UMBRELLA PROTOCOL SIOP-RTSG 2016
Integrated research and guidelines for standardized diagnostics and therapy for paediatric renal tumours

See also page 10-11 of the UMBRELLA protocol:

The main mission of the International Society of Paediatric Oncology (SIOP)
Renal Tumour Study Group
(RTSG) is to increase survival and to reduce acute treatment toxicity and late
effects in all children, adolescents and young adults diagnosed with any renal
tumour. In this context, SIOP-RTSG is aiming to offer all these patients the
same standardized high quality diagnostics and treatment, independent of the
tumour type, the socio-economic status or the geographic region where the
patient is living. To achieve these goals, the UMBRELLA protocol was developed.

Given the relative rarity of paediatric renal tumours and in particular rare
subgroups, our previous studies demonstrated that it is necessary to recruit as
many patients as are available at a population level. Over the last decades
more than 10,000 children have been prospectively enrolled in SIOP Wilms Tumour
studies and trials. Since SIOP 93-01 SIOP-RTSG registered nearly 8,000 patients
with a renal tumour from 261 centres across 28 countries. All of them have been
treated according to consensus European trials and protocols. This has resulted
in more standardised diagnostic procedures, improved risk stratification, and
adjusted treatment recommendations for most renal tumours.

The UMBRELLA SIOP-RTSG 2016 protocol (part A) serves as an entry for including
all children with a renal tumour in Europe and other participating centres in
the SIOP-RTSG. Subsequently, treatment of each participant*s renal tumour is
recommended according to the UMBRELLA treatment guidelines (part B), which
provides treatment strategies for all Wilms tumour patients and all children
with other renal tumours. These recommendations are based on previous studies
and trials performed by the International Society of Paediatric Oncology
(SIOP), Children's Cancer and Leukaemia Group (CCLG), Associazione Italiana
Ematologia Oncologia Pediatrica (AIEOP) and National Wilms Tumor Study Group
(NWTSG) / Children*s Oncology Group (COG).

The overall aim of the SIOP 2016 UMBRELLA protocol is to harmonize the clinical
relevant standard
diagnostic procedures for all paediatric renal tumours within SIOP and to
provide imaging studies and
biomaterial from all of these patients, to find new and better risk factors for
treatment stratification and
molecular targets for novel therapeutic approaches. This will help to improve
short and long term
outcomes for all children with renal tumours through the introduction of a more
*personalised*
approach.

Primary aim (see pages 18-19 in the UMBRELLA protocol)

1. To show the feasibility of storing serial blood, urine samples, tumour and
germline material at diagnosis and at specific time points during treatment for
international collaborative studies. These will be used to validate and
quantify in multivariate analysis, the relative adverse prognostic significance
of specified somatic molecular biomarkers (listed in aim 2) in relation to
blastemal volume (aim 3). They will also be used for exploratory analyses of
potential novel biomarkers, including circulating nucleic acids detectable in
blood and urine, for diagnosis and prognosis.

2. To assess genomic 1q gain and other copy number variants as a prognostic
biomarker in WT. Moreover, the feasibility of returning biomarker results to
treatment centres within a clinically relevant time frame will be tested.

3. To optimize the definition of high risk WT, *blastemal type* through
accurate measurement of the residual blastemal cells volume including
centralized *real time* pathology and radiology review. The blastemal cell
volume will be assessed in relation to other biomarkers and outcome measures
including overall and event-free survival.

4. To optimize radiological diagnostics/review by (real time) central review to
monitor and give appropriate feedback on diagnostic imaging quality, harmonies
diagnostic procedures and standardize reporting of radiology findings.
Additionally, diffusion-weighted imaging (DWI) results will be linked to
pathological assessment of the tumour. (See also chapter 7.1 on page 27-28).

5. To optimize pathological diagnostics/review by (real time) central review to
monitor and give appropriate feedback on local pathological diagnosis, stratify
treatment based on central pathological review and store biological material
according to standardized guidelines. (See also chapter 7.2 and 7.3 on page
28-34).

Secondary aims

1. To explore whether aberrations in any or a combination of the following
genes have a significant impact on event-free or overall survival WT: WT1,
CTNNB1, AMER1, TP53, MYCN, FBXW7, GPC3, MLLT1, DIS3L2, DICER1, DROSHA, DGCR8,
SIX1 and SIX2.

2. To explore the role of miRNAs in blood and tumour as biomarkers for kidney
tumours.

3. To establish a surgical review process for guiding local centres in
performing nephron sparing surgery (NSS) in uni - and bilateral WT or minimal
invasive surgery in unilateral renal tumours.

4. To perform explorative epidemiological analyses of the collected data.

5. To validate new tools developed within the e-Health project such as
p-medicine [4] and similar projects, to improve clinical treatment
decision-making based on integrated risk assessment and response modelling in
silico, in a selected well documented large subset of patients. The validation
will be performed against the background of the ALEA registered complete
dataset.

6. To characterise at a molecular level all subtypes of WT and non-WT and their
associated nephrogenic rests, using whole genome, epigenomic and proteomic
approaches.

7. To assess the feasibility of developing a targeted *next generation*
sequencing panel for WT and other childhood renal tumours.

8. To contribute to the development of ex vivo models for functional validation
of newly discovered molecular aberrations and biomarkers.

The study design of the UMBRELLA protocol includes data registration,
biological sample collection and biological studies:

Data registration
Participating patients will be registered in the SIOP database using the eCRF
system ALEA®. This system provides tools for patient registration, data
collection, querying and (remote) monitoring. In addition, Electronic Case
Record Forms (eCRFs) have been developed for baseline characteristics,
treatment details, pathology and outcome measures. Methods for allowing
reference centres to get access to imaging data (DICOM files) are being
developed. The SIOP database is located at the statistical centre of the
SIOP-RTSG in Amsterdam lead by Harm van Tinteren. All information in this
database will be coded.

Biological sample collection
Blood, urine and tumour samples will be collected at specified time points to
answer biological questions. Blood samples (1-2 tubes, 5-7,5 mL) will be taken
during routine blood exams needed for diagnosis and therapy monitoring, without
requiring additional invasive procedures. In the Netherlands, blood and urine
samples will be taken at diagnosis, before surgery, week 1 after surgery and at
the end of treatment. Tumour samples (fresh and frozen) will be taken during
surgery. Additionally, a small amount of blood will be taken from each parent
(1-2 tubes, 10-20mL) and stored for biological research questions. All samples
will be stored in the Princess Máxima Centrum Biobank (also DCOG/SIOP),
according to the Princess Máxima Centrum Biobank rules and regulations
(referentie: 2016-JD-0068).

Biological studies
Data and biological samples will be used for laboratory studies to answer the
above mentioned research questions (aims) of UMBRELLA.

Burden and risks associated with participation are considered to be minimal.
Possible burdens include the collection of extra blood and urine samples. Blood
samples will be taken during routine blood exams needed for diagnosis and
therapy monitoring, without requiring additional invasive procedures.