinoma in situ in adenomatous polyp                                                                   Formatted: Italian (Italy)
    82103         8210/3    Adenocarcinoma in adenomatous polyp                                                                           Formatted: Italian (Italy)
    82113         8211/3    Tubular adenocarcinoma
    82143         8214/3    Parietal cell carcinoma
    82153         8215/3    Adenocarcinoma of anal glands
    82202         8220/2    Adenocarcinoma in situ in familial polyp. coli                                                                Formatted: Italian (Italy)
    82203         8220/3    Adenocarcinoma in adenoma. polyposis coli                                                                     Formatted: Italian (Italy)
    82213         8221/3    Adenocarcinoma in mult. adenomatous polyps
                                                                                                                                          Formatted: Italian (Italy)
    82302         8230/2    Duct carcinoma in situ, solid type
                                                                                                                                          Formatted: Italian (Italy)
    82303         8230/3    Solid carcinoma, NOS
                                                                                                                                          Formatted: Italian (Italy)
    82313         8231/3    Carcinoma simplex
                                                                                                                                          Formatted: Italian (Italy)
    82463         8246/3    Neuroendocrine carcinoma
    82466         8246/6    Metastatic neuroendocrine carcinoma
    82473         8247/3    Merkel cell carcinoma                                                                                         Formatted: Font: 8 pt, Italic, Do not check
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    82503         8250/3    Bronchiolo-alveolar adenocarcinoma
    82513         8251/3    Alveolar adenocarcinoma
    82523         8252/3    Bronchiolo-alveolar carcinoma, non-mucinous                                                                   Formatted: Italian (Italy)
    82533         8253/3    Bronchiolo-alveolar carcinoma, mucinous                                                                       Formatted: Italian (Italy)
    82553         8255/3    Adenocarcinoma with mixed subtypes
    82603         8260/3    Papillary adenocarcinoma, NOS
    82612         8261/2    Adenocarcinoma in situ in villous adenoma                                                                     Formatted: Italian (Italy)
    82613         8261/3    Adenocarcinoma in villous adenoma                                                                             Formatted: Italian (Italy)
    82623         8262/3    Villous adenocarcinoma
    82632         8263/2    Adenocarcinoma in situ in tubulovillous adenoma                                                               Formatted: Italian (Italy)
    82633         8263/3    Adenocarcinoma in tubulovillous adenoma                                                                       Formatted: Italian (Italy)
    82703         8270/3    Chromophobe carcinoma
    82723         8272/3    Pituitary carcinoma, NOS
    82803         8280/3    Acidophil carcinoma
    82813         8281/3    Mixed acidophil-basophil carcinoma
    82903         8290/3    Oxyphilic adenocarcinoma
    83003         8300/3    Basophil carcinoma
    83103         8310/3    Clear cell adenocarcinoma, NOS
    83123         8312/3    Renal cell carcinoma
    83143         8314/3    Lipid-rich carcinoma
    83153         8315/3    Glycogen-rich carcinoma
    83163         8316/3    Cyst-associated renal cell carcinoma
    83173         8317/3    Renal cell carcinoma, chromophobe type
    83183         8318/3    Renal cell carcinoma, sarcomatoid
    83193         8319/3    Collecting duct carcinoma
    83203         8320/3    Granular cell carcinoma
    83223         8322/3    Water-clear cell adenocarcinoma
    83233         8323/3    Mixed cell adenocarcinoma
    83303         8330/3    Follicular adenocarcinoma, NOS
    83313         8331/3    Follicular adenocarcinoma well diff.
    83323         8332/3    Follicular adenocarcinoma trabecular
    83333         8333/3    Fetal adenocarcinoma
    83353         8335/3    Follicular carcinoma, minimally invasive
    83373         8337/3    Insular carcinoma
    83403         8340/3    Papillary carcinoma, follicular variant
    83413         8341/3    Papillary microcarcinoma
    83423         8342/3    Papillary carcinoma, oxyphilic cell
    83433         8343/3    Papillary carcinoma, encapsulated
    83443         8344/3    Papillary carcinoma, columnar cell
    83453         8345/3    Medullary carcinoma with amyloid stroma
    83463         8346/3    Mixed medullary-follicular carcinoma
    83473         8347/3    Mixed medullary-papillary carcinoma
    83503         8350/3    Nonencapsulated sclerosing carcinoma
    83703         8370/3    Adrenal cortical carcinoma
    83803         8380/3    Endometrioid carcinoma
    83823         8382/3    Endometrioid adenocarcinoma, secretory variant
                                                                                                                                          Formatted: Italian (Italy)
    83833         8383/3    Endometrioid adenocarcinoma, ciliated cell variant
                                                                                                                                          Formatted: Italian (Italy)
    83843         8384/3    Adenocarcinoma, endocervical type
    83903         8390/3    Skin appendage carcinoma                                                                                      Formatted: Font: 8 pt, Italic, Do not check
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    84003         8400/3    Sweat gland adenocarcinoma
    84013         8401/3    Apocrine adenocarcinoma
    84073         8407/3    Sclerosing sweat duct carcinoma
    84083         8408/3    Eccrine papillary adenocarcinoma
    84103         8410/3    Sebaceous adenocarcinoma
    84133         8413/3    Eccrine adenocarcinoma
    84203         8420/3    Ceruminous adenocarcinoma
    84303         8430/3    Mucoepidermoid carcinoma
    84403         8440/3    Cystadenocarcinoma, NOS
    84413         8441/3    Serous cystadenocarcinoma, NOS
    84503         8450/3    Papillary cystadenocarcinoma, NOS
    84523         8452/3    Solid pseudopapillary carcinoma
    84532         8453/2    Intraductal papillary-mucinous carcinoma, non-inv.
    84533         8453/3    Intraductal papillary-mucinous carcinoma, invasive
    84603         8460/3    Papillary serous cystadenocarcinoma
    84613         8461/3    Serous surface papillary carcinoma
    84702         8470/2    Mucinous cystadenocarcinoma, non-invasive
    84703         8470/3    Mucinous cystadenocarcinoma, NOS
    84713         8471/3    Papillary mucinous cystadenocarcinoma
    84803         8480/3    Mucinous adenocarcinoma
    84813         8481/3    Mucin-producing adenocarcinoma
    84823         8482/3    Mucinous adenocarcinoma, endocervical type
    84903         8490/3    Signet ring cell carcinoma
    85002         8500/2    Intraductal carcinoma, noninfiltrating, NOS
    85003         8500/3    Infiltrating duct carcinoma, NOS
    85012         8501/2    Comedocarcinoma, non-infiltrating
    85013         8501/3    Comedocarcinoma, NOS
    85023         8502/3    Secretory carcinoma of breast
    85032         8503/2    Noninfiltrating intraductal papillary adenocarcinoma
    85033         8503/3    Intraductal papillary adenocarcinoma with invasion
    85042         8504/2    Noninfiltrating intracystic carcinoma
    85043         8504/3    Intracystic carcinoma, NOS
    85072         8507/2    Intraductal micropapillary carcinoma
    85083         8508/3    Cystic hypersecretory carcinoma
    85103         8510/3    Medullary carcinoma, NOS
    85123         8512/3    Medullary carcinoma with lymphoid stroma
    85133         8513/3    Atypical medullary carcinoma
    85143         8514/3    Duct carcinoma, desmoplastic type
    85202         8520/2    Lobular carcinoma in situ
    85203         8520/3    Lobular carcinoma, NOS
    85213         8521/3    Infiltrating ductular carcinoma
    85222         8522/2    Intraductal and lobular in situ carcinoma
    85223         8522/3    Infiltrating duct and lobular carcinoma
    85233         8523/3    Infiltr. duct mixed with other types of carcinoma
    85253         8525/3    Polymorphous low grade adenocarcinoma
    85303         8530/3    Inflammatory carcinoma
    85413         8541/3    Paget disease. & infil. duct carcinoma
    85503         8550/3    Acinar cell carcinoma
    85513         8551/3    Acinar cell cystadenocarcinoma                                                                                Formatted: Font: 8 pt, Italic, Do not check
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    85603         8560/3    Adenosquamous carcinoma
    85623         8562/3    Epithelial-myoepithelial carcinoma
    85703         8570/3    Adenocarcinoma with squamous metaplasia
    85713         8571/3    Adenocarcinoma with cartilag. & osseous. metaplasia.
    85723         8572/3    Adenocarcinoma with spindle cell mataplasia
    85733         8573/3    Adenocarcinoma with apocrine metaplasia
    85743         8574/3    Adenocarcinoma with neuroendocrine differentiation.
    85753         8575/3    Metaplastic carcinoma, NOS
    85763         8576/3    Hepatoid adenocarcinoma
    85863         8586/3    Thymic carcinoma, NOS
    85893         8589/3    Carcinoma showing thymus-like element
    86403         8640/3    Sertoli cell carcinoma
    89413         8941/3    Carcinoma in pleomorphic adenoma
    90703         9070/3    Embryonal carcinoma, NOS
    90813         9081/3    Teratocarcinoma
    91003         9100/3    Choriocarcinoma
    91013         9101/3    Choriocarcinoma combined w/ other germ cell elements




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7.        Validation of cases of SPN within the nested case-control studies

Ascertainment of cases will be both retrospective (over the entire duration of follow-up) and prospective over a period of 2 years.

Pathology reports confirming the second primary malignancy, date of diagnosis, and tumour site will need to be obtained for each
case. Pathology reports need to be photocopied, anonymised (i.e., black-out names, hospital, consultant names etc), scanned (TIFF
format) and uploaded through an encrypted FTP-server or sent by encrypted email to UBHAM. Each pathology report needs to be
provided with an ICD code appropriate to the year the tumour was diagnosed (ie. ICD-10, ICD-9), a diagnosis date, and tumour site
description. Furthermore the ICD-0(3) topography and morphology codes need to be added to the document. UBHAM will review
the diagnosis and will have to confirm that the malignancy is eligible for inclusion in the case-control study.

To estimate the radiation dose received to the location of the second primary tumour it is of crucial importance that the exact site
of the second primary tumour will be determined. Unfortunately, pathology reports often do not specify the exact site of the
tumour and local study centres may have to write to the patient’s surgeon or oncologist to obtain medical records (e.g. surgical
notes) that contain this information. If this information cannot be obtained from medical records then it might be possible to ask
the relevant clinician to indicate the site of the tumour on an anatomical diagram.

8.        Selection of controls matched to SPN cases

One control will be selected centrally at the UBHAM from the underlying cohorts provided matched to each case on:

         Country
         Sex
         Age at first primary cancer diagnosis (+/- 1 year)
         Calendar year at first primary cancer diagnosis (+/- 3 years)
         First primary diagnosis of heritable/non-heritable retinoblastoma
         Length of follow-up; i.e. the SPN free interval from first primary tumour diagnosis in the control has to be at least as long
          as the interval between first primary tumour and second primary tumour in the matched case.

There will no matching on:

         Hospital – this would make cases and controls from the same hospital too similar with regard to the treatment received
          (i.e. overmatching)
         Geographical region – no matching on geographical region, unless this would cause practical problems.
         Type of childhood cancer other than heritable retinoblastoma.

A user written program in Stata statistical software will be written by the UBHAM to select controls from underlying cohorts. This
user written program will use density sampling to select controls (see figure below). It should be noted that a control can be a
control for more than one case. A control from one matched set may later be found to be a case, at which point the appropriate
controls will be selected for the new set.




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Figure 1. Example of control selection using density sampling


Controls will be selected by UBHAM and not by the local centers to avoid heterogeneity in control selection. A list of controls (only
id numbers) will be emailed to each local centre. If no eligible controls are available for a case, then calendar period will be relaxed
one year at the time with a maximum of 5 year until an eligible control will be found.

As a check, cohort analyses for available risk factor (e.g., type of childhood cancer, radiotherapy (yes/no), chemotherapy (yes/no))
should be conducted and then compared to initial case-control analyses to confirm that sampling of controls has been performed
correctly. Results from the cohort analysis should be similar (apart from sampling variation) to case-control analysis. For example, if
the relative risk for treatment with radiotherapy (yes/no) is 3.5 based on the cohort, then one would expect the odds ratio from the
case-control study to be of similar magnitude.

Deceased cases and controls
Deceased cases and controls should be included in the analysis, but controls need to satisfy the matching criteria above.

Control replacement
There will be no control replacement even if a control is untraceable or no medical records can be traced. It is nonetheless
important that as much information from such controls will be obtained. Reselection of controls may introduce bias into the study
and should therefore be avoided. All cases should be included in the study even if a case is not traceable or no medical records can
be obtained. Again, as much information as possible from such cases should be obtained.

Other medical conditions
Local study centres should record, if available, whether a patient has been diagnosed with genetic conditions such as heritable
retinoblastoma, Li-Fraumeni, Neurofibromatosis or any other diagnosis that could increase the risk of a second primary malignancy.
This would be collected at the same time as the chemotherapy and radiotherapy details.

9.        Radiotherapy records collection for the case-control studies

Details of all radiotherapy received during the period at risk should be collected. The period at risk for the case is the interval from
diagnosis of the index childhood cancer to the diagnosis of the second primary tumour. The period at risk for the control is an
interval from diagnosis of the index childhood cancer to an exit date which provides an identical period at risk as experienced by
the matched case. This includes radiotherapy for any primary neoplasm or recurrence.

Technical radiation therapy records should be obtained from medical records for each case and control. Local centres should
photocopy, anonymize, and scan (TIFF format) the radiation records and upload these to UBHAM through an encrypted FTP-server.
UBHAM will check radiotherapy records for completeness, readability, and will check whether anonymisation has been done
correctly. Radiotherapy records will then be made available to IGR for radiation dosimetry reconstruction. If no technical radiation
therapy records are available, all relevant information from medical records that is available on radiotherapy should be
photocopied, anonymised, scanned and uploaded to UBHAM.



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10.       Chemotherapy records collection for the case-control studies

The period at risk is identical to that specified above for radiotherapy records. An attempt should be made to collect chemotherapy
information from medical records for the first primary cancer of each case and control from relevant hospitals. This information
should also be obtained for any recurrences or primary tumours, experienced in the period at risk.

From the chemotherapy records the following information should be obtained and data entered into a database:

         Name and code of cytotoxic drug used (using the Anatomical Therapeutic Chemical Classification System)
         Number of cycles
         Start and end date of cycle
                                                                                               2
         Cumulative drug dose given in cycle (if not available: dose prescribed) in mg or mg/m
         Height and weight (at start and during chemotherapy course)
         Date height and weight was measured

It is crucial that chemotherapy abstraction is done in a standardized way. The WHO Anatomical Therapeutic Chemical Classification
                                                                                                                               2
System will be used to classify cytotoxic drugs. Cumulative doses for each individual drug should be recorded in mg or mg/m . It is
                                                                                                          2
of crucial importance that the local centres inform UBHAM whether drugs were recorded in mg or mg/m . If doses have been
recorded in mg, then it is important to collect information on height and weight of a subject during the course of the
                                                                                          2
chemotherapy. UBHAM will use a user written program to transfer doses from mg to mg . If height and weight are not available for
a subject, then a typical height and weight will be used from tables from the general population for boys and girls for the relevant
age group.




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11.       Questionnaires                                                                                                                  Formatted: French (France)
                                                                                                                                          Formatted: French (France)
                                                         DRAFT                                                                            Formatted: French (France)
                                                                                                                                          Formatted: French (France)
                                   Questionnaire Cardiac case control study                                                               Formatted: French (France)
                                                                                                                                          Formatted: French (France)
                                                                                                                                          Formatted: French (France)
Goal

1) to identify possible confounding factors or risk factors

Method: (up to data-providers)

Online questionnaire (will be prepared by WP3)

Paper questionnaire (will be prepared by WP3)

Telephone questionnaire



Time point;

Not more than 1 year before or after date of inclusion in the cardiac case control study


1. YOUR SPECIFIC CONDITIONS



1a) Do you have a cardiac birth defect                                                         YES NO NOT SURE
If yes,
Please describe diagnosis………..
Names of drugs………..
Do you still use these drugs….                                                                 YES NO
         Comments;………
Other treatment than drugs (for example surgery)                                               YES NO NOT SURE
If yes please describe…………….

1b) Do you have hypercholesterolaemia                                                          YES NO NOT SURE
If yes,
Data of diagnosis
Names of drugs………..
Do you still use these drugs                                                                   YES NO
        Comments;………

1c) Do you have hypertension                                                                   YES NO NOT SURE
If yes,
Date of diagnosis
Names of drugs……………………..
Do you still use these drugs                                                                   YES NO                                     Formatted: Font: 8 pt, Italic, Do not check
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         Comments;………

1d) Do you have diabetes mellitus                                                              YES NO NOT SURE
If yes,
Date of diagnose
Names of drugs………………..
Do you still use these drugs                                                                   YES NO
        Comments;………

1d) Do you have clotting disease,
      like protein S or C deficiency                                                           YES NO NOT SURE
If yes,
Please describe
Date of diagnosis
Names of drugs………………
Do you still use these drugs                                                                   YES NO
          Comments;………

1e) Do you have had a myocardial infarction?                                                   YES NO NOT SURE
If yes,
Date of diagnosis
Names of drugs………………
Do you still use these drugs                                                                   YES NO
        Comments;………
Other treatment than drugs                                                                     YES NO NOT SURE
        If yes please describe………..

1f) Do you have or had heart failure?                                                          YES NO NOT SURE
If yes,
Please describe symptoms………
Date of diagnosis………
Names of drugs………..
Do you still use these drugs                                                                   YES NO
        Comments;………

1g) Do you have or had cardiac arrhythmia?                                                     YES NO NOT SURE
If yes,
Please describe condition………
Date of diagnosis……….
Names of drugs………………
Do you still use these drugs                                                                   YES NO
        Comments;…………
Other treatment than drugs                                                                     YES NO NOT SURE
        If yes please describe………..

1h) Do you have or had cardiac valvular disease?                                               YES NO NOT SURE
If yes,
Please describe condition………..
Date of diagnosis…………..
Names of drugs………………
Do you still use these drugs                                                                   YES NO                                     Formatted: Font: 8 pt, Italic, Do not check
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        Comments;…………
Other treatment than drugs like surgery                                                        YES NO NOT SURE
        If yes please date and type ……………

1g) What is your weight?
..………………

1h) What is your length?
………………... inch
…………………cm

1i) We would like to calculate your waist-to-hip ratio.
The waist can be measured at its narrowest point, or it may be measured at about one inch above
the navel. The hip is measured at its widest point.

1j) What is your waist circumference (inch or cm)
………………… inch
………………… cm

1k) What is your hip circumference (inch or cm)
…………………. inch
…………………. cm

1l) Are there persons in your family who have had myocardial infarction, heart failure, high
blood pressure, hypercholesterolemia, congenital arrhythmia, clotting disease (protein C or S
deficiency) or diabetes mellitus?
Please provide only information for your full brothers and sisters; those with the same mother
and father and for your birth or natural parents. Please do not give details of step or foster or
adoptive parents.


        Describe relation:        Describe disease:                                          Age at               If alive:
        Brother, sister,          myocardial infarction, heart failure, high                 diagnosis?           What is the
        father, or mother         blood pressure, hypercholesterolemia,                                           current age?
                                  congenital arrhythmia, clotting disease
                                  (protein C or S deficiency) or diabetes
                                  mellitus
1
2
1
4
5
6




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2. SURGERY

Please indicate if you have ever had any of the following types of Surgery and give your
approximate age when you first had each type of operation.
Please also indicate which types of surgery you have never had by Ticking the no box.

                                                                                               YES NO NOT SURE

                                                                                               If YES please give age
                                                                                               this age first has this
                                                                                               surgery

2a)    coronary artery bypass surgery?
2b)    pericardiectomy (stripping of the sac around the heart)?
2c)    angioplasty (enlarging a heart vessel using a balloon)?
2d)    other heart surgery?
2e)    a heart transplant?
2 f)   a lung transplant?
2g)    a kidney transplant?
2h)    other organ transplant?



3. PHYSICAL ACTIVITY



3a) Did your health condition limited your ability for daily activities in the last 4 weeks like

                                                                                 Severe            Moderate           Not limited
                                                                                 limited            limited

Extensive exercising (i.e., running, sport)                                                                               
Moderate exercising (i.e., .cycling, lifting a table, house-hold
                                                                                                                          
tasks)
Lifting shopping bags                                                                                                     
Walking up some stairs                                                                                                    
Walking up one stair                                                                                                      
Bending over, kneeling, or bowing                                                                                         
Walking more than 0,3 miles (1 km)                                                                                        
Walking more than 0,3miles (0,5km)                                                                                        
Walking more than 0.03 miles (100m)                                                                                       
Washing and dressing yourself                                                                                             




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    3b) Please show us in this table how many hours you spend doing the next activities in
    summer and winter within 1 week

                                                                                   Hours of a specific activity within 1 week
    Type of activity in last year                                                             during the last year
                                                                                      in summer                  in winter
1. Walking (including going to work, shopping, and free time)                           … hour                    … hour
2. Cycling (including going to work, shopping, and free time)                           … hour                    … hour
3. Gardening                                                                            … hour                    … hour
   Doing odd jobs                                                                       … hour                    … hour
   Doing sports and other physical activities (i.e., .swimming,
   jogging, playing tennis, dancing)                                                       … hour                        … hour
   Doing household tasks (i.e. washing clothes, cleaning,
   cooking)                                                                                … hour                        … hour


    3c) In which category would you place your work regarding physical activities?
     Sitting (i.e.office)
     Standing or walking (i.e. shop, restaurant)
     Walking and heavy physical exercise (i.e. nurse in a hospital)
     Heavy physical exercise (i.e. cleaning work, farm)
     I have no job




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3c) Which sports did you do during your life and how many hours did you spend on these
sports? If you still sport, you can fill in your current age.

                    Sport
                                                                             How many hours in a
                                                                             week?                           Age

                                                                                                             from          To

1                                                                            … hour                          … yr          … yr

2                                                                            … hour                          … yr          … yr

3                                                                            … hour                          … yr          … yr

4                                                                            … hour                          … yr          … yr

5                                                                            … hour                          … yr          … yr

3                                                                            … hour                          … yr          … yr

7                                                                            … hour                          … yr          … yr

8                                                                            … hour                          … yr          … yr




4. SMOKING


4a) Have you ever smoked at least one cigarette, or one cigar or one pipe a week for at least
one year?                                                                YES NO

If no please go to question 5 on page …
If yes please answer the next questions:

4b) do you smoke cigarettes at all nowadays?                                                   YES NO


4c) about how many cigarettes a day or week do you usually smoke ?
.............per day
………..per week
Or less than 1 per week

4e) How old were you when you started to smoke cigarettes regularly?
...............years old
Or never smoked regularly

4f) Are you a current smoker                                                                   YES NO                                     Formatted: Font: 8 pt, Italic, Do not check
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If Yes please go to question 5
If No please answer the next questions:

4g) have you ever smoked cigarettes regularly?                                                      YES NO
If No go to question 5
If Yes please answer the next questions:

4h) About how many cigarettes did you smoke in a day or week in the year before your stopped
with smoking?
..............per day
………. per week
less than 1 per week

4. MEDICATION
We would like to know all of the drugs and medications that you have taken during the last 5
years, that is since the date exactly 5 years ago. we are interested in only those tablets, pills,
syrups, injections, patches and creams that were prescribed by a doctor, and which you took
regularly for more than one month, or for a total of 50 days or more in a year.

Please indicate below which types of drugs you have been prescribed and give the names of the
drugs. Please also indicate each type of drug you have not been prescribed by ticking the no
box.
                                                                          YES NO NOT SURE
Do you use

5 a) Oestrogen other than anticonception (female hormones)

5b) Thyroid medications
such as Thyroxine or others
Names of drugs ..................................................................................

5c) Other medications to replace body hormones
such as growth hormone, steroid hormones (hydrocortisone), DDAVP or others
Names of drugs ..................................................................................

..................................................................................

5d) Prescribed pain killers
such as Solpadol, Tylex, diclofenac, naproxen, dihydrocodeine, morphine or others
Names of drugs ..................................................................................

5e) For females: Did you have used or do you used the contraceptive pill
If no please go to question 5o

If yes
5f) At which age did you start with the contraceptive pill?
……………………
5g) At which age did you stop with the contraceptive pill? If you still use it you can fill in your
current age.
……………………..
Thank you for filling in the form, please return it to us in the postage paid envelope provided.                                          Formatted: Font: 8 pt, Italic, Do not check
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12.       DNA Collection for case-control studies

                                                               DRAFT

                                Cardiac case control study; DNA collection and analyses                                                   Formatted: English (United States)



Background

See page … of the protocol;
“Many studies have been performed relating DNA polymorphisms to cardiac diseases and their potential
interactions with environmental cardiac risk factors [28]. But there still is no consensus for genetic markers
of genetic susceptibility to cardiac diseases that have any usefulness in clinical practice [28]. In childhood
cancer survivors, the situation could notably differ. First, because the risk associated with anthracyclines
and radiation is very high and therefore their modifiers are easier to identify. Secondly, for the numerous
enzymes linked to anthracycline metabolism, DNA polymorphisms could modulate the variation in enzymes
activity or increase susceptibility to toxic metabolites, and therefore modulate the risk of cardiotoxicity.
Until now, only a few studies have been published on genetic susceptibility to anthracyclines and none have
appeared on radiation-induced cardiotoxicity [29, 30].”

Goal

To identify genetic variants associated with anthracycline cardiotoxicity.

Relevance

Identifying and validating gene variants responsible for radiation or anthracycline-induced cardiotoxicity is
essential to predict the risk for individual patients in the future. Such testing will allow physicians to take
preventive measures or choose alternative treatments and to provide individual follow-up care for
survivors. These new strategies will reduce the number of survivors with severe clinical cardiac events.

Methods

Inclusion of participants

Within the cardiac case control study all case and control patients will be invited provide DNA material.
Eligible patients will be approached by local dataproviders to participate in this study. Patients will receive a
written patient information document explaining in layman’s language all aspects of the study including the
aim, potential risks and benefits of participation, time requirements, sample collection method, privacy
guarantees and consent. Patients will be made aware that the anonymous biological samples and
anonymous clinical information regarding their cancer treatment and follow-up will be used for future
analyses in a collaboration with PancareSurFup WP3 participants. There will be no direct benefit for
participants. Individual participant results will not be made available or shared.



Collection of material

Genomic DNA will be extracted from blood or saliva (Oragene) and will be stored in each country.
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Analyses

The analysis of the genetic markers will be out of the scope of this protocol and grant. The data-providers
within WP3 will write a collaborative proposal for the analyses of the DNA samples in the third year of the
PancareSurFup project. Because we expect more knowledge about possible genes which could be
associated with clinical cardiac events during the first years of our project, we made no selection yet for the
analysis.



To do

Precise description how to store blood and saliva for DNA material.                                                                       Formatted: English (United States)




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13.       PanCareSurFup International Data Collection Systems for the SPN case-control studies


Purpose
Conform to the requirements of the PanCareSurFup study to facilitate data entry from European locations and store it centrally and
securely.

System Overview
The system will consist of database applications developed by the Centre for Childhood Cancer Survivor Studies (CCCSS), University
of Birmingham (UBHAM). The systems will be used by administrators at UBHAM and by authorised personnel at local centres. The
applications will be hosted and administrated by UBHAM.

System Architecture
A web server will deliver web forms which are linked to a database server (see diagram). The web server and database server will
both sit on the UBHAM domain campus network and therefore behind the UBHAM firewall. Both servers will be sited in a secure
office.

                                                University campus network (in UBHAM Office)
  Internet                    Site                Web server         Web              Database               Database
                              firewall            firewall           server           firewall               Server




The web server will run Internet Information Services (IIS7) a web hosting management application, on Windows Server 2008 Web
Edition. The database server will run SQL Server 2008 Standard Edition on Windows Server 2008.

Software Development
The system will be carefully documented and designed before programming starts. These components will be checked and agreed
by UBHAM and collaborators. Each stage of the system will be reviewed and piloted by the UBHAM and collaborators. Changes to
the system go though the same process. Before the system is deployed, the system will need to be agreed by the UBHAM and all
collaborators

Software design
Database applications will have two main parts:

         A website which will consists of HTML pages and code behind. This code will be written in ASP or ASP.NET. An
          appropriate web development package (e.g., CodeCharge or IronSpeed) will be used to facilitate development.
         A SQL Server database which will consists of tables, views and data processing procedures.

The HTML pages will consist of ‘forms’ for data entry. The code behind takes the data input, validates it and then sends it the
database. The forms can also be populated with the data to allow viewing and editing of the data. These forms will be designed to
match the Study requirements (e.g. Study questionnaire)

Validation
Validation of data would be achieved in two ways:

         Some fields must be in a certain format or range otherwise the data cannot be saved
         Some fields may be saved if they don’t meet the requirements but the user is warned that the data should be checked.
          This can be done at data entry or at a later point using data checking reports.



User access and accessibility
To access the application/website all a user will need is a computer with access to the internet and a suitable (modern) browser
with Javascript and cookies enabled. All websites will be tested with the latest version of Internet Explorer and the previous version    Formatted: Font: 8 pt, Italic, Do not check
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and for compatibility with the latest versions of other popular browsers such as Firefox, Chrome and Safari. Every user will be
required to login to the website and identify the location of their part of the study. Each user will be assigned ‘roles’ which will
restrict or grant access to particular pages and data only relating to survivors only recruited at the study location. These roles and
permissions will be defined in the Study requirements.

Auditing
Every logon to the system, including the time date and the username will be recorded. If required every change to data could be
recorded with a time date, user, old value and new value.

Data access and reporting
Only the administrators at the UBHAM will have complete access to the data and have the ability to write queries for data
extraction and, if required, provide anonymised datasets that can then be fed into statistical programs. Any reporting services
required (e.g. data collection progress, data checking) will be part of the database application.

Security
No information entered through the website should contain personal identifiable data. If required, all traffic to and from the
website can be automatically encrypted using SSL (128 bit). All users will be required to log on to the website using a username and
strong password. Collaborating institutions will provide a list of users who require usernames and passwords. The passwords can
be encrypted using one way encryption and stored in the database. Users will be allowed to set and reset their passwords. The
administrators at the UBHAM will have the rights to add users, remove users and grant permissions using role based security. A
user will automatically get locked out form the system if they enter their password incorrectly more than a specified number of
times. This can be unlocked only by the study administrators. The database server will only be accessible from within the university
network by UBHAM administrators and the firewall will be configured to allow access from specific machines only. The database
application, SQL server, allows specified access at a table level to view, add, edit and delete. This can act as additional security on
top of that enforced by the website.

Continuity plans
All databases will be backed up incrementally hourly with a full backup once a day. This will allow a ‘point in time restore’ if
required. This means that we can revert to a previous version of the database if needed. The daily backup will be encrypted and
then backed up to tape. Both servers will also have a disk image taken regularly so that in the event of a hardware failure the
servers could be restored as they were at that time very quickly. In anticipation of hardware failures the servers will use multiple
hard disks in RAID configuration meaning that if one was to fail then no data would be lost. The servers will also have dual power
units and will be protected from power failures and surges by an Uninterruptible Power Supply (UPS). The servers will be under
warranty with 4-hour support for repairs.

Email
All email correspondence regarding potential study subjects or whenever data is attached should be send by encrypted email. A
password will be needed to open such emails.




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14.       Consent Forms and Information Sheets



                                                        TEMPLATE CONSENT FORM



                                                              PanCareSurFup

                                   A Study of Long-Term Follow-Up of Europeans Treated during
                                               Childhood or Adolescence for Cancer

                                   CONSENT FORM (table borders can be removed. I left them in for clarity)

Permission to participate                                                                                          Please tick one
I declare that I have read the written patient information sheet, or I have had it explained to me. I give my
consent for a representative of the PanCareSurFup study to contact the relevant hospital(s), doctors and/or                          
Cancer Registries to obtain details of my previous illness(es) and their treatment(s). I understand that only
authorized study personnel will examine my medical records. I understand that strict confidentiality will be       Yes                No
maintained. I understand that my name will never be stored in the central data repository, nor given to
researchers.
I understand and consent to my participation in this study, PanCareSurFup, which consists of completing a
questionnaire, providing a biological sample, and allowing my data to be stored in a central data registry.

Permission to contact doctor                                                                                                         
I agree that study personnel can contact my General Practitioner (GP)/specialist to obtain information about       Yes           No
my health status from time to time.

Permission to store and use DNA
I give consent for my biological sample and extracted DNA to be stored and used for current and future
research projects that have received appropriate scientific and ethical approval. I understand that the overall                      
purpose of these DNA tests is to see if adverse late effects of cancer and/or its treatment can be linked to       Yes           No
genetic changes.


Permission to feed back clinically significant results
In the unlikely event that we find that you might have an increased risk of an adverse late effect, because of a
genetic change in your DNA, would you like us to inform you? If this happens, with your permission, study
personnel could help set up an appointment for you to be retested in your regional genetics service.

Yes, I do wish to be informed of the results of genetic tests that could be important to me                                          
                                                                                                                   Yes           No
Permission to send newsletter
The study personnel will prepare a newsletter to keep participants informed of the course of the study and the
main study findings. Would you like to receive a copy of the newsletter?
                                                                                                                                     
                                                                                                                   Yes           No

FULL NAME _____________________________________________________________________
              Print your name here

SIGNATURE ______________________________________                      Today’s date     ___|___|_____
              Sign your name here                                                            dd   mm yyyy

ADDRESS FOR NEWSLETTER ___________________________________________________
_______________________________________________________________________________




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                                          TEMPLATE CONSENT FORM FOR PROXY INTERVIEW


                                                              PanCareSurFup

                                   A Study of Long-Term Follow-Up of Europeans Treated during
                                               Childhood or Adolescence for Cancer

                                                            CONSENT FORM

Permission to participate                                                                                             Please tick one
I declare that I have read the written patient information sheet, or I have had it explained to me. I give my
consent for a representative of the PanCareSurFup study to contact the relevant hospital(s), doctors and/or                             
Cancer Registries to obtain details of (name’s) previous illness(es) and their treatment(s). I understand that only
authorized study personnel will examine (name’s) medical records. I understand that strict confidentiality will be    Yes               No
maintained. I understand that (name’s) name will never be stored in the central data repository, nor given to
researchers.



I understand and consent to (name’s) participation in this study, PanCareSurFup, which consists of completing
a questionnaire, and allowing (name’s) data to be stored in a central data registry.                                                    
                                                                                                                      Yes               No




FULL NAME _____________________________________________________________________
              Print your name here

SIGNATURE ______________________________________                      Today’s date     |___|___|_____|
              Sign your name here                                                       dd mm yyyy

Proxy for _________________________________________________________________________ (name of survivor)




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                                                TEMPLATE INFORMATION SHEET


                                                              PanCareSurFup

                                      Long-Term Follow-Up Study of Europeans Treated during
                                               Childhood or Adolescence for Cancer

                                                        INFORMATION SHEET

You are invited to participate in a new pan-European research study of adverse late effects after cancer during childhood or adolescence.
The name of the study is PanCareSurFup. It has been planned and will be done by a consortium of scientists from 12 European countries.
The study is funded by the 7th Framework Programme of the EU, and its local partners. You can find out more about the study from the
website, www.pancaresurfup.eu.

This INFORMATION SHEET explains why we are doing this study, and what it might mean to you.

Why research into late effects?
Continuing improvements in treatments for cancer during childhood or adolescence have meant that many more patients now survive
their cancer and live into adulthood. While this is a very positive trend, some treatments can be intense and may have adverse side effects.
Not all side effects are immediate, some only show up year later. Nor do we know what the full range of side effects can be.
PanCareSurFup will evaluate the risk of specific late effects, such as second cancers and heart disease. Once these are determined, we will
set up guidelines for treatment of late effects, and we will develop ways to get this new information out to you, the survivors, families, the
medical communities and the general public. In this way, we hope to begin programmes to prevent late effects. Because cancer in young
people is rare, a pan-European effort is needed to fully understand the spectrum of late effects. Your help is crucial to our effort.

Why have I been chosen? For Cases & controls
You are being asked to participate in this study because you were diagnosed with cancer. This fact is recorded in the national cancer
registry of (country/region). The study will pool survivors from a number of cancer registries across Europe as a starting point. Your
contact details are not on the registry, which is anonymous, but they came from your (GP/specialist/etc).

Do I have to take part?
You do not have to take part. However, our results need to be based on the largest numbers possible, so that we can have confidence
that they apply to many, different groups of people. Therefore, we hope that you will agree to participate in this first, and important pan-
European study.

How do I take part?
To take part, all you have to do is phone this free telephone help line (xxx). Study personnel will answer your call, and arrange a time that
is convenient for you to answer a telephone interview. We have enclosed a copy of the interview for your information. The interview
will take about (xxxx) minutes. The questions asked cover aaa, bbb, ccc etc.

DNA studies
We would also like to obtain a saliva sample from you, for future studies of DNA. The sample kit will be posted to you and will include a
pre-paid mail-back envelope to make it easy for you.

What if I do not wish to take part?
If you do not wish to take part, you are free to decline. This will have no effect on your current or future treatment. If you do not wish
to take part, just phone the Study Centre at xxxxxx, to let us know. We will then update your records so that you will not receive any
further information about the study. If you change your mind, and decide at a future date that you would like to participate, you can do
that too, by phoning the Study Centre at xxxx.

Are there any advantages or disadvantages to taking part?
There are no risks to your participation in this study. The telephone interview is without risk and your data will be protected to the degree
possible. The saliva kit is also harmless and painless, and carries no risk to you. All the information that you provide (interview and
DNA) will be stripped of personal identifying data. The results from the study will be grouped in such a way that no one individual can be
identified.

What are the benefits from taking part?
There may be no direct or immediate benefit from your participation, beyond the sense that you are contributing to a very large study
intended to benefit many children and families. Existing survivors may benefit from increased awareness and early diagnosis of late
effects. In the future, survivors should benefit from modification of treatment protocols that are associated with late effects. It may also
be that future DNA research could help identify survivors at higher risk of certain late effects, who could benefit from increased
surveillance and prevention.

Is there special insurance for this study?
In some countries, special research insurance is needed for some studies that are considered to be high risk. This PanCareSurFup study is
not considered high-risk. So no special insurance is needed.                                                                                     Formatted: Font: 8 pt, Italic, Do not check
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What if I have a question?
If you have a concern about any part of the study, you can phone the Study Centre at xxxxxx. The Study staff will do their best to answer
your question.

What about my privacy and protection of my personal data?
Your privacy will be protected at all times, since your personal data will be stripped from the data you provide and replaced by a study
number that is specific to this study. The data that will be stored centrally and analysed will be identified only the study number. All staff
participating in PanCareSurFup are trained and retrained in data protection. The data is kept under lock and key, and only accessible to
staff with special permission. All procedures for handling, processing, storing and destruction of data comply with the Data Protection
Act of 1998 (or similar. Xxxx).

How long will the data and DNA be stored? Alternatives
       The study data will be stored until the study is completed. After completion of the study, the data will be destroyed.
       The study data will be stored as long as possible to carry out studies related to the activities of PanCareSurFup. However, all
        future studies will require a separate approval from the relevant Research Ethics Boards before the data can be used.

What will be done with the DNA? Alternatives
        Studies on your DNA would consist of those related to increased risks for cardiac disease or a second cancer. They might
         consist of genome-wide studies, looking for relationships between disease and a change in any part of your DNA. Or these
         studies might consist of evaluations of changes in single genes associated with specific disease.
        Since these DNA samples and the data collected within PanCareSurFup are a very valuable and unique resource, it is possible
         that other studies, not related to the questions being asked in PanCareSurFup, might be possible. In that case, a separate
         approval from the relevant Research Ethics Board would be sought.

Will I be informed of the study results? Alternatives
         If you wish to be informed of the overall results of PanCareSurFup, you can indicate on the consent form that you wish, or do
          not wish, to receive the newsletter. The progress of the study and the grouped study results will be described in the newsletter.
          However, typically it takes several years to complete the analysis of data and to publish the findings in the scientific literature.
          So, results in the newsletter may take some years.

         Your individual DNA results will not be available to you, since this study is for research purposes only, and we do not know
          what the results mean for your general health.

         In working with your DNA, researchers may find a disease or problem for which medical treatment is available, a so-called
          “incidental finding”. Please be assured that this happens very rarely. But, if it should happen, your treating physician
          (GP/specialist) will contact you to make an appointment for further tests. If you do not want your doctor to inform you about
          such incidental findings, you cannot contribute a sample to the DNA bank, though you can complete the interview.

What will happen to the results of the PanCareSurFup study?
The results of this study will be published in scientific and medical journals. Only grouped results will be published. Your name will
never appear in any PanCareSurFup report.

What if I have questions or complaints?
If you have a question or complaint about this study, you can contact your GP/specialist, or phone the study centre at xxxx, or other
special complaints body.

Ethics Review
This study has been reviewed and approved by the Ethics Group (xxxx) at (xxxx) on (date).




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 PanCareSurFup Research Protocol (WP1-5)                                                                                         Page 56



 15.       Schedule of Deliverables

                                                                                                                             Delivery Date
                                                                   Lead       Estimated               Dissemi    Delivery       mm/yy
Delivera                                                  WP
                        Deliverable Title                       Beneficiary   indicative   Nature     nation      date,        (based on
ble No.                                                   no.
                                                                    No.           pm                   level      month      start date of
                                                                                                                             01/02/2011)
 D2.1       List of the sources of uncertainty in the     2         12           12          R           PU         18        1-Aug-2012
                     dose estimation process
 D5.1            Protocol of data requirements            5         1            16          R           PP         18        1-Aug-2012
 D2.2         Modified dose-estimation software           2         12           12          O          CO          36         1-Feb-14
            incorporating new treatment machines
 D2.3      Results of experimental validation of new      2         12           12          R           PU         36         1-Feb-14
                            software
 D1.1      Benchmarking report of status in Europe        1         16           23          R           PU         36         1-Feb-14
 D1.2      Four retrospective databases of long-term      1         4            23          R           RE         54         1-Aug-15
                             survivors
 D1.3       Virtual pan-European database of long-        1         4           23.5         R           RE         54         1-Aug-15
                          term survivors
 D2.4       Results of comparison with other dose-        2         12           12          R           PU         54         1-Aug-15
                      estimating software
 D2.5      Positioning of second malignancies in WP4      2         12           12          R           PP         54         1-Aug-15
 D2.6       Estimates of radiation doses received to      2         12           12          R           PU         54         1-Aug-15
              the heart by WP3 cases and controls
 D2.7       Estimates of radiation doses received to      2         12           11          O          CO          54         1-Aug-15
              the site of the second cancer by WP4
 D5.3         Measures of the validity of causes of       5         1            15          R           PP         54         1-Aug-15
             death from official mortality registries
 D5.4       Recommendations for data abstraction          5         1           14.5         R           PP         54         1-Aug-15
                  and coding of causes of death
 D3.1      Absolute risks of cardiovascular disease --    3         7            75          R           PU         60         31-Jan-16
                            cohort study
 D3.2      Risk of cardio-vascular disease in relation    3         7           75.5         R           PU         60         31-Jan-16
               to radiotherapy and chemotherapy
 D4.1      Report on absolute risks of sarcoma after      4         13           37          R          CO          60         31-Jan-16
                         childhood cancer
 D4.2      Report on absolute risks of common adult       4         13          36.5         R          CO          60         31-Jan-16
               carcinomas after childhood cancer
 D4.3      Report on risks of sarcomas in relation to     4         13          36.5         R          CO          60         31-Jan-16
                  cumulative radiotherapy and
                  chemotherapeutic drug doses
 D4.4         Report on risk to adult carcinomas in       4         13           36          R          CO          60         31-Jan-16
                   relation to radiotherapy and
                  chemotherapeutic drug doses
 D5.5       Final report on the evaluation of project     5         1            15          R           PP         60         31-Jan-16
           activity and drafting of the main scientific
                               paper




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PanCareSurFup Research Protocol (WP1-5)                                                                                                Page 57


16.       Schedule of Milestones

                                                                                        Expected
                                                                                                                      Delivery Date
                                                                          Work           date in
           Milestone                                                                               Means of          mm/yy (based on
 MS No.                              Milestone Name                     Packages         months
           No. by WP                                                                               verification       start date of
                                                                        involved          since
                                                                                                                      01/02/2011)
                                                                                          start

 MS41          6.1       Formation of working group                          6             1       WP6, Internal        1-Feb-11
                                                                                                   document
                         Set up project office and recruit project
 MS54          8.1                                                           8             3                            1-May-11
                         manager                                                                   New staff

 MS55          8.2       Website up and running                              8             3       Website              1-May-11
                                                                                                   available
                         Start data collection for case-control                                    WP1,2,3,4,
 MS17          3.6                                                       1, 2, 3, 4       12       internal             1-Feb-12
                         study
                                                                                                   document
 MS42          6.2       Summary of current LTFU practice                    6            12       WP6 internal         1-Feb-12
                                                                                                   document
                         Ascertainment and validation of cardiac                                   WP 1, 2, 4
 MS13          3.2                                                        1, 2, 4         12       internal             1-Feb-12
                         disease (cases)
                                                                                                   document
                                                                                                   WP1,2,3,4
                         Ascertainment and validation of SMNs
 MS25          4.2                                                       1, 2, 3, 4       12       internal             1-Feb-12
                         (cases)
                                                                                                   document
                                                                                                   WP1, 2, 4
                         Identification and establishment of
 MS12          3.1                                                        1, 2, 4         12       Internal             1-Feb-12
                         cohorts within individual countries
                                                                                                   document
 MS14          3.3       Control selection                               1, 2, 3, 4       12       WP1-4 internal       1-Feb-12
                                                                                                   document
                         Identification and establishment of                                       WP1-4 internal
 MS24          4.1                                                       1, 2, 3, 4       12                            1-Feb-12
                         cohorts within individual countries                                       document

 MS26          4.3       Selection of controls                           1, 2, 3, 4       12       Internal             1-Feb-12
                                                                                                   document
                         Input from Scientific Advisory Board &                                    Report
 MS56         8.3a                                                           8            12                            1-Feb-12
                         Ethics Board                                                              available
                         Evaluation of use of data sources for WP                                  WP1-5,
 MS1           1.1                                                     1, 2, 3, 4, 5      18       internal             1 Aug 12
                         2-5
                                                                                                   document
                                                                                                   WP1 - 5,
                         Evaluation of routine population-based
 MS4           1.4                                                     1, 2, 3, 4, 5      18       internal             1-Aug-12
                         data sources and benchmarking
                                                                                                   document
                                                                                                   Software
                         Completion of data entryand controls of
 MS7           2.1                                                        2, 3, 4         18       validated by an      1-Aug-12
                         WP3-4
                         Availability of information on vital status                               independent
 MS34          5.1                                                         1, 5           18       WP1,5 internal
                                                                                                   QA company           1-Aug-12
                         and cause of death in different                                           document
                         European countries
 MS43          6.3       Workshop (selection of topics)                      6            18       WP6, Internal        1-Aug-12
                                                                                                   document
                                                                       1, 2, 3, 4, 5,
 MS49          7.1       Formation of working group                                       18                            1-Aug-12
                                                                        6, 5, 7, 8                 Meeting held
                                                                       1, 2, 3, 4, 5,
 MS50          7.2       Dissemination Plan                                               18                            1-Aug-12
                                                                          6, 7, 8                  Meeting held

 MS44          6.4       Formation of topic subgroups                        6            18       Internal             1-Aug-12
                                                                                                   document
                         Input from Scientific Advisory Board &                                    Report
 MS56         8.3b                                                           8            24                            1-Feb-13
                         Ethics Board                                                              available
                         Establishment of a pan-European cohort                                    Internal
 MS15          3.4                                                     1, 2, 3, 4, 5      30                            1-Aug-13
                         study data file                                                           document
                         Establishment of a pan-European case-                                     Internal
 MS19          3.8                                                     1, 2, 3, 4         30                            1-Aug-13
                         control study file                                                        document

 MS16          3.5       Cohort analysis                               1, 2, 3, 4,        30       Internal             1-Aug-13
                                                                                                   document
                         Establishment of pan-European cohort                                      Internal
 MS27          4.4                                                     1, 2, 3, 4, 5      36                            1 Feb 14
                         study data file                                                           document

 MS28          4.5       Cohort analysis                                 1, 2, 3, 4       36       Internal             1-Feb-14
                                                                                                   document
                         Completion of data entry for 60% of                                       Database
 MS8           2.2                                                        2, 3, 4         36       completed and        1-Feb-14
                         cases and controls of WP3 and WP4
                                                                                                   validated
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PanCareSurFup Research Protocol (WP1-5)                                                                               Page 58

                         Validation of the adaptation of dose-                             Database
 MS9           2.3                                                      2, 3, 4       36   completed and   1-Feb-14
                         estimating software
                                                                                           validated
                         Feasibility of obtaining additional                               Internal
 MS35          5.2                                                        1, 5        36                   1-Feb-14
                         information concerning cause of death                             document
                         Consolidation of the database for                                 Database
 MS3           1.3                                                        1, 3        36   completed and   1-Feb-14
                         cardiac toxicity
                                                                                           validated
                                                                                           Database
                         Consolidation of the database for
 MS4           1.4                                                        1, 4        36   completed and   1-Feb-14
                         second primary tumors
                                                                                           validated
                         Complete data collection for case-                                Internal
 MS18          3.7                                                     1, 2, 3, 4     36                   1-Feb-14
                         control study                                                     document
                         Establishment of a pan-European cohort                            Internal
 MS15          3.4                                                   1, 2, 3, 4, 5    36                   1-Feb-14
                         study data file                                                   document

 MS16          3.5       Cohort analysis                               1, 2, 3, 4     36   Internal        1-Feb-14
                                                                                           document
                         Establishment of a pan-European case-                             Internal
 MS29          4.6                                                   1, 2, 3, 4, 5    36                   1-Feb-14
                         control study file                                                document
                         Feasibility of obtaining information                              Internal
 MS36          5.3       regarding treatment of the paediatric            1, 5        36                   1-Feb-14
                                                                                           document
                         tumour of a cohort of survivors with
                         Database
 MS37          5.4                                                        1, 5        36   Internal        1-Feb-14
                         follow-up for vital status and cause of                           document
                         death
                         Positioning of all second malignancies in                         Internal
 MS10          2.4                                                        2, 4        36                   1-Feb-14
                         WP4                                                               document
                         Input from Scientific Advisory Board &
 MS56         8.3c                                                         8          36                   1-Feb-14
                         Ethics Board                                                      Reports

 MS30          4.7       Case-control analyses                       1, 2, 3, 4       48   Internal        1-Feb-15
                                                                                           document

 MS45          6.5       Production of evidence summaries                  6          48   Internal        1-Feb15
                                                                                           document
                         Completion of data entry for all cases                            Internal
 MS11          2.5                                                      2, 3, 4       48                   1-Feb-15
                         and controls of WP3 and WP4                                       document
                         Identification of the causes of death                             Internal
 MS38          5.5       that are in excess as compared to the             5          48                   1-Feb-15
                                                                                           document
                         background population
                         Workshops (development of draft for                               Internal
 MS46          6.6                                                         6          48                   1-Feb-15
                         practice recommendations)                                         document
                                                                     1, 2, 3, 4, 5,        Conference
 MS51          7.3       Conference                                                   48   held,           1-Feb-15
                                                                        6, 7, 8
                                                                                           programme
                         Input from Scientific Advisory Board &
 MS56         8.3d                                                         8          48   available       1-Feb-15
                         Ethics Board                                                      Reports
                         Produce accessible information to           1, 2, 3, 4, 5,        Internal
 MS31          4.8       inform survivors in liaison with WP6 and                     48                   1-Feb-15
                                                                     6, 7                  document
                         wP7
                         Produce accessible information to           1, 2, 3, 4, 5,        Internal
 MS32          4.9       inform health care professionals in                          48                   1-Feb-15
                                                                     6, 7                  document
                         liaison with WP6 and for standardized
                         Evaluate implications WP7                   1, 2, 3, 4, 5,        Internal
 MS33         4.10       clinical follow-up guidelines in liaison                     48                   1-Feb-15
                                                                     6, 7, 8               document
                         with WP6 and WP7
                         Input from Scientific Advisory Board &                            Report
 MS56         8.3d                                                         8          48                   1-Feb-15
                         Ethics Board                                                      available
                         Production of accessible information to     1, 2, 3, 4, 5,        Internal
 MS21         3.10       inform survivors in liaison with WP6 &                       54                   1-Aug-15
                                                                        6, 7, 8            document
                         WP7
                         Production of accessible information        1, 2, 3, 4, 5,        Internal
 MS22         3.11       health care professionals in liaison with                    54                   1-Aug-15
                                                                         6, 7              document
                         Evaluate WP7
                         WP6 andimplications for standardized
                                                                     1, 2, 3, 4, 5,        Internal
 MS23         3.12       clinical follow-up guidelines in liaison                     54                   1-Aug-15
                                                                         6, 7              document
                         Analyses and WP7
                         with WP6of relative, cumulative and
 MS39          5.6                                                         5          54   Internal        1-Aug-15
                         absolute risk fo dying from defined                               document
                         causes
 MS47          6.7       Develop final guidelines                          6          54   Internal        1-Aug-15
                                                                                           document
                         Establishment of a virtual pan-European                           Internal
 MS6           1.6                                                        1, 5        54                   1-Aug15
                         database of long-term survivors                                   document

 MS48          6.8       Development of performance measures               6          54   Internal        1-Aug-15
                                                                                           document
                                                                     1, 2, 3, 4, 5,        Workshop
 MS52          7.4       Workshop                                                     54   held,           1-Aug-15
                                                                        6, 7, 8
                                                                                           proceedings                          Formatted: Font: 8 pt, Italic, Do not check
                                                                                           available                            spelling or grammar
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PanCareSurFup Research Protocol (WP1-5)                                                                               Page 59

                         Consolidation of the database for late                            Database
 MS5           1.5                                                       1, 5         54   completed and   1-Aug-15
                         mortality
                                                                                           validated
                         Input from Scientific Advisory Board &
 MS56         8.3e                                                         8          60                   1-Feb-16
                         Ethics Board                                                      Reports
                         Relative, cumulative and absolute risk of                         Internal
 MS40          5.7       dying from defined causes by treatment          1, 5         60                   1-Feb-16
                                                                                           document
                         modality                                                          Workshop
                                                                     1, 2, 3, 4, 5,
 MS53          7.5       Workshop                                                     60   held,           1-Feb-16
                                                                        6, 7, 8,
                                                                                           proceedings
                                                                                           According to
                         First & subsequent reports accepted by
 MS57          8.4                                                         8          60   available
                                                                                           grant           1-Feb-16
                         EC
                                                                                           agreement;
                         Twice yearly meetings of the Executive      1, 2, 3, 4, 5,        In total, 10
 MS58          8.5                                                                    60   report
                         Board                                          6, 7, 8,           meetings
                                                                                           available
                         Yearly meetings of the General              1, 2, 3, 4, 5,        In total, 5
 MS59          8.6                                                                    60
                         Assembly                                       6, 7, 8            meetings
                         Structural interaction with relevant end
 MS60          8.7                                                         8          60
                         users and stakeholders




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