AIRFORCE output report

Commentaren

Transcriptie

AIRFORCE output report
1
Personalized chemo-radiation of lung,
head and neck cancer
Executive Summary
2
Respiratory epithelial cancers, i.e. lung cancer (LC) and head and neck cancers (HNCs) are
leading causes of cancer mortality, in both men and women. Yearly about 9,000 Dutch persons
are diagnosed with LC while 8,850 die of the disease. For HNC these numbers are 1,400 and
850. Currently patients with LC and HNC are treated with surgery, radiotherapy and/or
chemotherapy. Radiotherapy is often combined with classical chemotherapy such as cisplatin
(CDDP) or targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors. While
initial response rates can be impressive, survival rates are still disappointedly short, and
treatment related morbidity is high.
By linking molecular knowledge of LC and HNCs such as markers of radioresistance with recent
advances in molecular imaging and novel techniques for selective irradiation, within the AirForce
consortium we aimed for optimally targeted individualized chemo-radiotherapy with improved
therapeutic outcome, i.e. survival and quality of life.
AirForce has addressed these unmet clinical needs by developing biomarker tests and imaging
approaches to come to (1) better prediction of therapy response, (2) avoidance of ineffective
treatment with high morbidity, (3) therapy tailoring: adaptation of treatment when needed, (4)
improvement of therapy decision making, and (5) reduction of costs of treatment.
Prof. dr. Guus van Dongen
Principal Investigator of the AIRFORCE consortium
"In the AIRFORCE consortium academic and industrial
partners with unique complementary expertise in the
fields of e.g. molecular and cell biology, biotechnology,
clinical drug development, informatics, medical
technology assessment and electronics will collaborate
closely together, aiming the improved treatment of
patients with tumors of the upper aero-digestive tract. In
this project innovative molecular navigation tools will be
developed and exploited for high precision tumor
eradication by personalized chemo-radiotherapy. I think
working in such a multidisciplinary translational setting is
unique for Europe, and the grant we obtained will
enable us to make a firm step forwards in a short time
period."
Highlights include the identification of predictive and prognostic candidate biomarkers for chemoand/or radiotherapy efficacy and toxicity, such as secreted protein biomarkers, expression
markers, methylation markers, markers on tumor stem cells and markers in exhaled breath.
Several novel drug targets were identified. A panel of hypoxia tracers was developed and in vivo
validated as well as a panel of EGFR, angiogenesis and multi-target tracers derived from
monoclonal antibodies and tyrosine kinase inhibitors (TKI). Tracers were clinically evaluated. A
large set of PET-CT software tools was developed to allow accurate and reproducible tumor
definition and to quantify and characterize tracer uptake. Tools were loaded in a software
platform for broad scale data integration called Oncology Research Workstation Imalytics.
Mathematical models such as nomograms were developed and validated that predict
progression free survival, overall survival and toxicity (dysphagia, dyspnea), and let to the
introduction of decision support systems that outperform doctors prediction. Improved strategies
for radiation dose boosting were introduced. Some cost effectiveness studies on diagnostic and
therapeutic procedures in LC and HNC were performed. Several of these findings have resulted
in product development and follow up studies, mostly with private partners, for further clinical
implementation.
Translational Concept - WP1
3
BIOMARKERS FOR PERSONALIZED THERAPY
More advanced stage lung- and head-neck cancer are treated by chemoradiation, the combination of
systemic cisplatin-containing chemotherapy and concomittant irradiation. Alternative treatments are at
hand, but there are no biomarkers available to personalize treatment.
Treatment is invasive and
cisplatin causes serious toxicities. Development of personalized treatment approaches, improvement
of treatment protocols and substitution of cisplatin by targeted radiosensitizers may reduce toxicity and
increase treatment efficacy. Toxicity of cisplatin costs 11 M€ per year on hospital stays in head-neck
cancer patients only.
CLINICAL NEED
TOOLS
New biomarkers are required to
Biomarkers are identified by:
personalize treatment for the specific
tumor in the particular patient. Also
improved treatment protocols are required
with identical or improved efficacy but with
less toxicity.
• Genomics, methylomics and proteomics methods.
• In addition, volatile compounds in exhaled breath have been exploited as biomarkers.
• Using genome-wide functional siRNA screens, the relevant genes involved in cisplatin
and radiation response are identified, and novel druggable targets are found.
• Finally, prognostic risk models are generated to stratify patients on basis of survival
outcome.
Translational Concept – WP2
4
PET TRACERS FOR GUIDANCE OF CHEMO-RADIATION
For optimal chemoradiation of lung- and head-neck cancer, accurate delineation of the tumor is a first
requirement. However, individual tumors differ in their sensitivity to treatment . It is know that tumor cell
metabolism, proliferation and the level of tumor angiogenesis are major contributors to tumor response
to radiotherapy. Some drugs directed against targets involved in proliferation and angiogenesis are
capable to improve the efficiency of chemoradiation. For high-precision individualized therapy, PET
tracers are need of value for prediction and monitoring of chemoradiation efficacy.
Innovative PET-CT Colonoscopy has the highest sensitivity to detect colorectal cancer and is
HNthe gold standard diagnostic test, also for follow up of patients with a
therefore considered
11
C
O
N
positiveO stool test. Nevertheless,
colonoscopy can not distinguish low risk colorectal
O
O
N
adenomas from high-risk adenomas and carcinomas, leading to overtreatment . Moreover,
Erlotinib
colonoscopy is an invasive technique with discomfort to the patient. Combining biomarkers
PET imaging of radiolabeled drug
predicts therapeutic efficacy
CLINICAL NEED
TOOLS
New PET tracers are needed to guide the
A panel of PET tracers for detection/delineation of tumors, and for visualisation and
optimal application of chemoradiation: the
quantification of (1) tumor characteristics related to chemo-radiosensitivity, (2) biodistribution
right treatment, for the right patient, at the
of radiosensitizing targeted drugs, (3) early tumor response.
right dose, at the right place, at the right
time.
Translational Concept – WP3
5
Development and validation of PET-CT Imaging software tools
Quantification of PET tracer uptake has added value for diagnosis, prognosis, prediction and response
assessment. Quantitative PET may therefore play and important role for enhancing individualised
medicine. However, quantification of PET radiotracer uptake is limited by several factors, such as
patient motion, limited spatial resolution of PET imaging systems, tracer uptake heterogeneity.
Moreover, more new radiotracers are needed to allow for a more extensive in vivo assessment of tumor
biology and characteristics. This new and more accurate information can then be used to enhance
radiotherapy treatment planning, based on either tumor delineation/contouring or on dose painting.
During this projects several tools were developed to address the above mentioned issues. The
developed tools will give rise to better diagnosis, reduced inter-observer variation for delineation, and
better possibilities for targeting a part of the tumor (dose painting). This work package is primarily
aimed towards lung tumors (where motion is an issue), but will be applied in head-neck cancer as well,
where PET is used for tumor delineation.
CLINICAL NEED
TOOLS
New image analysis tools are needed to
Improving tumor tracer uptake quantification and tumor delineation for treatment planning
guide the optimal application of
and response assessment by means of development of new methods (1) for tumor
chemoradiation: the right treatment, for
delineation, (2) to correct for partial volume effects and (3) patient motion, (4) development
the right patient, at the right dose, at the
of tools to measure changes in tumor tracer uptake and characteristic for treatment response
right place, at the right time.
assessment and (5) methods to incorporate motion and biological information into
radiotherapy treatment planning system.
Translational Concept – WP4
6
MOLECULAR DIAGNOSTICS AND TOOLS
Integration and validation of pre-therapeutic molecular diagnostic and molecular imaging information in a
user-friendly tool and to use this information in innovative treatment.
•
Model prediction outperforms doctors’ prediction for dyspnea, dysphagia and survival
•
HX4 uptake represents tumor hypoxia on a macroscopic level
•
Uncertainty based planning has the potential to reduce dose to organs at risk
Fontanarosa et al. 2013
Dubois et al. 2011
Oberije et al. 2013
CLINICAL NEED
TOOLS
To improve the accuracy for predicting
By
side effects and survival of lung- and
biomarkers. By comparing new imaging modalities with pathology. By using an innovative
head-neck patients. To gather useful
treatment planning system and by collecting new “molecular” information about specific tumor
information on the intra-tumor
cell populations
heterogeneity. To deliver specific
inhomogeneous radiation doses to the
tumor (dose painting).
using existing validated and published predictive algorithms and improving them with new
Translational Concept – WP6
7
ONCOLOGY RESEARCH WORKSTATION (ORW)
The Philips research workstation Imalytics was used as the basis for the ORW. The
workstation operates on a local DICOM image database and can be connected to other
DICOM network nodes (e.g. PACS systems or imaging equipment). It was extended with a
programming interface and that was used to integrate tumor segmentation algorithms, PET
motion compensation, advanced image alignment, partial volume correction and remote control
for serial analysis.
MULTI-CENTER CLINICAL AND IMAGE DATABASE
WP6 supported the implementation of eCRF for the Umbrella protocol in which treatment
information of 1589 lung cancer patients has been collected. To augment this data a possibility
has been created to include DICOM scans, dose cubes, etc. from the PACS system for data
mining. The eCRF can be exported to standard ODM CDISC format. Of the linked image data,
a full anonymized UIDs are included for each event. This means that detailed correspondence
between the event and scan is recorded by the submitted hospital avoiding extensive data
CLINICAL NEED
Easy-to-use integrated software package
for optimal and standardized PET-CT
imaging for individualized healthcare:
management at the central site and allowing unattended data analysis (e.g., with Imalytics).
TOOLS
• PET/CT analysis
• Workflow & integration
ORW for lung and head-neck cancer
• Data collection through ECRF
Better knowledge of treatment parameters
• Data mining
and images in clinical trials
Public-Private Partnership
8
GENERATE KNOWLEDGE…
…TRANSLATE INTO APPLICATIONS
…NEW CURE/CARE SOLUTIONS
APPLICATION
SCIENCE
PATIENT
Select the optimal treatment regime for
individual patients and to find resistant
regions within tumors where localized
chemo-radiotherapy should be focused
Academic partners
Supporting Foundations
Industrial partners
Organization and Partners
ADVICE
9
BG Medicine (USA)
Genmab (DK)
MDxHealth (BE)
Advisory board
ISAC CTMM
UMCG
DECISIONS
SteeringCie
Partner Representatives
CTMM
Project Team
PI: Prof. G. van Dongen, (VUMC)
Co-PI: Prof. P. Lambin (MUMC+)
All WP leaders
All industrial partners
Dr. A.C. van Denderen (VUMC)
Dr. E. Caldenhoven (CTMM)
NKI
VUmc
Cyclotron
Agendia
Workpackage leaders
OPERATIONS
CTMM
Partners
Coordination
Finance
Publications
WP1: Prof. R. Brakenhof (VUMC)
WP2: Prof. G. van Dongen (VUMC)
WP3: Prof. R. Boellaard (VUMC)
WP4: Prof. P. Lambin (MUMC)
WP5: Prof. H. Groen (UMCG)
WP6: Dr. M. van Herk (NKI)
WP7: Prof. C. Uyl (EUR)
Philips
CTMM
MUMC +
Maastro
Mubio
DSM
Budget: CTMM manages the flow of funds
10
Funding:
- 25% Academia
- 25% Industrial
- 50% Government Subsidy
Project costs:
- Personnel
- Materials
- Use of existing equipment
- Investments
- Third parties
- Management (5%)
Facts & Figures
11
Academic Partners
Budget
Start
End
Partners
Industrial Partners Large
Distribution of the
AIRFORCE consortium
budgets to perform the
R&D activities
16,9 M €
2008
2013
13
Industrial Partners SME
CTMM investments
CASH COSTS
5.000.000
4.000.000
3.000.000
Academic cash costs
2.000.000
Industrial cash costs
1.000.000
0
PhD
PostDoc
Sen. Staff
Supp. Staff
IT Staff
M&S
Investments
KIND COSTS
5.000.000
4.000.000
3.000.000
Academic in kind costs
2.000.000
Industrial in kind costs
1.000.000
0
PhD
PostDoc
Sen. Staff
Supp. Staff
IT Staff
M&S
Investments
Facts & Figures
12
Budget
Start
End
Partners
Charity
Persons
FTE
16,9 M €
2008
2013
13
0
87
111 (5 years period)
Output
No
Papers
78
19 papers in submission - mean impact factor all published AIRFORCE papers: 5,6
Theses
10
1 planned for 2016
Personal Grants
0
Patent Filings
0
Spin-off
Companies
0
Raising Capital
(> 1 M€)
0
Awards
0
Public
Media
0
█ FP7 project entitled ArtForce (2011-2016), being “Adaptive and innovative Radiation Treatment FOR improving Cancer patients
treatment outcomE. AvL/NKI and MUMC; █ Kansen voor West: Projectplan Tracing & Trading. Tracer Center Amsterdam. Proeftuin van
VUmc Imaging Center Amsterdam; █ Innovative Training Networks (ITN) Call: H2020-MSCA-ITN-2014 “PET3D” (PET Imaging in Drug
Design and Development); █ ALPH/KWF 7072, 2014. A multiparameter radiogenomics-based decision support system for personalized
treatement of advanced stage head and neck cancer patients, DESIGN. 1.6 M€, four centers.
Scientific Value Creation - Breakthroughs
13
•
Candidate biomarkers identified for cisplatin response prediction with preliminary validation in clinical material
•
Production of the long-lived PET radionuclides zirconium-89 and iodine-124 was established for worldwide
distribution.
•
BRCA-Fanconi anemia pathway was found as major determinant of cisplatin response in squamous cell
carcinomas
•
Over 350 genes sensitize lung cancer cells for radiotherapy.
•
Over 300 genes are essential for lung cancer as well as head and neck cancer cells, and form novel
druggable gene targets for targeted treatment approaches.
•
Novel marker for identification of the cancer stem cells in head and neck cancer was found, and number of
stem cells in HPV+ve tumors is associated with outcome.
•
HPV-attributable fraction of HPV in oropharyngeal carcinoma was increased from 5% in 1990 till 30% in 2010.
•
HPV-based prognostic risk models for oropharyngeal cancer outperform TNM staging.
•
P16 immunostaining followed by HPV DNA PCR is a well-validated assay for routine use on archival
oropharyngeal cancer specimen and has been introduced in clinical care.
•
Models, based on clinical information, have been developed for overall survival, radiation-induced dyspnea
and radiation induced dysphagia. www.predictcancer.org. We developed two umbrella protocols one for head
and neck cancer one for lung cancer. The lung protocol was published open source.
•
Validation of the newly established non-invasive hypoxia PET marker HX4 by comparison with the golden
standard immunohistochemical exogenous hypoxia marker pimonidazole showed HX4 uptake does represent
tumor hypoxia on a macroscopic level.
•
Innovative probabilistic treatment planning system for radiotherapy allowing radiation dose painting: The
probabilistic planning and evaluation approaches to head and neck (HNC) and non-small cell lung (NSCLC)
cancer patients showed that serious mis-dosage may occur and that this approach is a valid solution for
uncertainties management in dose painting by numbers
Highest Impact Papers – mean 16,0
1.
Leemans C.R. et al (2011), Nat Rev Cancer. 2011 Jan;11(1):9-22
2.
Lambin P. et al (2013), Nat Rev Clin Oncol. 2013 Jan;10(1):27-40
3.
Aerts H.J. et al ( 2014), Nat Commun. 2014 Jun 3;5:4006
4.
Dubois L et al (2011), Proc Natl Acad Sci U S A. Aug 30;108(35):14620-5
5.
Poot A.J. et al (2013, Clin Pharmacol Ther. 2013 Mar;93(3):239-41
Mean Impact Factor
International - oncology
4,4
CTMM - oncology
6,8
0
2
4
1 - Panaxea 2013. Steute et al Impact Analysis CTMM (internal report, paper in preparation).
2 - Mean impact factor based on 200 papers from the CTMM oncology first call projects.
6
8
10
Scientific Value Creation - Theses
14
Thesis
Partner
Year
Steven Petit
MUMC+
2010
Maud Starmans
MUMC+
2011
Cary Oberije
MUMC+
2011
Patsuree Cheebsumon VUMC
2012
Matthijs Kruis
NKI
2014
Sanne Martens – de
Kemp
VUMC
2014
Eva Schaake
NKI
2014
Marlies Bongers
VUMC
2015
Sarah Peeters
MUMC+
2015
Vikram Rao
Bollineni
UMCG
2015
Gerald Kerner
UMCG
planned
15
Clinical and Economic Value Creation of
AIRFORCE
New ‘products’ for clinical care
Antibody based assays to stratify SCLC, NSCLC and HNSCC patients
16
PRODUCT
PARTNERSHIP
AIRFORCE aims to develop molecular tools to enable
prediction of chemo/radio-therapy response and
toxicity in lung- and head and neck cancer patients.
Protein-based methods are key for this purpose as
proteins (1) are a direct reflection of tumor biology, (2)
can be coupled to antibody-based assays, and (3) are
compatible with routine clinical pathology practice.
PATIENTS
Progress obtained in translational pipeline
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
•
Immunohistochemical patient stratification (right) through
protein biomarkers discovered by proteomics (left)
Discovery and validation of protein markers.
By using high resolution mass spectrometry-based
proteomics, proteins are identified and quantified to
yield candidate biomarkers. Promising candidates are
selected for immunohistochemical validation in patient
tumor tissues. Proteins associated with cisplatin
sensitivity and resistance were identified. These
proteins are implicated in a wide range of biological
processes (DNA repair including members of the
BRCA pathway, RNA processing/splicing, membrane
/vesicle trafficking among others). Suitable
immunohistochemical protocols were developed for 3
candidates of which 2 correlate with survival in a
preliminary validation study.
Leading Company: MuBio/BGMedicine
•
Protein biomarker identification: Most chemotherapy
regimens in lung- and head and neck cancer include
cisplatin. Therefore, we focused on this drug in our
discovery study. Candidate predictive protein
biomarkers for cisplatin response were identified in a
panel of NSCLC cell lines (53 sensitivity and 32
resistance candidates). Based on the level of significant
regulation between sensitive and resistant cells and the
correlation to the cisplatin IC50 value, the most
promising markers were selected for follow-up in
NSCLC tumor tissues of patients that received paltinabased chemotherapy.
Protein biomarker validation: For 3 candidates suitable
immuno-histochemical staining protocols were
developed. For 2 proteins, a DNA repair protein and a
nuclear methylation protein, a correlation was found with
survival in squamous NSCLC carcinoma. A larger
sample size is needed to confirm these findings.
Future outlook:
Predictive immunohistochemical test for platina-based
chemotherapy regimens in lung- and head and neck
cancer
rapy selection
The
Selection
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Discovery
Pathways
biomarkers
Number of LC and HNC patients per year: 1.8 and 0.56 million
Total healthcare cost per year: $US 25-40 billion
Expected impact of the products
Scientific: The proteomic landscape and cisplatinrelated biology uncovered in this project along with
promising candidate biomarkers will help to make
personalized cancer treatment a reality.
Societal: Routine protein-based assays will guide
clinicians in a better selection of patients for cancer
treatment with burdensome platinum-based
therapy,.
Economic: Tailoring therapy to patients that are
likely to respond will ultimately result in improved
cost-effectiveness of care.
Technology platform to measure volatile tumor-specific compounds for
stratification of lung cancer patients
17
PRODUCT
Progress obtained in translational pipeline
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
-
(1) preparation of the TD-tubes and Tedlar bags;
(2) Onsite sampling of exhaled breath onto 2 TDtubes via 2x5 (duplicate) liter Tedlar bags;
(3) Analysis of the TD-tubes by TD-GC-MS and
(4) Data processing using homemade chemometric
tools.
Leading Company: DSM
Selection
Pathways
biomarkers
-
2013
Main results in CTMM:
A molecular assay based on thermal desorption
coupled to gas chromatography and mass
spectrometry (TD-GC-MS) was successfully
developed and validated
- In collaboration with Maastro Clinic, this assay
proved to be a non-invasive and easy
sampling for lung cancer patients.
- Typically between 400 and 600 compounds
are detected.
- Metabolic markers for smoking (e.g. 2,5-dime-furan) are readily detected in smokers
breath
- The assay is robust with respect to sampling
and analysis.
- The limit of detection is at low volume ppt
levels.
- Good reproducibility. Variation (cv%) less than
10%.
Comprehensive
two-dimensional
gas
chromatography mass spectrometry (GCxGC-MS)
proved to be promising with respect to separation
power and sensitivity.
rapy selection
The
Discovery
Pathways
biomarkers
The whole assay encloses four main steps:
Besides GC-MS also solid phase micro extraction
coupled to comprehensive two-dimensional gas
chromatography and mass spectrometry (SPMEGCxGC-MS) was investigated. This technique
provides a more detailed chemical exhaled breath
profile and lower detection limits compared to GCMS; however sampling with SPME proved to be less
practical and less robust than TD.
PATIENTS
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
A molecular assay was developed and validated
which could be used to predict treatment response in
(lung-) cancer patients. The molecular assay is
based on the chemical analysis of exhaled breath
from cancer patients by using thermal desorption
coupled to gas chromatography and mass
spectrometry (TD-GC-MS). By TD-GC-MS a
comprehensive chemical profile of volatile organic
compounds (VOCs) in exhaled breath is determined.
Cancer treatment and treatment response will cause
changes (trends) in the chemical exhaled breath
profiles which could be used to predict or
personalize the cancer treatment.
PARTNERSHIP
Sensitive and robust molecular assay based on TD-GC-MS for
exhaled breath profiling of lung cancer patients
Expected impact of the products
Scientific:
This assay (full molecular exhaled breath profile)
could potentially be used for early diagnosis,
prevention, treatment, personalizing treatment and
monitoring of lung cancer patients.
Societal:
Future outlook:
Assay proved to be non-invasive and patient
friendly. Assay could assist in early diagnosis and
personalizing treatment.
-
Employing assay to future clinical studies
Economic:
-
Transferring developed TD approach to GCxGC
technologies
Assay could lead to early treatment and/or tailoring
of therapy thereby increasing efficiency of care.
CD98 based antibody assay for chemoradiation prediction in patients
with HPV+ve head and neck cancers
18
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2013
2008
Main results in CTMM:
-
The antigen recognized by mAb K984 is CD98
-
CD98high
-
CD98 immunostaining predicts outcome in
patients with HPV+ tumors
rapy selection
The
Discovery
Pathways
biomarkers
cells are enriched for cancer stem cells
Previously we identified a mouse monoclonal
antibody (mAb), specifically staining the basal cells
in normal mucosa and well-differentiated tumors.
This mAb might be a more suitable tool to enrich and
study stem cells in mouse models, and evaluate the
relevance of these cells in clinical specimen.
Problem is that it can only detect immunoprecipitated
antigen.
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Tumors are organized as normal tissues with cells,
also called stem cells, that fuel the tissue and give
rise to all cell lineages in the tissue. Mucosal stem
cells are assumed to reside in the basal layer.
Likewise, cancer stem cells (CSCs) are the fuelling
source of the tumor, are generally treatment
resistant, assumed to be located in the basal cells of
well-differentiated tumors, and the cause of tumor
relapses. In order to study the presence and
molecular characteristics of (cancer) stem cells,
markers are required. CD44 has been suggested as
CSC marker, but it is expressed by many cells in the
tumor and on the normal mucosa as was also
demonstrated in imaging studies within AirForce.
PARTNERSHIP
100,000 HPV+ve HNSCC patients per year overtreated
Younger patients and the incidence is rising
Expected impact of the products
Scientific:
CD98 immunostaining can be implemented for the
selection of patients who are candidate for deescalation therapies.
Societal:
Despite a favorable prognosis, patients with HPVpositive head and neck tumors are still treated with
high toxicity regimen.
Leading Company
Further development by VUmc
Future outlook:
Economic:
Suitable test for selection of patients with HPV-positive
tumors in treatment de-escalation trials
Reduction of toxicity by de-escalation of therapy will
reduce health care costs.
Epigenetic predictive biomarkers in lung cancer and head and neck
cancer
19
Discovery
Identification
Pathways
Verification
biomarkers
The Differential Methylated (DM) markers between
N0 and N+ samples as well as between in vitro
radiosensitive (RS) and radioresistent (RR) cell lines
were ranked by decreasing likelihood of DM.
This analysis resulted in a genelist of which some
have been associated with cancer development
previously (ARHGEF4, TBC1D15, TAL1, WISP1,
EMX2, KCNIP1, CNRIP1, SOBP, CCT6A, GPD2,
PAX7 and GAS7).
Leading Company: MDxHealth
Market
introduction
Progress within CTMM
2008
MethylCap_Seq is a new high resolution technology
to uncover DNA-methylation in a truly genome-wide
manner. The approach is based on the identification
of DNA CpG methylation by capturing DNA
fragments with proteins containing methyl binding
domains followed by next-generation nucleotide
sequence analysis on the Illumina GA II platform
(pair-end tag). Using this approach, we obtained the
unique global methylation status of a series of 12
head&neck carcinomas and 6 head&neck cancer
cell lines.
Validation
Clinical
Evaluation
cohorts
TOWARDS PATIENTS
2013
Main results in CTMM:
For the technical validation of the MethylCap-Seq
approach, we designed and performed MSPs for
ARHGEF4, KCNIP1, GPD2, CTPS, TMEM117,
SGPL1, NFE2L1, ZDBF2, GAS7 and DLGAP4. MSP
analysis of NFE2L1, ZDBF2, GAS7 and DLGAP4
revealed that only methylation of GAS7 showed an
association with N-status in a small series of N+
(n=20) and N0 OSCC FFPE tissues (n=20) (p=0,10).
GAS7 (for growth arrest-specific protein 7) was
previously shown to be epigenetically silenced in
cancer. Based on refined filtering we selected 6
additional genes that showed a marked difference in
the mean methylation status between the N0 and N+
group for validation by BSP-pyrosequencing and
QMSP (NR2E1, GPR135, EDNRB, FAM90A24P,
KIF1A and VOPP1).
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Epigenetics is the study of changes in gene
expression or cellular phenotype, caused by
mechanisms other than changes in the underlying
DNA sequence, hence the name epigenetics. Most
of these changes are heritable. In many diseases,
abnormalities in gene expression have been linked
to aberrant levels of DNA methylation (epimutations).
TRANSLATIONAL PIPELINE
rapy selection
The
RATIONALE
Expected impact of the products
Scientific: Biomarkers play a critical role in improving
the drug development process as well as in the larger
biomedical research enterprise. Understanding the
relationship between measurable biological processes
and clinical outcomes is vital to expanding our arsenal
of treatments for all diseases, and for deepening our
understanding of normal, healthy physiology.
Societal: Better biomarkers will prevent under- and
overtreatment.
Future outlook:
Test independent cohort to establish clinical utility
Economic: Predictive biomarkers will be used for
more efficient drug development and for tailoring of
therapy, ultimately resulting in improved costeffectiveness of care.
Mitochondrial DNA variation as a marker for stratification
of lung cancer patients
20
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2012
2013
Main results in CTMM:
Validation of the predictive value of our proprietary
mtDNA analysis for radiation induced lung toxicity.
In collaboration with Ghent University Hospital, the
proprietary mtDNA analysis was finetuned and
validated. Datasets of 321 lung cancer patients
treated at Maastro Clinic and 66 lung cancer patients
treated at Ghent were available. We considered as
an endpoint grade of maximal dyspnea >= 2 within 06 months after radiotherapy, irrespective of the
baseline dyspnea (at the start of radiotherapy). All
positions in the mtDNA were analyzed, and the
positions with a variant vis-à-vis a reference
sequence were noted. Variants were grouped into
functional categories which were feeded into the
prediction algorithm. The performance of our model
was significantly better than the gold standard, mean
lung dose.
rapy selection
The
Discovery
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
AirForce aims to identify and validate prognostic and
predictive non-imaging biomarkers. Radiationinduced lung toxicity (RILT) is dose-limiting for
radiotherapy of lung cancer and the current
prediction parameters in use are only moderately
associated with RILT. A contribution of genetic
parameters possibly associated with RILT has been
postulated. Maastro Innovations have shown in
preliminary results that variants in mitochondrial
DNA (mtDNA) are associated with patient related
variability in lung toxicity after radiation. In other
words mtDNA can be used as predictive biomarkers
of lung toxicity.
PARTNERSHIP
Number of LC patients per year: 1.8 million
Total healthcare cost per year: $US 25-40 billion
Expected impact of the products
Scientific: Stratifying patients according to their
risk level for radiation-induced toxicity and
selecting radiation treatment accordingly would
provide a promising tool for individualised
radiotherapy.
Societal: Identifying the patients at low or high
toxicity risk will prevent under- and overtreatment.
Leading Company
Maastro Innovations / ptTheragnostic
Future outlook:
A collaboration with several international research groups
will result in a second external validation cohort for lung
toxicity and the testing of the same approach for prostate,
breast and head and neck radiotherapy.
Economic: Treating patients with the optimal dose
will result in improved cost-effectiveness of care.
Druggable targets: targeted therapy of HNSCC and NSCLC
21
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
-
We found 362 siRNAs that are lethal for both lung
and head and neck cancer cells
-
Over 80% have been validated in multiple tumor
cell lines and not in normal cells
-
We found 344 siRNAs that sensitize lung cancer
cells for irradiation and 104 siRNAs that sensitize
head and neck cancer cell lines to cisplatin
-
As proof of principle we tested the drug ispinesib
targeting KIF11
rapy selection
The
Discovery
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
The 5-years survival of head and neck cancer
patients is 50% and of lung cancer patients a mere
10-20%, despite intensive treatment protocols.
These treatments cause toxicity and morbidity,
increasing heath care costs and suffering. Improved
treatment regimens that are preferably less toxic are
urgently awaited. We performed genome-wide
siRNA screens to identify druggable gene targets to
improve treatment of lung and head and neck
cancer.
PARTNERSHIP
Millions of cancer patients are treated by toxic
regimens, and there are many less toxic alternatives
Expected impact of the products
Scientific:
Many new drug targets identified for further
research.
Leading Company
Societal:
Further development by VUmc
Improvement of therapy by targeted agents is
urgently awaited to increase the survival rates of
these diseases with grim prognosis
Economic:
Future outlook:
There is a wealth of opportunity to improve
therapy by targeting the druggable genes that
were identified.
The treatment of cancer is costly and not very
effective causing a large burden on health care.
PET tracers to guide high-precision chemoradiation
22
PRODUCT
PARTNERSHIP
Airforce aims to develop imaging tools for highprecision treatment of lung- and head and neck
cancer
patients
with
radiotherapy
and/or
chemotherapy. Tracers for Positron Emission
Tomography (PET) are key for this purpose as they
can (1) delineate tumors or resistant tumor areas
accurately, (2) guide selective targeting of the
disease, and (3) monitor at an early stage whether
treatment is effective.
PATIENTS
Progress obtained in translational pipeline
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
•
Development PET radionuclides and tracers
PET radionuclides are produced by cyclotron
technology. By using dedicated labeling methods the
radionuclides are inertly coupled to diagnostic or
therapeutic agents that target tumors selectively to
form so-called “PET tracers”. Next to PET
radionuclides also fluorescent dyes can be coupled
to allow optical imaging. Tracers were developed to
image tumor metabolism, proliferation, angiogenesis
and hypoxia and to image so-called targeted drugs
like monoclonal antibodies and tyrosine kinase
inhibitors in the human body.
•
PET radionuclide and tracer production:
Production of the long-lived PET radionuclides
zirconium-89 and iodine-124 was established for
worldwide distribution. Among others, a series of
hypoxia tracers was developed. Reagents and
standard protocols were made worldwide
available for Good Manufacturing Practicecompliant labeling of antibodies (immuno-PET,
photoimmuno-detection) and TKIs (TKI-PET).
Tracer validation: in collaboration with many large
international pharma companies the value of
aforementioned PET tracers was assessed .
Imaging tools as developed within AirForce were
implemented in two new initiatives aiming for
more efficient drug development and application:
The Dutch Imaging Hub and the European
Infrastructure
for
Translational
Medicine
(EATRIS).
Future outlook:
Leading Company: Cyclotron BV
(worldwide) distribution of PET radionuclides and
tracers of
value for drug development and image-guided
rapy selection
The
Selection
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Discovery
Pathways
biomarkers
Number of LC and HNC patients per year: 1.8 and 0.56 million
Total healthcare cost per year: $US 25-40 billion
Expected impact of the products
Scientific: PET studies with new tracers will allow
more precise detection and biological
characterisation of tumors, beter understanding of
drugs, more precise targeting of therapy, and earlier
assessment whether therapy is effective.
Societal: High precision quantitative PET imaging
will prevent under- and overtreatment.
Economic: Tracers will be used for more efficient
drug development and for tailoring of therapy,
ultimately resulting in improved cost-effectiveness of
care.
PET-CT software tools for high precision chemoradiation:
Motion compensation
23
PRODUCT
The motion compensation tool has been
integrated into the Imalytics, Philips’ research
workstation (see below).
Figure 1. Screenshot of the motion compensation tool within the
Imalytics framework.
Progress obtained in translational pipeline
Discovery
Pathways
biomarkers
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
We have tested the product on phantom data, and
investigated the effects of motion compensation in
terms of detected tumour volume and local uptake
concentrations for lung and liver data. Furthermore
we have investigated how the use of 4D PET/CT
improves attenuation correction, in comparison to 3D
data.
For both lung and liver
tumours, motion
compensation led to an
increase in tracer
concentration (up to
25%) and a decrease in
tumour volume
(extremes up to 50%).
Furthermore we found
Figure 2. Phantom respiration
that ungated attenuation
effects for different sphere sizes.
correction can introduce
Static, moving (2cm amplitude)
tracer uptake errors of
and motion compensated PET
data are shown.
up to 25%.
Future outlook:
Investigation of effects of motion compensation
on radiotherapy plans
rapy selection
The
We have developed a motion compensation
method for 4D PET/CT data. It constructs a
motion model from the 4D CT data, which is
used to deform the 4D PET data, after which
the frames of the 4D PET are summed
together.
PATIENTS
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Motion and deformation of the target during
imaging is a limiting factor for quantification of
PET data. Therefore, methods are required for
motion correction of PET images using
information about motion (deformation) within
the patient during PET scanning.
PARTNERSHIP
Expected impact of the products
Scientific:
Motion compensation will make PET imaging more
quantitative, which improves reproducibility of
results in scientific studies.
Societal:
Motion compensation will lead to better visibility of
tumours, and thereby improves the diagnostic value
of the modality. Target volumes for radiotherapy will
be smaller and need smaller margins.
Economic:
The product will improve image quality without
increasing tracer dose or scan duration.
PET-CT software tools for high precision chemoradiation:
Pharmacokinetic modeling and data analysis
24
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
Pharmacokinetic modeling tools implemented and
adapted for tracers developed within the Airforce
project.
Leading Company: Philips Research
Screening
prevention
Patient
stratification
Early
diagnosis
Assessment of optimal data analysis strategies, i.e.
quantitative measures and kinetic analysis methods
for tracers developed within the AirForce project
Expected impact of the products
Implementation and optimization of PET based tumor
delineation methods for deriving quantitative tracer
uptake measures from PET/CT studies
Scientific:
Advanced pharmacokinetic modeling implemented in a
worldwide available research software platform
Societal:
Patients profit from more precise diagnostic, treatment
and monitoring procedures based on advanced
pharmacokinetic modeling
In order to obtain quantitative parameters from those
images, we have used Voxulus, he Pharmacokinetic
modeling tool of Imalytics, Philips research
workstation.
Voxulus performs an efficient voxel-wise estimation,
while allowing complete control over the model
parameters as well as a flexible combination of
models for the input and target. functions
Treatment
& monitoring
tic innovat
gnos
ion
Dia
Discovery
Pathways
biomarkers
rapy selection
The
Pharmacokinetic modeling is a technique to
describe the absorption, distribution, metabolism and
excretion of a drug based on dynamic medical
imaging data.
PARTNERSHIP
Future outlook:
Use of voxulus toolbox for PET pharmacokinetic
analysis and quantification of (new) tracers in vivo
Economic:
Knowing and understanding the exact distribution and
retention of the agent inside the body helps for
personalized usage of drugs
PET-CT software tools for high precision chemoradiation:
Partial volume correction
25
PRODUCT
PARTNERSHIP
Due to the limited resolution of a given imaging
system, the apparent activity in small objects or
regions (partial volume) can be underestimated.
Progress obtained in translational pipeline
•
Recovery-Coefficients-Method
•
Geometric-Transfer-Matrix-Method
•
Lucy-Richardson-Deconvolution
•
Blind-Deconvolution
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
Within Airforce the performance of several commonly
used and new PET based tumor delineation and PVC
methods were developed, implemented and
evaluated. Delineation methods included were
absolute and relative (%) isocontour based on
SUVmax or SUVpeak both with and without local
contrast corrections. Moreover, iterative and gradient
based methods were evaluated as well. Evaluations
were based on mathematical phantoms and clinical
data and a comparison was made with pathology
derived tumor sizes.
This research has shown that an automated PET
delineation method based on 50% isocontour of
SUVpeak corrected for local contrast showed best
test-retest performance and correlated well with
pathology derived tumor sizes. Moreover, use of PVC
results in more accurate quantification of radiotracer
uptake.
.
Future outlook:
Leading Company: Philips Research
Metrics to characterize and quantify tracer uptake
distributions and heterogeneity have become available
and will be further explored and more metrics will be
implemented
rapy selection
The
Selection
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Discovery
Pathways
biomarkers
Therefore, in order to compensate this effect, it is
necessary to apply the so called Partial Volume
Correction, a series of techniques that modifies the
volume-of-interest statistics to ensure a proper
quantification, which takes into consideration spillovers and spill-ins between regions.
In this project we worked with Imalytics, Philips’
research workstation, which offers four different
algorithms for the correction of the Partial Volume
Effect:
PATIENTS
Expected impact of the products
Scientific:
Achieved results on correction for partial volume
effect allow careful selection of the correction
methods for different applications
Societal:
Images corrected for partial volume effect and
analysed using optimal tumor delineation methods
can provide higher diagnostic value because of
enhanced (more accurate and more precise) image
quantification
Economic:
Implementation of PVC may allow to increase
diagnostic quality and therefore be more cost
effective
Radiomic analysis as tool for treatment planning of both lung
and head and neck cancer
26
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
Figure 1: Phenotypic differences as seen on CT images.
Advances in both acquisition and analysis methods
of medical imaging technologies, allow for the
extraction of reliable and informative image features
to quantify these differences. This is an emerging
field and many of these phenotypic characteristics
are not routinely quantified or yet used in clinical
decision-making. Radiomics addresses this issue by
converting medical images into minable data with the
high-throughput application of data-characterization
algorithms (figure 2).
Intensity
Shape
Texture
A radiomic signature for NSCLC and HNSCC:
A total of 440 radiomic features, quantifying
phenotypic differences based on tumor image
intensity, shape and texture, were extracted from
computed-tomography (CT) images of 1019 patients
with lung or head and neck cancer and analyzed for
their association with overall survival. A large number
of radiomic-features were found to have strong
prognostic power.
A
radiomic-signature
capturing
intra-tumor
heterogeneity,
was
strongly
prognostic
in
independent validation datasets of lung and head and
neck cancer patients, and associated with underlying
gene-expression patterns. These results suggest that
radiomic-features decode a prognostic phenotype
existing in both lung and head and neck cancer,
which may generalize to other tumors.
rapy selection
The
Discovery
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
AIRFORCE aims to devolop image analysis tools to
identify and validate prognostic and predictive
imaging biomarkers. Human oncologic tissues
exhibit strong phenotypic differences, such as intratumour heterogeneity or an irregular shape (figure
1).
PARTNERSHIP
Number of LC and HNC patients per year: 1.8 and 0.56 million
Total healthcare cost per year: $US 25-40 billion
Expected impact of the products
Scientific: Imaging is routinely used in clinical
practice, worldwide, in all stages of diagnoses and
treatment, Radiomics will allow for more precise
tumor characterization and better early assessment
of treatment effect.
Societal: Radiomics may aid to prevent under- and
overtreatment
Figure 2: Radiomics workflow. The tumor is segmented,
followed by extraction of imaging features and analysis.
Leading Company
ptTheragnostic / Maastro Innovations
Future outlook:
the results should stimulate further research of
image-based quantitative features and be applied
to other image modalities (e.g. PET, MR).
Economic: Radiomics provides an unprecedented
opportunity to improve medical decision-support,
which may in turn result in an overall improved costeffectiveness of care.
www.predictcancer.org: A prediction tool for treatment planning of both
lung and head and neck cancer
27
PRODUCT
Progress obtained in translational pipeline
Discovery
Pathways
biomarkers
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
The website (www.predictcancer.org) was
launched in May 2010 and contains models for
outcome prediction for NSCLC patients
(dyspnea, dysphagia and survival), and Head
and Neck cancer (overall survival, local
recurrence and cost effectiveness of proton
versus photon treatment). For each model
extensive information is given as well as an
interpretation of the model output.
rapy selection
The
Therefore, the aim of this (sub)project was to
develop a website on which the prognostic and
predictive models are published, results of AirForce
can be disseminated, and the use of the models can
be stimulated (See Figure).
PATIENTS
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Although many clinical prediction models have
been developed, validated and published, they are
seldom used in daily clinical practice. To stimulate
this, models should be easy to understand and to
use. Moreover, clinicians should have easy access
to the models.
PARTNERSHIP
Expected impact
Scientific:
The website facilitates dissemination of the results
of our project. It stimulates use and implementation
of the models in daily clinical practice.
Societal:
Clinicians and patients are provided with additional
prognostic information. This also facilitates the
shared decision making process.
Future outlook:
Leading Company
Further development by Maastro
Models will be updated and improved with new
predictive andprognostic variables. Models for other
outcomes and other cancers will be added.
Economic:
The use of the models will result in less over- and
undertreatment and thus decrease health care
costs.
Optimized uncertainty based planning system for radiotherapy
28
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
Our studies showed that uncertainty based planning
has potential to reduce dose to organs at risk,
minimizing the overlap area between the irradiated
volume and the surrounding structures. This way also
treatment toxicity can be reduced. We also proved
that when uncertainties are not properly taken into
account in voxel-based prescriptions major
discrepancies can occur between the calculated and
the delivered dose distributions, resulting in serious
target underdosage.
FIG. 1: A head and neck cancer patient planned with standard
technique (left) or probabilistic planning (right).
Probabilistic planning and evaluation provides a tool
to incorporate uncertainties into the treatment
workflow even when margin expansion is not
feasible. Using monte carlo sampling of errors,
potentially allows the most personalized treatment
strategies.
Leading Company: Philips Research
In particular, we realized that voxel-based dose
painting approaches, without accommodations for
geometric uncertainties, suffer from an intrinsic
difficulty in controlling the high peak areas.
rapy selection
The
Discovery
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Radiotherapy treatments need accurate patient
position uncertainties management. Standard
approaches as margin expansion are not always
effective. Prescribing non uniform dose distributions
based on functional or molecular imaging is
becoming increasingly more common. When this
approach is followed, and dose prescription is voxelbased, uncertainties management can become
impossible with standard tools as margin expansion
requires volume-based prescription.
PARTNERSHIP
Number of LC and HNC patients per year: 1.8 and 0.56 million
Total healthcare cost per year: $US 25-40 billion
Expected impact of the products
Scientific: increased awareness of the risks of
underestimating uncertainties when planning with
the advanced strategies described.
Societal: Dose painting strategies allow for more
aggressive therapies on the target, e.g. allowing
dose escalation strategies. This increases treatment
efficacy and therefore patients survival rates.
Future outlook:
This work is being implemented in the Pinnacle
treatment planning system and hopefully will
become a standard planning tool.
Economic: The work performed was implemented
in a plugin for a treatment planning system (Philips
Pinnacle) increasing its clinical value and making it
a more interesting tool for hospitals willing to
approach new advanced planning strategies.
Oncology Research Workstation (ORW) for lung and head and neck
cancer
29
PRODUCT
Progress obtained in translational pipeline
Discovery
Pathways
biomarkers
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2013
Main results in CTMM:
The integration of partner’s algorithms provided
an independent test of these algorithms and
allowed all Airforce partners to use them for their
research projects.
rapy selection
The
- A programming interface for external algorithms
- DICOM-RT support
- Advanced PET segmentation algorithms from the
VU
- Motion compensation from NKI
- Image alignment for response monitoring from
UMCG
- Partial volume correction
- Serial image analysis
PATIENTS
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
The Philips research workstation Imalytics was
used as the basis for the Oncology Research
Workstation (ORW). The workstation operates on
a local DICOM image database and can be
connected to other DICOM network nodes (e.g.
PACS systems or imaging equipment). During the
course of the project the ORW was extended to
include:
PARTNERSHIP
Expected impact of the products
Scientific: Enables PET tracer studies where
advanced image processing, registration and
segmentation algorithms provide a higher accuracy
of the response measurement, allowing earlier
adaptation of non-optimal chemo- or radiotherapy.
Example: image analysis workflow for response
monitoring used at UMCG
Leading Company: Philips Research
Future outlook:
The method of integration of research algorithms
in a commercial image analysis system should be
adopted by other products.
Societal: A timely adaptation of cancer treatment to
replace, e.g., non-effective drugs will lead to better
patient outcome in terms of quality of life, response
and complications
Economic: Selected tools will become part of
Philip’s novel imaging products
Release of ECRF PACS connection as open source software
30
PRODUCT
PATIENTS
Progress obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2013
2008
Main results in CTMM: The connection of an
ECRF and a PACS allows safe, simple and
unambiguous collection of any DICOM data that
is associated with clinical trial patients. This
provides researchers working with clinical trial
data with much more information about
individual treatments, allowing better analysis
and discovery
ofserver
novel –
imaging
Gateway
browsebiomarkers
mode
Outside hospital
DICOM server
Screening
prevention
Patient
stratification
Early
diagnosis
Expected impact of the products
Web server
Web browser
SFTP server
A small button allows linking anonymized PACS data
with case reports for clinical trials – a technique not
available in any trial database system up to now
Treatment
& monitoring
Inside hospital
ECRF server
Web server
rapy selection
The
Discovery
Pathways
biomarkers
tic innovat
gnos
ion
Dia
Many clinical trials use Electronic Case Report
Forms (ECRF), e.g., from OpenClinica. Trial data is
augmented if DICOM scans, dose cubes, etc. from
the Picture Archiving and Communication System
(PACS) are included for data mining. Unfortunately,
there is as yet no structured way to collect DICOM
objects in trial databases. In this paper, we obtain a
tight integration of ECRF and PACS using open
source software. Methods: DICOM identifiers for
selected images/series/studies are stored in
associated ECRF events (e.g., baseline). Our ECRF
centric approach supports automatic data mining by
iterating over the cases in the ECRF database,
providing the identifiers to load images and the
clinical data to correlate with image analysis results.
PARTNERSHIP
DICOM server
PACS
Leading Company:
Future outlook:
Further development by NKI/AvL
We expect that structured collection of DICOM
information in the clinic will become the standard way
of collecting advanced patient information.
Scientific: Rather than collecting image and dose
metrics as variables in a clinical trails, the system
allows collection of the full image data. The
collected data will allow discovery of novel imaging
biomarkers.
Societal: The increased power of clinical trial data
analysis, will allow faster hypothesis generation to
define new trials. As a result, novel improved
treatments will be introduced faster.
.Economic: The system is open-source and is used
in open-source OpenClinica and closed-source
FormsVision
Early HTA: Key Elements and Findings
31
Key findings AIRFORCE
There is a dearth of cost-effectiveness
evaluations of radiotherapy treatment in
non-small cell lung cancer (NSCLC).
Elements of early HTA
Health economic modeling
Cost-effectiveness studies in cancer care are often health-economic evaluations alongside clinical
trials or relatively simple health-economic models in which a homogeneous cohort of patients is
simulated. These models are easy to understand for decision makers, transparent and relatively easy
to build. However, as decision making in health care is becoming increasingly complex, disease
models need to include more detail. With the shift towards individualized therapy, treatments are
increasingly tailored to the specific characteristics of a patient and a tumour. To obtain clinical
predictions that accurately estimate patient outcomes, integration of the clinical, molecular and
imaging information on patient and tumours in is needed. This means that for a proper evaluation of
long-term costs and effects of individualized strategies, cost-effectiveness models need to incorporate
patient and tumour features that may affect treatment decisions, disease progression, survival,
adverse events and quality of life.
Cost-effectiveness analysis
Cost-effectiveness analysis (CEA) involves a comparative analysis of the health and cost
consequences of alternative courses of action. To support decision making, there is an urgent need for
economic evaluations in the area of radiotherapy, comparing new technologies with each other and
with conventional schemes.
On the basis of a model-based costeffectiveness evaluation, we conclude that
positron emission tomography (PET)based isotoxic accelerated radiation
therapy treatment (PET-ART) is likely to be
cost-effective compared to conventional
fixed-dose CT-based radiation therapy
treatment in NSCLC. We found a 36%
probability that PET-ART improves health
outcomes at reduced costs and a 64%
probability that PET-ART is more effective
at slightly higher costs.
Model-based assessment of optimized
sequential and concurrent chemo-radiation
strategies revealed that these more
effective and cost-effective than the current
conventional sequential and concurrent
strategies in NSCLC. Concurrent chemoradiation with a daily low dose cisplatin
regimen is the most cost-effective
treatment option for locally advanced
inoperable NSCLC patients.
Early HTA: Potential Impact of New Technologies
32
Health economic model
We developed a micro-simulation model for
cost-effectiveness analysis of
individualized radiotherapy in lung cancer.
Four clinical states were included in the
model: ‘Alive without progression’, ‘Local
Recurrence’, ‘Metastasis’, and ‘Death’.
Individual patients are simulated by
repeatedly sampling a patient profile,
consisting
of
patient
and
tumour
characteristics. The model tracks clinical
events over time and takes patient and
tumour
features
into
account.
The
transitioning of patients between the health
states is governed by personalized time
dependent hazard rates, which were
obtained by multi-state statistical modelling.
Model outcomes are life years, QALYs, and
costs. The time horizon is life time. A
hospital perspective was taken. Two types
cost-effectiveness evaluations were carried
out using the model.
Cost-effectiveness analysis of positron emission tomography (PET)-based
isotoxic accelerated radiation therapy treatment (PET-ART)
The average incremental costs per patient of PET-ART were €569 for 0.42 incremental
Lys and 0.33 QALYs gained. The base-case scenario resulted in an ICER of €1360/LY
gained and an ICUR of €1744/QALY gained. The probabilistic sensitivity analysis gave a
36% probability that PET-ART improves health outcomes at reduced costs and a 64%
probability that PET-ART is more effective at slightly higher costs. On the basis of the
available data, individualized PET-ART for NSCLC seems to be cost-effective compared
with conventional fixed-dose CT-based radiation therapy .
Cost-effectiveness analysis of optimized sequential and concurrent chemo-radiation
strategies
Four strategies were evaluated: PET-CT based isotoxic accelerated sequential chemoradiation (SRT2) and concurrent chemo-radiation with daily low-dose cisplatin (CRT2) to
standard sequential (SRT1) and concurrent chemo-radiation (CRT1). Compared to the
reference strategy (SRT1), the ICER was €38024/QALY for CRT1, €6249/QALY for SRT2,
and €346/QALY for CRT2. CRT2 was highly cost-effective compared to SRT1. Moreover,
CRT2 was more effective and less costly than CRT1 and SRT2. Based on our model,
optimized sequential and concurrent chemo-radiation strategies are more effective and costeffective than the current conventional sequential and concurrent strategies.
Model structure
Partners
33
Maastricht University Medical Center (MUMC+)
Maastricht
Netherlands Cancer Institute (NKI)
Amsterdam
University Medical Center Groningen (UMCG)
Groningen
VU University Medical Center (Vumc)
Amsterdam
Agendia BV
Amsterdam
BG Medicine Inc.
Waltham (US)
BV Cyclotron VU
Amsterdam
DSM Research BV
Sittard
Genmab A-S
Kopenhagen (DK)
Maastro Innovations BV
Maastricht
MDxHealth
Herstal (BE)
Mubio BV
Maastricht
Royal Philips
Eindhoven
List of Publications
34
1. Bongers ML, De Ruysscher D, Oberije C, Lambin P, Uyl-de Groot CA, Coupé VM. Multistate Statistical Modeling: A Tool to Build a Lung Cancer Microsimulation Model That Includes
Parameter Uncertainty and Patient Heterogeneity. Med Decis Making. 2015 Mar 2. pii: 0272989X15574500
2. Fontanarosa D, Witte M, Meijer G, Shakirin G, Steenhuijsen J, Schuring D, van Herk M, Lambin P. Probabilistic evaluation of target dose deterioration in dose painting by numbers for
stage II/III lung cancer. Pract Radiat Oncol. 2015 Jul-Aug;5(4):e375-82
3. Nagel R, Stigter-van Walsum M, Buijze M, van den Berg J, van der Meulen IH, Hodzic J, Piersma SR, Pham TV, Jiménez CR, van Beusechem VW, Brakenhoff RH. Genome-wide siRNA
Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC. Mol Cancer Ther. 2015 Jun;14(6):1434-44
4. Oberije C, De Ruysscher D, Houben R, van de Heuvel M, Uyterlinde W, Deasy JO, Belderbos J, Dingemans AM, Rimner A, Din S, Lambin P A Validated Prediction Model for Overall
Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.Int J Radiat Oncol Biol Phys. 2015 Jul 15;92(4):935-44
5. Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, Cavalho S, Bussink J, Monshouwer R, Haibe-Kains B, Rietveld D, Hoebers F, Rietbergen MM, Leemans CR, Dekker A,
Quackenbush J, Gillies RJ, Lambin P. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun. 2014 Jun 3;5:4006
6. Bahce I, Huisman MC, Verwer EE, Ooijevaar R, Boutkourt F, Vugts DJ, van Dongen GA, Boellaard R, Smit EF. Pilot study of (89)Zr-bevacizumab positron emission tomography in patients
with advanced non-small cell lung cancer. EJNMMI Res. 2014 Dec;4(1):35
7. Bollineni VR, Koole MJ, Pruim J, Brouwer CL, Wiegman EM, Groen HJ, Vlasman R, Halmos GB, Oosting SF, Langendijk JA, Widder J, Steenbakkers RJ. Dynamics of tumor hypoxia
assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: possible implications for radiotherapy treatment planning strategies. Radiother Oncol.
2014 Nov;113(2):198-203
8. Dekker A, Vinod S, Holloway L, Oberije C, George A, Goozee G, Delaney GP, Lambin P, Thwaites D. Rapid learning in practice: A lung cancer survival decision support system in routine
patient care data. Radiother Oncol. 2014 Sep 18. pii: S0167-8140(14)00343-0
9. Oberije C, Nalbantov G, Dekker A, Boersma L, Borger J, Reymen B, van Baardwijk A, Wanders R, De Ruysscher D, Steyerberg E, Dingemans AM, Lambin PA prospective study
comparing the predictions of doctors versus models for treatment outcome of lung cancer patients: a step toward individualized care and shared decision making. Radiother Oncol. 2014
Jul;112(1):37-43
10.Peeters SG, Zegers CM, Lieuwes NG, Van Elmpt W, Eriksson J, Van Dongen GAMS, Dubois L, Lambin P. A comparative study of the hypoxia tracers [18F]HX4, [18F]FAZA, and
[18F]FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys 91, 2014 351-359
11.Rios Velazquez E, Hoebers F, Aerts HJ, Rietbergen MM, Brakenhoff RH, Leemans RC, Speel EJ, Straetmans J, Kremer B, Lambin P. Externally validated HPV-based prognostic
nomogram for oropharyngeal carcinoma patients yields more accurate predictions than TNM staging. Radiother Oncol. 2014 Dec;113(3):324-30
12.Roelofs E, Dekker A, Meldolesi E, van Stiphout RG, Valentini V, Lambin P. International data-sharing for radiotherapy research: an open-source based infrastructure for multicentric clinical
data mining. Radiother Oncol. 2014 Feb;110(2):370-4
13.Spijkerman J, Fontanarosa D, Das M, Van Elmpt W. Validation of nonrigid registration in pretreatment and follow-up PET/CT scans for quantification of tumor residue in lung cancer
patients. J Appl Clin Med Phys. 2014 Jul 8;15(4):4847
14.van Velden FH, Nissen IA, Hayes W, Velasquez LM, Hoekstra OS, Boellaard R. Effects of reusing baseline volumes of interest by applying (non-)rigid image registration on positron
emission tomography response assessments. PLoS One. 2014 Jan 28;9(1):e87167
15.van Velden FH, Nissen IA, Jongsma F, Velasquez LM, Hayes W, Lammertsma AA, Hoekstra OS, Boellaard R. Test-retest variability of various quantitative measures to characterize tracer
uptake and/or tracer uptake heterogeneity in metastasized liver for patients with colorectal carcinoma. Mol Imaging Biol. 2014 Feb;16(1):13-8
16.Bahce I, Smit EF, Lubberink M, van der Veldt AA, Yaqub M, Windhorst AD, Schuit RC, Thunnissen E, Heideman DA, Postmus PE, Lammertsma AA, Hendrikse NH. Development of
[(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res. 2013 Jan 1;19(1):183-93
17.Bollineni VR1, Kerner GS, Pruim J, Steenbakkers RJ, Wiegman EM, Koole MJ, de Groot EH, Willemsen AT, Luurtsema G, Widder J, Groen HJ, Langendijk JA. PET imaging of tumor
hypoxia using 18F-fluoroazomycin arabinoside in stage III-IV non-small cell lung cancer patients. J Nucl Med. 2013 Aug;54(8):1175-80
18.Brakenhoff RH. Potentially novel options for treatment of HPV-attributable head and neck cancer. Cell Cycle. 2013 Apr 1;12(7):1020-1
List of Publications
35
19.Carvalho S, Leijenaar RT, Velazquez ER, Oberije C, Parmar C, van Elmpt W, Reymen B, Troost EG, Oellers M, Dekker A, Gillies R, Aerts HJ, Lambin P. Prognostic value of metabolic
metrics extracted from baseline positron emission tomography images in non-small cell lung cancer. Acta Oncol. 2013 Oct;52(7):1398-404
20.Chen C, Uyterlinde W, Sonke JJ, de Bois J, van den Heuvel M, Belderbos J. Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy. Radiother
Oncol. 2013 Aug;108(2):337-41
21.Cohen R, Vugts DJ, Stigter-van Walsum M, Visser GW, van Dongen GA. Inert coupling of IRDye800CW and zirconium-89 to monoclonal antibodies for single- or dual-mode fluorescence
and PET imaging. Nat Protoc. 2013 May;8(5):1010-8
22.Fontanarosa D, van der Laan HP, Witte M, Shakirin G, Roelofs E, Langendijk JA, Lambin P, van Herk M. An in silico comparison between margin-based and probabilistic target-planning
approaches in head and neck cancer patients. Radiother Oncol. 2013 Dec;109(3):430-6
23.Hardcastle N, van Elmpt W, De Ruysscher D, Bzdusek K, Tomé WA. Accuracy of deformable image registration for contour propagation in adaptive lung radiotherapy. Radiat Oncol. 2013
Oct 18;8:243
24.Kerner GS, Schuuring E, Sietsma J, Hiltermann TJ, Pieterman RM, de Leede GP, van Putten JW, Liesker J, Renkema TE, van Hengel P, Platteel I, Timens W, Groen HJ; CTMM Air Force
Consortium. Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome. PLoS One. 2013 Jul 29;8(7):e70346
25.Kruis MF, van de Kamer JB, Houweling AC, Sonke JJ, Belderbos JS, van Herk M. PET motion compensation for radiation therapy using a CT-based mid-position motion model:
methodology and clinical evaluation. Int J Radiat Oncol Biol Phys. 2013 Oct 1;87(2):394-400
26.Kruis MF, van de Kamer JB, Sonke JJ, Jansen EP, van Herk M. Registration accuracy and image quality of time averaged mid-position CT scans for liver SBRT. Radiother Oncol. 2013
Dec;109(3):404-8
27.Lambin P, Roelofs E, Reymen B, Velazquez ER, Buijsen J, Zegers CM, Carvalho S, Leijenaar RT, Nalbantov G, Oberije C, Scott Marshall M, Hoebers F, Troost EG, van Stiphout RG, van
Elmpt W, van der Weijden T, Boersma L, Valentini V, Dekker A. 'Rapid Learning health care in oncology' - an approach towards decision support systems enabling customised
radiotherapy'. Radiother Oncol. 2013 Oct;109(1):159-64
28.Lambin P, van Stiphout RG, Starmans MH, Rios-Velazquez E, Nalbantov G, Aerts HJ, Roelofs E, van Elmpt W, Boutros PC, Granone P, Valentini V, Begg AC, De Ruysscher D, Dekker A.
Predicting outcomes in radiation oncology--multifactorial decision support systems. Nat Rev Clin Oncol. 2013 Jan;10(1):27-40
29.Martens-de Kemp SR, Brink A, Stigter-van Walsum M, Damen JM, Rustenburg F, Wu T, van Wieringen WN, Schuurhuis GJ, Braakhuis BJ, Slijper M, Brakenhoff RH. CD98 marks a
subpopulation of head and neck squamous cell carcinoma cells with stem cell properties. Stem Cell Res. 2013 May;10(3):477-88
30.Martens-de Kemp SR, Dalm SU, Wijnolts FM, Brink A, Honeywell RJ, Peters GJ, Braakhuis BJ, Brakenhoff RH. DNA-bound platinum is the major determinant of cisplatin sensitivity in head
and neck squamous carcinoma cells. PLoS One. 2013 Apr 17;8(4):e61555
31.Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, Brakenhoff RH. Functional genetic screens identify genes essential for
tumor cell survival in head and neck and lung cancer. Clin Cancer Res. 2013 Apr 15;19(8):1994-2003
32.Nagel R, Martens-de Kemp SR, Buijze M, Jacobs G, Braakhuis BJ, Brakenhoff RH. Treatment response of HPV-positive and HPV-negative head and neck squamous cell carcinoma cell
lines. Oral Oncol. 2013 Jun;49(6):560-6
33.Nalbantov G, Kietselaer B, Vandecasteele K, Oberije C, Berbee M, Troost E, Dingemans AM, van Baardwijk A, Smits K, Dekker A, Bussink J, De Ruysscher D, Lievens Y, Lambin P.
Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients. Radiother Oncol. 2013 Oct;109(1):100-6
34.Poot AJ, Slobbe P, Hendrikse NH, Windhorst AD, van Dongen GA. Imaging of TKI-target interactions for personalized cancer therapy. Clin Pharmacol Ther. 2013 Mar;93(3):239-41
35.Poot AJ, van der Wildt B, Stigter-van Walsum M, Rongen M, Schuit RC, Hendrikse NH, Eriksson J, van Dongen GA, Windhorst AD. [¹¹C]Sorafenib: radiosynthesis and preclinical evaluation
in tumor-bearing mice of a new TKI-PET tracer. Nucl Med Biol. 2013 May;40(4):488-97
36.van Elmpt W, Das M, Hüllner M, Sharifi H, Zegers CM, Reymen B, Lambin P, Wildberger JE, Troost EG, Veit-Haibach P, De Ruysscher D. Characterization of tumor heterogeneity using
dynamic contrast enhanced CT and FDG-PET in non-small cell lung cancer. Radiother Oncol. 2013 Oct;109(1):65-70.
37.van Velden FH, Boellaard R. Reply to: Area under the cumulative SUV-volume histogram is not a viable metric of intratumoral metabolic heterogeneity. Eur J Nucl Med Mol Imaging. 2013
Sep;40(9):1469-70
List of Publications
36
38.Velazquez ER, Parmar C, Jermoumi M, Mak RH, van Baardwijk A, Fennessy FM, Lewis JH, De Ruysscher D, Kikinis R, Lambin P, Aerts HJ. Volumetric CT-based segmentation of NSCLC
using 3D-Slicer. Sci Rep. 2013 Dec 18;3:3529
39.Verwer EE, van Velden FH, Bahce I, Yaqub M, Schuit RC, Windhorst AD, Raijmakers P, Lammertsma AA, Smit EF, Boellaard R. Pharmacokinetic analysis of [18F]FAZA in non-small cell
lung cancer patients. Eur J Nucl Med Mol Imaging. 2013 Oct;40(10):1523-31
40.Vugts DJ, Visser GW, van Dongen GA. 89Zr-PET radiochemistry in the development and application of therapeutic monoclonal antibodies and other biologicals. Curr Top Med Chem.
2013;13(4):446-57
41.Zegers CM, van Elmpt W, Wierts R, Reymen B, Sharifi H, Öllers MC, Hoebers F, Troost EG, Wanders R, van Baardwijk A, Brans B, Eriksson J, Windhorst B, Mottaghy FM, De Ruysscher
D, Lambin P. Hypoxia imaging with [¹⁸F]HX4 PET in NSCLC patients: defining optimal imaging parameters. Radiother Oncol. 2013 Oct;109(1):58-64
42.Bongers ML, Coupé VM, Jansma EP, Smit EF, Uyl-de Groot CA. Cost effectiveness of treatment with new agents in advanced non-small-cell lung cancer: a systematic review.
Pharmacoeconomics. 2012 Jan;30(1):17-34
43.Cheebsumon P, Boellaard R, de Ruysscher D, van Elmpt W, van Baardwijk A, Yaqub M, Hoekstra OS, Comans EF, Lammertsma AA, van Velden FH. Assessment of tumour size in
PET/CT lung cancer studies: PET- and CT-based methods compared to pathology. EJNMMI Res. 2012 Oct 3;2(1):56
44.Cheebsumon P, Boellaard R, de Ruysscher D, van Elmpt W, van Baardwijk A, Yaqub M, Hoekstra OS, Comans EF, Lammertsma AA, van Velden FH. Assessment of tumour size in
PET/CT lung cancer studies: PET- and CT-based methods compared to pathology. EJNMMI Res. 2012 Oct 3;2(1):56
45.De Ruysscher D, van Elmpt W, Wanders R, van Baardwijk A, Dingemans C, Reymen B, Bootsma G, Lambin P, Sonke J, Belderbos J. Acute Toxicity of full-dose cisplatin-etoposide
concurrently with high-dose hypofractionated chest radiotherapy for stage III non-small cell lung cancer: subset analysis of non-randomised patients in the pet-boost phase II trial. Ann
Oncol. vol 23, sept 2012.
46.Kwint M, Uyterlinde W, Nijkamp J, Chen C, de Bois J, Sonke JJ, van den Heuvel M, Knegjens J, van Herk M, Belderbos J. Acute esophagus toxicity in lung cancer patients after intensity
modulated radiation therapy and concurrent chemotherapy. Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):e223-8.
47.Slobbe P, Poot AJ, Windhorst AD, van Dongen GA. PET imaging with small-molecule tyrosine kinase inhibitors: TKI-PET. Drug Discov Today. 2012 Nov;17(21-22):1175-87
48.Starmans MH, Chu KC, Haider S, Nguyen F, Seigneuric R, Magagnin MG, Koritzinsky M, Kasprzyk A, Boutros PC, Wouters BG, Lambin P. The prognostic value of temporal in vitro and in
vivo derived hypoxia gene-expression signatures in breast cancer. Radiother Oncol. 2012 Mar;102(3):436-43
49.van Elmpt W, De Ruysscher D, van der Salm A, Lakeman A, van der Stoep J, Emans D, Damen E, Öllers M, Sonke JJ, Belderbos J. The PET-boost randomised phase II dose-escalation
trial in non-small cell lung cancer. Radiother Oncol. 2012 Jul;104(1):67-71
50.van Elmpt W, De Ruysscher D, van der Salm A, Lakeman A, van der Stoep J, Emans D, Damen E, Öllers M, Sonke JJ, Belderbos J. The PET-boost randomised phase II dose-escalation
trial in non-small cell lung cancer. Radiother Oncol. 2012 Jul;104(1):67-71
51.van Elmpt W, Ollers M, Dingemans AM, Lambin P, De Ruysscher D. Response assessment using 18F-FDG PET early in the course of radiotherapy correlates with survival in advancedstage non-small cell lung cancer. J Nucl Med. 2012 Oct;53(10):1514-20
52.van Elmpt W, Öllers M, Lambin P, De Ruysscher D. Should patient setup in lung cancer be based on the primary tumor? An analysis of tumor coverage and normal tissue dose using
repeated positron emission tomography/computed tomography imaging. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):379-85
53.van Velden FH, van Beers P, Nuyts J, Velasquez LM, Hayes W, Lammertsma AA, Boellaard R, Loeckx D. Effects of rigid and non-rigid image registration on test-retest variability of
quantitative [18F]FDG PET/CT studies. EJNMMI Res. 2012 Mar 10;2(1):10
54.Voets AM, Oberije C, Struijk RB, Reymen B, De Ruyck K, Thierens H, Vandecasteele K, De Neve W, Houben R, De Ruysscher D, Smeets HJ, Lambin P. No association between TGF-β1
polymorphisms and radiation-induced lung toxicity in a European cohort of lung cancer patients. Radiother Oncol. 2012 Dec;105(3):296-8
55.Cheebsumon P, van Velden FH, Yaqub M, Frings V, de Langen AJ, Hoekstra OS, Lammertsma AA, Boellaard R. Effects of image characteristics on performance of tumor delineation
methods: a test-retest assessment. J Nucl Med. 2011 Oct;52(10):1550-8
56.Cheebsumon P, van Velden FH, Yaqub M, Hoekstra CJ, Velasquez LM, Hayes W, Hoekstra OS, Lammertsma AA, Boellaard R. Measurement of metabolic tumor volume: static versus
dynamic FDG scans. EJNMMI Res. 2011 Dec 14;1:35
List of Publications
37
57.Cheebsumon P, Yaqub M, van Velden FH, Hoekstra OS, Lammertsma AA, Boellaard R. Impact of [¹⁸F]FDG PET imaging parameters on automatic tumour delineation: need for improved
tumour delineation methodology. Eur J Nucl Med Mol Imaging. 2011 Dec;38(12):2136-44.
58.Dehing-Oberije C, Aerts H, Yu S, De Ruysscher D, Menheere P, Hilvo M, van der Weide H, Rao B, Lambin P. Development and validation of a prognostic model using blood biomarker
information for prediction of survival of non-small-cell lung cancer patients treated with combined chemotherapy and radiation or radiotherapy alone (NCT00181519, NCT00573040, and
NCT00572325). Int J Radiat Oncol Biol Phys. 2011 Oct 1;81(2):360-8
59.Dubois L, Lieuwes NG, Janssen MH, Peeters WJ, Windhorst AD, Walsh JC, Kolb HC, Ollers MC, Bussink J, van Dongen GA, van der Kogel A, Lambin P. (2011)Preclinical evaluation and
validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci U S A. Aug 30;108(35):14620-5.
60.Egelmeer AG, Velazquez ER, de Jong JM, Oberije C, Geussens Y, Nuyts S, Kremer B, Rietveld D, Leemans CR, de Jong MC, Rasch C, Hoebers F, Homer J, Slevin N, West C, Lambin P.
Development and validation of a nomogram for prediction of survival and local control in laryngeal carcinoma patients treated with radiotherapy alone: a cohort study based on 994
patients. Radiother Oncol. 2011 Jul;100(1):108-15
61.Heuveling DA, de Bree R, van Dongen GA. The potential role of non-FDG-PET in the management of head and neck cancer. Oral Oncol. 2011 Jan;47(1):2-7
62.Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011 Jan;11(1):9-22
63.Petit SF, van Elmpt WJ, Oberije CJ, Vegt E, Dingemans AM, Lambin P, Dekker AL, De Ruysscher D. [¹⁸F]fluorodeoxyglucose uptake patterns in lung before radiotherapy identify areas
more susceptible to radiation-induced lung toxicity in non-small-cell lung cancer patients. Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):698-705
64.Starmans MH, Fung G, Steck H, Wouters BG, Lambin P A simple but highly effective approach to evaluate the prognostic performance of gene expression signatures. PLoS One.
2011;6(12):e28320
65.van Elmpt W, Ollers M, van Herwijnen H, den Holder L, Vercoulen L, Wouters M, Lambin P, De Ruysscher D. Volume or position changes of primary lung tumor during (chemo)radiotherapy cannot be used as a surrogate for mediastinal lymph node changes: the case for optimal mediastinal lymph node imaging during radiotherapy. Int J Radiat Oncol Biol Phys.
2011 Jan 1;79(1):89-95
66.Van Elmpt W, Pöttgen C, De Ruysscher D. Therapy response assessment in radiotherapy of lung cancer. Q J Nucl Med Mol Imaging. 2011 Dec;55(6):648-54
67.van Velden FH, Cheebsumon P, Yaqub M, Smit EF, Hoekstra OS, Lammertsma AA, Boellaard R. Evaluation of a cumulative SUV-volume histogram method for parameterizing
heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies. Eur J Nucl Med Mol Imaging. 2011 Sep;38(9):1636-47
68.Vosjan MJ, Perk LR, Roovers RC, Visser GW, Stigter-van Walsum M, van Bergen En Henegouwen PM, van Dongen GA. Facile labelling of an anti-epidermal growth factor receptor
Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):753-63
69.Wanders R, Steevens J, Botterweck A, Dingemans AM, Reymen B, Baardwijk Av, Borger J, Bootsma G, Pitz C, Lunde R, Geraedts W, Lambin P, De Ruysscher D. Treatment with curative
intent of stage III non-small cell lung cancer patients of 75 years: a prospective population-based study. Eur J Cancer. 2011 Dec;47(18):2691-7
70.Dehing-Oberije C, De Ruysscher D, Petit S, Van Meerbeeck J, Vandecasteele K, De Neve W, Dingemans AM, El Naqa I, Deasy J, Bradley J, Huang E, Lambin P. Development, external
validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients. Radiother Oncol. 2010 Dec;97(3):455-61
71.Hoetjes NJ, van Velden FH, Hoekstra OS, Hoekstra CJ, Krak NC, Lammertsma AA, Boellaard R. Partial volume correction strategies for quantitative FDG PET in oncology. Eur J Nucl Med
Mol Imaging. 2010 Aug;37(9):1679-87
72.Lambin P, Petit SF, Aerts HJ, van Elmpt WJ, Oberije CJ, Starmans MH, van Stiphout RG, van Dongen GA, Muylle K, Flamen P, Dekker AL, De Ruysscher D. The ESTRO Breur Lecture
2009. From population to voxel-based radiotherapy: exploiting intra-tumour and intra-organ heterogeneity for advanced treatment of non-small cell lung cancer. Radiother Oncol. 2010
Aug;96(2):145-52
73.Petit SF, van Elmpt WJ, Lambin P, Dekker AL. Dose recalculation in megavoltage cone-beam CT for treatment evaluation: removal of cupping and truncation artefacts in scans of the
thorax and abdomen. Radiother Oncol. 2010 Mar;94(3):359-66
74.van Dongen GA, Vosjan MJ. Immuno-positron emission tomography: shedding light on clinical antibody therapy. Cancer Biother Radiopharm. 2010 Aug;25(4):375-85
75.van Loon J, Janssen MH, Ollers M, Aerts HJ, Dubois L, Hochstenbag M, Dingemans AM, Lalisang R, Brans B, Windhorst B, van Dongen GA, Kolb H, Zhang J, De Ruysscher D, Lambin P.
PET imaging of hypoxia using [18F]HX4: a phase I trial. Eur J Nucl Med Mol Imaging. 2010 Aug;37(9):1663-8
List of Publications
38
76.Vosjan MJ, Perk LR, Visser GW, Budde M, Jurek P, Kiefer GE, van Dongen GA.’ Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the
bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010 Apr;5(4):739-43
77.Börjesson PK, Jauw YW, de Bree R, Roos JC, Castelijns JA, Leemans CR, van Dongen GA, Boellaard R. Radiation dosimetry of 89Zr-labeled chimeric monoclonal antibody U36 as used
for immuno-PET in head and neck cancer patients. J Nucl Med. 2009 Nov;50(11):1828-36
78.Starmans MH, Zips D, Wouters BG, Baumann M, Lambin P. The use of a comprehensive tumour xenograft dataset to validate gene signatures relevant for radiation response. Radiother
Oncol. 2009 Sep;92(3):417-22
39
Co funded by
International
Scientific Advisory
Committee
Prof. R.S. Reneman, Ph.D. (Chair)
Prof. J.A. Andersson, M.D., Ph.D.
J.P. Armand, M.D., MSc.
R.S.B. Balaban, Ph.D.
J.B. Bassingthwaighte, Ph.D.
R.G. Blasberg, M.D.
Prof. L. Degos
H. Hermjakob, Ph.D.
W.J. Jagust, Ph.D.
Prof. D.J. Kerr
Prof. U.D.A. Landegren, M.D., Ph.D.
R.I. Pettigrew, M.D., PhD.
A. Tedgui, Ph.D.
Prof. T.P. Young
Center for Translational
Molecular Medicine
High Tech Campus 84
5656 AG Eindhoven, The Netherlands
T +31 (0)40 800 23 00
F +31 (0)40 800 23 15
[email protected] | www.ctmm.nl
Chamber of Commerce 17198356
September 1, 2015

Vergelijkbare documenten

89 Zr-Immuno-PET

89 Zr-Immuno-PET assessment. Quantitative PET may therefore play and important role for enhancing individualised medicine. However, quantification of PET radiotracer uptake is limited by several factors, such as pa...

Nadere informatie