Impact of new approaches to pharmacological management of patients with renal cell carcinoma: a population-based study of process and outcomes in The Netherlands

For patients with (advanced) renal malignancies many randomized clinical trials
(RCTs) of anticancer drug efficacy have been performed worldwide. Recent RCTs
have shown promising results. Based on this, clinical guidelines are being
developed to improve RCC treatment effectiveness in *routine* clinical
practice. New drugs such as the tyrosine kinase inhibitors (TKI) sunitinib and
sorafenib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus and
the monoclonal antibody bevacizumab targeting the vascular endothelial growth
factor (VEGF)) have become available for the treatment of patients with
(advanced) renal carcinoma.
In the most general sense, sunitinib, bevacizumab combined with
interferon-alpha (IFN), and temsirolimus led to increased progression-free
survival of 2 to 6 months in RCTs. Sunitinib and the combination of bevacizumab
yielded partial responses in approximately 30% of patients. Furthermore,
sunitinib has been shown to improve overall survival. In a RCT, temsirolimus
has also been shown to improve overall survival in patients with unfavorable
prognostic features, while sorafenib doubles progression-free survival in
patients pre-treated with cytokines, the old first-line standard. However the
improved outcomes obtained by these novel drugs come at the expense of toxicity
which is sometimes severe. Many patients (up to 67%) experience mild to severe
toxicity. Furthermore, the costs of these compounds are considerable
(approximately 3000-4000 Euro per month). To what extent these treatments lead
to improved survival in daily clinical practice and with how much side effects
is unclear. Empirical data on everyday clinical practice variation and its
effects on disease outcome may lead to improvements of quality of care and even
cost savings per life-year saved. Even in the absence of such data, it is very
clear that there is a strong need for improved stratification of patients in
order to come to tailored, individualized treatment of patients with better
response rates, less toxicity and much more efficient drug use. Another issue
is the patients* treatment location, i.e. in expert or normal community
hospitals. Because a good prognostic classification is still not available, and
treatments are rather complex and regularly result in severe toxicity, it is
questionable whether these patients can be treated optimally outsideexpert
centers.

The 1st main objective is to collect detailed quantitative data on the everyday
management of mRCC in the Netherlands, the clinical outcome of this management,
as well as the resulting quality of life and financial costs. Treatment
selection for mRCC patients is mainly based on routine assessment of classical
parameters: tumor histopathology and prognostic features. Determination of the
patients* and tumors* molecular makeup and activity of kinase cell signaling
pathways before initiation of targeted treatment is likely to improve
prognostic stratification of patients. The 2nd main objective is therefore to
identify prognostic groups of mRCC patients based on classical ánd
non-classical parameters in order to achieve a more tailored approach thereby
avoiding toxicities and extremely expensive treatment in patients who don*t
benefit from it. The specific aims are:
- To assess the approximate absolute and relative number of mRCC patients per
year in the Netherlands who have an indication for treatment with targeted
agents.
- To identify patient, tumor, and treating physician related determinants of
prescription of these drugs.
- To assess progression-free-survival (PFS) and overall survival (OS) after
treatment with these drugs in everyday clinical practice.
- To assess the probability, type and severity of side effects of these drugs.
- To assess the impact of treatment with targeted agents on quality of life.
- To build a population-based germline DNA biobank of RCC patients to
facilitate pharmacogenomics research (in some university centers, such biobanks
for pharmacogenetics research are already being created; an additional aim of
the current proposal is to arrive at a concerted action for such biobanks)
- To genotype responding and non-responding patients for all genes that are
known to be involved in the different pathways which are involved in targeted
therapies (in collaboration with ongoing activities in academic centers).
- To get insight in the effectiveness of new targeted treatments, as compared
to the efficacy as reported from the clinical
trials.
- To get insight in the cost-effectiveness of new targeted treatments, as
compared to the efficacy as stated in the clinical trials.
- To investigate the possibility to build a frozen-tissue biobank of RCC tumors
through the Dutch pathology Departments.

In this project we will collect and analyze population-based data regarding
clinical management, clinical outcome, quality of life, results of prognostic
parameters and new (costly) treatments of mRCC. In addition, we will collect
blood samples from RCC patients, isolate the DNA and genotype the DNA of
patients treated with targeted therapies for the VEGF and mTOR pathways and
correlate the findings with response and toxicity to treatment. Through this,
we will improve the suboptimal classical prognostic assessment of patients with
mRCC.

Study population

Prospective study

The challenge of the project will be the recruitment of patients very early
after their diagnosis. The reason for the necessity to recruit them early has
to do with the poor prognosis of mRCC patients and with the desire to collect
QoL data and symptom, co-morbidity and side effects questionnaires related to
the primary treatment. Because the cancer registry has a delay of about 6
months before patients are registered, it is not possible to recruit all
patients through the cancer registry. Because 17% of all patients have no
histological confirmation [3] and this is the group that consists of patients
with metastasized tumors it is also not possible to use the pathology registry
(PALGA) as the only source of identification. For that reason, the following
recruitment scheme will be followed:
1. The study will be explained to and consent requested from all medical
oncologists and urologists in the hospitals of the 4 comprehensive cancer
centers.
2. Cancer registry personnel will visit the hospitals weekly and (with the help
of hospital personnel) select all new patients in the hospital information
system with a medical oncology Diagnosis Treatment Code (DBC) 83400
(*nierkanker*) or a urology DBC 10 (*(bij)niertumor*).
3. Eligibility for the study (patients with renal cancer of any stage) will be
verified through contacts with the treating physician.
4. Patients will be invited for the study by the cancer registry departments of
the 4 comprehensive cancer centers in the name of the treating physician.
Hospitalized patients will be invited by the treating physicians themselves.
Written informed consent will be requested.
5. In case of informed consent, symptom and QoL questionnaires will be sent to
the patient.
6. Also, 2 plastic EDTA tubes will be sent to the patient in postal packages.
It will be requested to take these tubes to their treating physician at the
next visit and ask the physician for a blood draw. After that, the blood can be
sent by normal mail to the Urology Research Laboratory of the Radboud
University Nijmegen Medical Center.
7. Cancer registry personnel collect extensive clinical data from the medical
files in addition to the routinely collected data. Specific emphasis will be
given to prognostic parameters that are part of the Memorial Sloan Kettering
Cancer Center score. A slightly modified version of the widely used Charlson
co-morbidity index will be used for recording co-morbidity. Follow-up data will
be collected with emphasis on response, recurrence, late effects of treatment
and survival.
This routine has been proven feasible within the EU 6th framework program
Polygene. In this project IKO has collected questionnaire data, clinical info
and germline DNA from more than 5000 patients in the last 2 years (e,g,
Kiemeney et al, 2008). Through the recruitment in the 4 CCC areas covering 55%
of the hospitals in the Netherlands and a total catchment population of 9
million, approximately 800 new patients with renal cancer can be identified
each year. With a recruitment period of 2 years, 1600 patients. We aim at
recruiting at least 1000 of them. From these 1000 patients, basic clinical data
and questionnaires will be collected. More detailed information will be
collected from the group of primary mRCC patients. The size of the latter group
will be approximately 300. At least 100 additional primary non-mRCC will
develop metastasized disease during the duration ofthe study. Therefore, ~400
patients with an indication for targeted therapies will be included.

Retrospective study

Retrospectively, all patients diagnosed with mRCC in the hospitals of the 4
CCCs since January 2008 will be selected from the cancer registry. Since that
date, treatment with targeted drugs has been routinely recorded in the cancer
registry and can be used as a stratification parameter for the comparison of
patient and tumor characteristics between treatment groups. mRCC patients
treated in the four regions will be stratified according to MSKCC prognostic
parameters in order to investigate the correlation between therapy outcome and
good/intermediate/poor risk score patients in relation to the specific drug. To
obtainsufficiently detailed information, patient files will be screened to
collect this information in a uniform manner. Furthermore, toxicity profiles
will be collected retrospectively. This analysis will provide the necessary
background information to investigate the correlation between these parameters
and treatment outcome in The Netherlands.

Genomic DNA data.
As stated before, in the prospective study, patients will be requested to
donate a blood sample for genetic analyses of drug pathways. The blood samples
will be sent by normal mail to Radboud University Nijmegen Medical Center
(RUNMC) for analysis. Isolated DNA will be arrayed on custom-made (Illumina
Goldengate platform) SNP arrays, interrogating kinome-related pathways. Covered
target genes will include known TKI targets and off-targets. Pharmacogenomic
profiles will be compared with toxicity profiles to determine any correlative.

Frozen tissue samples
One of the goals of this project is to build a tissue biobank of patients with
renal cancer. We attempt to do this by initiating discussions among
pathologists, medical oncologists and urologists about the necessity of such a
biobank for future mechanistic studies into targeted drug response.

Cost-effectiveness analyses
This study will include all patients with renal cancer but has a focus on
patients with advanced and/or metastatic renal cell cancer (Stage IV or
recurrent disease). Cost-effectiveness will be assessed for the whole patient
group. Furthermore, specific sub-analyses will be performed focusing on the
hospital drugs temsirolimus and bevacuzimab. Temsirolimus is registered for
patients with advanced and/or metastatic renal cell cancer with a poor
prognosis (defined as Karnofsky performance status of60%-70%, among other
clinical measures such as more than one metastatic organ site, less than 1 year
from time of initial RCC diagnosis to treatment). To assess the
cost-effectiveness of temsirolimus the focus will lie on mRCC with poor
prognosis. Bevacuzimab in combination with IFN-alpha is registered as
first-line treatment in patients with mRCC. To assess the cost-effectiveness of
bevacuzimab the focus will lie on first line mRCC.

Study comparator:
The comparators will be interferon alpha and/or other drugs used in daily
practice.

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