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Fig. 1: Tumour volume, TMR
max
and mean ADC before and
after 10 fractions of RT. Red dashed-line depicts the
mean, black the median, lower and upper hinges the 25
and 75 percentile, respectively.
Conclusion
Intra- and intertumoural heterogeneity in hypoxia
distribution and fMRI parameters were observed. FMISO
uptake after irradiation decreased and ADC-value
increased during radiotherapy as a surrogate for
reoxygenation and lower cell density or increasing
necrotic areas, respectively. Our data will be extended
with various tumour models and will form the preclinical
data base for the development of an integrated
multiparametric prediction model for personalised RT in
HNSCC.
PO-0968 The Role of epithelial to mesenchymal
transition (EMT) as Biomarker for Radioresistance in
HNSCC
I. Kurth
1,2
, D. Digomann
2
, L. Hein
2
, A. Linge
1,2,3,4
, L. Koi
5
,
S. Loeck
2
, K. Maebert
2
, H. Stephan
2
, C. Peitzsch
1
, M.
Krause
1,2,3,4,5
, M. Baumann
2,3,4,5,6
, A. Dubrovska
2,5
1
NCT Partnerstandort Dresden, Translationale Onkologie,
Dresden, Germany
2
OncoRay-National Center for Radiation Research in
Oncology, Faculty of Medicine and University Hospital
Carl Gustav Carus, Dresden, Germany
3
Department of Radiation Oncology, Faculty of Medicine
and University Hospital Carl Gustav Carus, Dresden,
Germany
4
German Cancer Consortium DKTK Dresden, German
Cancer Research Center DKFZ, Dresden, Germany
5
Helmholtz-Zentrum Dresden-Rossendorf, Institute of
Radiation Oncology, Dresden, Germany
6
Deutsches Krebsforschungszentrum DKFZ, Heidelberg,
Germany
Purpose or Objective
It is described that epithelial-to-mesenchymal transition
(EMT) plays an important role in head and neck squamous
carcinomas (HNSCC) progression and resistance to therapy
[1]
. Recent studies suggest that for instance the expression
of EMT related microRNAs may cause intrinsic
radioresistance in HNSCC
[2]
. During the process of EMT
epithelial cancer cells obtain a more mesenchymal-like
motile and invasive phenotype, which has been argued to
sustain survival and therapy resistance of those tumor
cells and facilitate cancer progression. Radiotherapy is
one of the main approaches to treat HNSCC. However,
tumor radioresistance often impedes the success of
radiotherapy and has been found to drive tumor
aggressiveness and expansion. In this study we asked the
question, if radioresistant HNSCC populations display EMT
features on a molecular as well as on a functional level
and whether we can correlate those characteristics to
treatment outcome.
Material and Methods
We used multiple irradiated HNSCC lines (IR) as an
established model to investigate the traits of
radioresistance
[3]
. Global gene expression, protein
analysis in vitro and on xenograft models and functional
radiobiological analyis was applied.
Results
Interestingly, global gene expression analysis revealed a
negative correlation of genes associated with cell motility
and migration in the IR derivatives of two HNSCC cell lines,
namely Cal33, FaDu. We functionally validated those
findings and screened for known EMT marks from
literature by functional migration assays and EMT-related
protein expression in several HNSCC model cell lines and
established xenografts as well as in their IR-derivatives in
order to correlate the acquired findings to radiotherapy
outcome. The only positive correlation was found for the
initial-before therapy protein expression
in vitro
and
in
vivo
for
Slug, a zinc-finger protein encoded by the
SNAI2
gene and c-Met, a receptor tyrosine kinase encoded by the
MET
gene. Functional knockdown of Slug or c-Met
expression let to radiosensitization in 3-D clonogenic
survival assays of several HNSCC cell lines.
Conclusion
Currently the expression of these molecules is scored for
clinical outcome to better understand the context of EMT
biomarkers for HNSCC progression and the development of
a
potential
well-directed
combinational
radiochemotherapy.
PO-0969 Accelerated fractionation should start early
for laryngeal/ hypopharyngeal cancer.
C. Terhaard
1
, N. Kasperts
1
, H. Dehnad
1
, E. Smid
1
, L.
Janssen
2
, R. Wigggenraad
3
, C. Raaijmakers
1
1
UMC Utrecht, Radiation Oncology Department, Utrecht,
The Netherlands
2
UMC Utrecht, Head and neck surgical oncology, Utrecht,
The Netherlands
3
RCWEST- Medisch Centrum Haaglanden, radiotherapy,
Den Haag, The Netherlands
Purpose or Objective
Accelerated repopulation during radiotherapy is a main
cause of local recurrence after conventional radiotherapy
for H&N cancer. Based on meta-analysis accelerated
fractionation (AF) is superior to conventional
fractionation. In most studies around 70 Gy is given in 6
weeks. The objective of this study is to analyze 3 AC
schedules with three start points of acceleration: at week
3, 4 and 5, looking for the optimum.
Material and Methods
Since 1995 we treat T2-3 larynx (including bulky T2
glottic) and hypopharynx cancer with AF. Three schedules
have been used. AF started in week 4 for the
hyperfractionated AF (HAS, n=28), in week 3 for the ASO
schedule (n=283), and in week 5 in the ARCON study
(n=86). Since local control was equal
2
, results of both
arms were combined. Mean follow-up was 75 months. Age
ranged from 32-87 years, 25% ≥ 70 years. WHO
performance was 0-1 in 95%. T2, T3,T4, was 57%, 35%, and
8%; 27% was N+. Distribution between the schedules was
equal for gender, stage, WHO p. , and age. Tumor
location was glottis, supraglottis and hypopharynx, in 44%
45% and 11%, respectively.
Results
Treatment delay was only seen in 5%, independent of the
schedule. Actuarial local control rates and disease free
survival rates differed significantly between the schedules
(table 1). In univariate analysis actuarial local control was
significantly correlated with T stage (T2,n=228, 82%,
T3,n=135 79%, T4 45%),sex (female fared better),
stage, and marginally significant years of treatment.
Local control was equal for patients < age 70 and above
(80%). In multivariate analysis the only independent
prognostic factors for local control were stage, sex and
treatment schedule. Independent factors for disease free
survival were stage and, marginally, treatment schedule.