Protocol
Pediatric Inflammatory Bowel Disease; cancer and mortality (PIBD C&M)
Summary
Death from inflammatory bowel disease (IBD) in children is devastating but fortunately rare,
and may be due to IBD associated complications, or complications associated with medical or
surgical interventions. Recently, the risk of cancer from active disease or from treatment has
become more apparent. The aim of the study is quantify the exact risk of cancer and mortality
within pediatric IBD, to better define the risk/benefit ratio of our therapeutic strategies.
A prospective population based survey for 3 years (July 2013-July 2016) will be performed to
identify all cases of cancer or mortality occurring in pediatric IBD within 20-25 countries
around the world.
Background
Incidence of pediatric inflammatory bowel disease (PIBD) in European countries has risen
significantly in the past two decades, as shown by several recent studies.(1-3)
Over this same period medical treatment of PIBD has changed considerably, with a tendency
for using more aggressive immunosuppressive medications earlier in the disease course. In
addition, pediatric onset IBD is more often extensive, as compared with adults, more severe
and patients have a longer anticipated duration of disease.(4,5)
Death from IBD in children is devastating but fortunately rare, and may be due to IBD
associated complications, or complications associated with medical or surgical interventions.
Recently, the risk of cancer from active disease or from treatment has become more apparent.
Disease associated cancers are usually adenocarcinomas arising from chronic inflammation,
while lymphoproliferative disorders (e.g. Ebstein Bar Virus associated lymphomas or
hepatosplenic T cell lymphomas) have been clearly associated with specific treatments, most
notably- thiopurines.(6) In addition, cervical cancer and skin cancers have been recognized as
an adverse event of immunosuppressive medications, including biologics. The need to control
active disease, decrease steroid exposure and prevent complications has led to an increase in
exposure to thiopurines, biologics and calcineurin inhibitors on the one hand, (7-9) and
hesitation in using combination therapy with a biologic and immunomodulator for patients
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who have failed monotherapy. It is difficult to assess the risk of malignancy and mortality in
small pediatric clinical trials with short-term follow-up.
To further assess the benefit/risk ratio the Porto Pediatric IBD working Group of ESPGHAN
conducted a retrospective multi-national based survey of malignancy and mortality in
pediatric IBD. Within the period 2006-2011 44 children (18 cases of cancers and 32 deaths; 6
due to cancer) from 20 European countries and Israel were identified.
Aim
The aim of the study is quantify the exact risk of cancer and mortality within pediatric IBD, to
better define the risk/benefit ratio of our therapeutic strategies.
Methods
We will perform a prospective population based survey for 3 years (July 2013-July 2016) to
identify all cases of cancer or mortality occurring in pediatric IBD. The survey will take place
in 20-25 countries in Europe, Canada, New Zealand and Israel. The survey will determine
exposure to medications, as well as causes of death (infection, disease, drugs, surgery,
neoplasia, or other). In order to perform this study, each country will have a steering
committee composed of a national representative from the fields of pediatric gastroenterology
and oncology. An effort to include an adult gastroenterologist will be made to ensure that
adult colleagues can be queried in the same fashion. Every 6 months the delegated national
representatives (gastroenterologist and oncologist) will query every pediatric
gastroenterologist to collect data regarding new cases of cancer or mortality. The local
representative will contact the treating gastroenterologist for information regarding the
duration of disease from the diagnosis of IBD or to cancer, duration of disease from diagnosis
of IBD to mortality. We will collect anonymous information regarding types of medications
used (such as thiopurines and biologics) and duration of use, reason for death and types of
cancers as well as information to ascertain if cancer/mortality is related to disease, drugs
and/or infection. Data regarding surgeries and mortality from the post operative period will
also be collected (find attached questionnaire). The patients Crohn's Colitis association from
each country will verify by a separate hotline that each physician has received the emails for
reports and responded and verify the physicians participation. EFFCA (European Federation
of Crohn's and Ulcerative Colitis Association) will take part by creating a national spirit of
cooperation and collaboration for a common goal in each participating country. This project
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will be their organizational goal project for the next 3 years. In addition, the oncologists will
screen national cancer registries to identify associations and cross check information.
After collecting the data anonymous data will be sent to a central database in Rotterdam and
will be managed by Dr de Ridder.
Pilot study:
In order to justify the viability of the study we already performed a retrospective study
covering 5 years in 23 countries. Data from this study have given insight into the number of
cancer cases that are IBD associated or treatment associated, and into potential pitfalls in data
collection. From these preliminary data we have found 31 cases of deaths in patients under the
age of 19 years, most related to disease but not to cancer (16% cancer) and only 6 cancer
cases are definitely related to therapy, 2 cancers to disease complications. These data were
presented by Dr. Lissy de Ridder and Prof. Arie Levine at the ECCO (European Crohn's and
Colitis Organization) meeting in Vienna and the study was launched on May 8 2013.
Importance of study:
At present the only way to assess the risk is from longitudinal cohorts that may take a decade
just to identify a few cases, these cohorts are only assessing cancer but not mortality, and are
thus flawed. In attempting to identify every case in 25 countries we will have large scale
population based data, and the ability to understand the scale of the problem, and to evaluate
how many cancers actually lead to mortality. The scale of treatment associated cancers might
be much larger or much smaller than appreciated, but if they are the cause of a small minority
of fatalities while under-treatment is a bigger risk, it would help physicians in treatment
strategies.
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Inclusion criteria
Diagnosis of IBD before age of 19 years. Diagnosis of IBD should be based on
oesophagogastroduodenoscopy, ileocolonoscopy including histology of multiple biopsies and
small bowel imaging, according to the Porto criteria.(10)
Patients, after disease onset of IBD, diagnosed with any type of malignancy before age 26 or
patients who died from any cause before age 26.
Collection of cases

Each participating country will have a national representative (a pediatric
gastroenterologist). The national representative will organize an email mailing list of
all pediatric gastroenterologists in his or her country , and contact all his/her pediatric
gastroenterology colleagues every July and January. In case other physicians treat
pediatric IBD patients within the country represented, they will also be contacted and
informed about the study. Every 6 months (so in total 6 times) all colleagues will be
contacted by email and/or telephone, and asked whether they have seen cases fitting
the inclusion criteria. The email should explain the reason for the query (Pan European
study supported by ESPGHAN, EFFCA National patient Organization, National GI or
IBD association if this is obtained). If the answer is NO, the physician should reply
NO, if the answer is YES he or she will be contacted for further details. An active
reply from every participant is required. In case they have one or more cases, a
questionnaire will be send by mail to inform for further data via a standardized
questionnaire (see attachment). If no reply is received within four weeks, a second
email should be sent

The national representative will select and invite a national pediatric oncologist
representative. The national pediatric oncologist will contact all his/her pediatric
oncology colleagues and will inquire for cancer cases in pediatric IBD patients. The
oncologist will access national cancer databases for malignancies cross referencing for
IBD, and also try to identify reported cases of malignancy to verify exact type of
malignancy.

Whenever possible, the national pediatric GI representative will contact an adult
counterpart from the same country through the national IBD association or national GI
association (adult) and ask to collaborate. In this case, adult gastroenterologists will be
contacted as described every 6 months by the adult of pediatric representative and
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asked if they have encountered a case of cancer or mortality in a patient <26 years of
age, who developed IBD prior to age 19. This will enable national representatives to
identify cases that may have transitioned to adult care, as well as patients who have
developed cancer or died within 10 years of IBD of pediatric onset.

The central/coordinating pediatric gastroenterologist to whom all cases will be sent is
Lissy de Ridder (The Netherlands) while the central/coordinating pediatric oncologist
will be Andrica de Vries (The Netherlands).

This study will be conducted with support of both the European (European Federation
of Crohn and Colitis; EFCCA) and the national patient organizations, an attempt will
be made to involve ECCO as well.

The national pediatric gastroenterologist will contact the national patient organization,
inform them on the study and make appointments for collaboration (e.g. financial and
administrative support, spread the news to the patients, contact adult care givers,
opening a 'hotline' so physicians can easily report cases).

The study will be presented at the national meetings and thus create a national network
with all pediatric and adult gastroenterologists (and others in case they would be
treating pediatric IBD patients).

An attempt will be made to access all pertinent national registries (IBD registries,
cancer registries) in order to verify data and obtain incidence prevalence for IBD in
children or local incidence of malignancies (age adjusted).

The sum of 100 Euros will be paid as an honorarium for every case reported by a
physician as (one honorarium per patient, no honorarium if patient previously
reported). The initial funding was obtained from ESPGHAN, and efforts will be made
to increase funding.
Ethics
Patient data will be collected anonymized (month of birth/year of birth will be enough to
identify doubles). Contact by telephone with the secretary of the medical ethical committee of
the Erasmus MC revealed that consent is not needed due to the nature of the study. However,
formal report of this will follow.
The requirements for ethical consent will differ within the countries involved. Therefore,
every national representative should contact his/her ethical committee to consult what
procedures are needed to get ethical consent for this study.
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Steering Committee and Roles
Principal Investigators
Dr Lissy de Ridder, MD, PhD
Prof. Arie Levine, MD
Coordinator
Rotem Sigall Boneh.
Epidemiology Committee
Prof. Dan Turner, MD, PhD
Dr. Tine Jess, Copenhagen
Prof. Anne Griffiths, MD, PhD
Prof. David C Wilson, MD, PhD
Prof. Harland Winter, MD PhD
Additional ECCO Adult GI member as needed
References
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E; on behalf of the SPIRIT-IBD Working Group of SEGHNP (Sociedad Española de
Gastroenterología, Hepatología y Nutrición Pediátrica). Increasing incidence of
pediatric inflammatory bowel disease in Spain (1996-2009): The SPIRIT registry.
Inflamm Bowel Dis. 2013;19:73-80.
2. Lehtinen P, Ashorn M, Iltanen S, Jauhola R, Jauhonen P, Kolho KL, Auvinen A.
Incidence trends of pediatric inflammatory bowel disease in Finland, 1987-2003, a
nationwide study. Inflamm Bowel Dis. 2011;17(8):1778-83.
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EL, Drummond HE, Anderson NH, Van Limbergen J, Russell RK, Satsangi J, Wilson
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Satsangi J, Wilson DC. Definition of phenotypic characteristics of childhood-onset
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6. Thai A, Prindiville T. Hepatosplenic T-cell lymphoma and inflammatory bowel
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Capelle P, Marteau P, Lemann M, Colombel JF, Khouri E, Bonaz B, Carbonnel F.
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Bonaz B, Denet C, Marteau P, Gambiez L, Beaugerie L, Faivre J, Carbonnel F. Small
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hepatology and nutrition (ESPGHAN). Inflammatory bowel disease in children and
adolescents: recommendations for diagnosis-The Porto criteria. J Ped Gastroenterol
Nutr 2005;41:1-7.
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