European genetics study of hearing impairment in patients with cancer during childhood treated with cisplatin.

Survival rates after childhood cancer now reach nearly 80% in developed
European countries as a result of more effective therapies and better
supportive care. However, the treatments that have improved survival are harsh
and cause serious side-effects in the long term. Platinum-based chemotherapy is
used for a variety of cancers and is questioned by its ototoxic long-term
effects, influencing speech and language development, social-emotional
development and educational achievement. Hearing loss may affect from 26% to
80% of childhood cancer survivors. Since cisplatin is used in the treatment of
several childhood cancer types and the degree of hearing impairment is highly
variable in cisplatin-treated patients, it is imperative to identify the
patients that are at risk for ototoxicity. The cumulative dose of the
anticancer drug, the treatment schedule, the concomitant use of diuretics and
aminoglycosides, as well as the patient*s age at diagnosis only partially
explain the inter-individual variability in the ototoxic responses. The
variation in hearing impairment in similarly treated children, suggests that
genetic variation may influence ototoxicity. Currently, the studies that have
been performed in children with cancer are based on studies in limited numbers
of patients or survivors. Also, previous studies did not include genome-wide
screening, and some studies suffered from selection bias.

The aim of this study is to validate known, and identify novel allelic variants
which may play a role in the risk of cisplatin-induced ototoxicity in a
substantial international cohort of children diagnosed with cancer.

The study, set up as retrospective and prospective cohort study, is coordinated
by the Erasmus Medical Center (EMC), but GWAS will be performed in the EMC and
the Universitaetsklinikum Ulm (Germany). In total, we will recruit data from
approximately 600 newly diagnosed patients and previously treated patients
(survivors), treated with cisplatin-based chemotherapy, without cranial
irradiation.

For the detection of gene polymorphisms in this study the participation of
individual volunteers includes three pure-tone audiograms as part of routine
follow-up visits in the clinic and a single blood sample, simultaneously with a
blood sample takenin the context of diagnosis.
In case of refusal of an extra blood sample, participants will be send a saliva
kit, including a pre-paid mail-back envelope. Patients can collect the saliva
at home or during regular visit at the hospital according to the instructions.
During regular hospital visits a hearing test will be performed three times:
before treatment, between the second and the third cycle, and at stop
treatment. Audiometry is provided in normal post-closure plan already However,
until recently these tests were not carried out at the same time in all
children. With this study we want to ensure there will be an improvement in the
structure of audiometry.

Once treated patients have given access to their medical recods, audiological
data and a single blood sample, data will be collected. In the case of refusal
of a single blood sample, participants will be send a saliva kit and will
include a pre-paid mail-back envelope. Patients can collect the saliva at home
according to the instructions.

With relatively simple methods and with minimal load (three times an audiogram
during regular hospital visit and a single blood sample, simultaneously with a
blood sample taken in the context of patient care), an impression can be
obtained from the hearing status and the genetic profile of the patient. The
acquired knowledge will help us to answer future questions.

Hearing tests are done as part of the routine follow-up visits in the clinic.
Until recently, the hearing tests were not carried out in every child at the
same time during the treatment. With this research, we also want to ensure an
improvement in the structure of the hearing tests (before treatment, during
treatment and at stop of treatment).

Invasive diagnostic measures or interventions with the patients are not
necessary in the context of the study. The study cannot be carried out on
adults only since the planned studies are examined in childhood cancer
survivors, treated for different types of cancer occurring before age 18. The
study will be carried out with these study subjects since we are studying the
direct effect and the role of the genetic profile on the development of hearing
loss in this specific population.