Screening for Familial Gastric Cancer in first degree relatives

Familial gastric cancer (FGC) concerns about 10% of all gastric cancers. It has
an impressive impact on both emotional and physical wellbeing of first degree
relatives of patients with (early) onset of gastric cancer. FGC can in 1-3% be
attributed to one single hereditary syndrome, the hereditary diffuse gastric
cancer (HDGC). HDGC is associated with a CDH1 mutation in about 40 % of the
cases. In case there is no CDH1 mutation, referred to as familiar diffuse
gastric cancer (FDGC), it remains uncertain how to guide and/or screen family
members. The same applies for the rare familial intestinal type gastric cancer
(FIGC). In this study we want to determine the value of endoscopic screening in
members of families with FGC, both FDGC and FIGC. Also, we will analyze the
associations of life style factors, including dietary habits with the
development of FDGC, to be able to built preventive strategies. Finally, we
want to assess the psychological impact of our screening protocol.

Primary, to determine whether staining of the gastric mucosa increases the
number of detected (pre)malignant foci of diffuse type gastric cancer, in
individuals from families with FDGC as well as dysplastic, adenomatous and
early intestinal cancers in individuals from families with FIGC. Secondary: A
To determine the optimal pathological work-up the detection rate of
(pre-)malignancy. B To determine clinical and life style factors that are
associated with the two types of FGC. C To determine the psychosocial impact
of the screening protocol in this population. D To develop a strategy for
screening individuals from FGC families and creative advise for preventive
measures.

The setup of this stydy is a randomized controlled trial included in a
prospective cohort analysis. During this study the effect of staining of the
gastric mucosa during endoscopy on the number of detected (pre)malignant foci
will be determined. Therefore, during a follow-up period of 5 years, each
individual has a gastroduodenoscopy at baseline, year 1, 3 and 5. During each
endoscopy, 6 biopsies will be taken from 5 predetermined regions for
histological examination. Additionally, 2 biopsies will be frozen immediately
in liquid nitrogen and stored at -80°C. Also, biopsies will be taken from all
visual lesions. During the baseline endoscopy half of the individuals will be
randomized for chromoendoscopy, and half for a normal white light HD endoscopy.
During the second endoscopy all individuals will have a chromoendoscopy.
Hereafter, an interval analysis will be performed, to determine if
chromoendoscopy will be continued or not. Additionally, at baseline, from each
individual blood will be withdrawn for determination of possible risk factors
for the development of a diffuse and intestinal gastric cancer, DNA- analysis
(if not performed in advance), and possible future mutation analysis. Also,
questionnaires concerning worry and psycho/anxiety and psychological impact
will be taken.

In general, this study aims to restrict the physical and mental burdens for the
subject as much as possible. The physical risks that are introduced by this
study to the participating individuals are the risks associated with the
duodenoscopies and sedation. The mortality risk associated with endoscopy is 1:
20.000. This mortality is associated with increased age of the patient (>70),
type of procedure (interventions such as ERCP) and co-morbidity. In our
relatively young patient populations, these risk factors are not expected. As
such, this risk is estimated to be very low or even negliglible. The risk
derived from the venous puncture that has to be performed for blood withdrawal
will be minimal. We take the samples of whole blood almost always in the
context of a routine clinical blood withdrawal to avoid extra venous punctures.
So in this scenario the subjects may undergo one venous puncture on clinical
visit. From all selected subjects maximal 40 cc is collected additionally,
which normally should have no influence on the health status of the subject.
Both acetic acid, as well as Indigo carmine are innocent colouring adds which
are used in food industry. From both chemical substances no harm is expected
for the participants of this study.
Additional to the standard treatment, all individuals will receive a PPI once
daily for 14 days after each endoscopy to minimize any possible discomfort
following the endoscopy. Side effects of PPI are rare and mild (nausea,
dizziness, abdominal discomfort, diarrhoea), and the benefit for the patient in
the prevention of discomfort is considerable. To prevent differences in
discomfort by bias as a result of differences in PPI, we agreed with our
pharmacy to organize that all patients will receive the same PPI for the period
of the study.
The mental burden for the included subjects in general is predicted to be low,
but is part of this research project. On one hand an individual may draw
considerable benefit in survival if an underlying pre(malignancy) is detected.
On the other hand, for each individual screening may have a different impact,
even if no (pre)malignancy is detected.
To establish a reasonable basis for the cooperation of the individual patients,
a common consent agreement will be signed by the patient prior to
participation.