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a dominant approach as a primary treatment for these
lesions. Current principles are governed by strong
observational studies that described outcomes determined
by overall treatment time in addition to RT dose and
fractionation, and the hazard associated with accelerated
proliferation. Subsequently clinical trials and their
combination in individual patient meta-analyses
confirmed these principles (e.g. MARCH, 2006). At the
same time the same investigators have shown an added
benefit to addition of concurrent chemotherapy (CTx)
compared to standard fractionated RT alone (MACH-NC
2000, 2009). In essence, the combination of RT with CTx
needs to be considered in unison, since outcomes today
are frequently immutably linked to the application of both
approaches. Following these studies significant evolution
in a variety of areas has taken place. These include the
emergence of HPV-related disease on the one hand and a
developing significant sub-population of elderly patients
who may be unable to tolerate intensive treatments used
for younger patients and whose biology may differ. In
addition, new treatment approaches have emerged as
well, including potential combination of systemic agents
with altered RT fractionation (where increased efficacy
appears to be present), use of induction CTx, the use of
biotherapies, the introduction of trans-oral surgical
approaches (including robotic approaches that may also
require additional application of adjuvant RT) and the
nascent introduction of immunotherapy. For these
reasons, while the focus of this talk is on radiobiology, and
predominantly in HPV-negative tumors, it remains
necessary to address principles of combination with other
agents and approaches. For example, exploration of
biomarkers in the microenvironment of surgical wounds
may influence outcome of post-surgical adjuvant RT +/-
CTx. Understanding RT-CTx interaction requires an
understanding of the principles of spatial cooperation,
synergy, and independent cell kill, including ways to
exploit biological phenomena, such as apoptosis, hypoxia,
or directly enhancing the direct cell kill through influence
on DNA repair or on double strand breakage. A sustained
search for biomarkers of response to agents that may
influence RT outcomes is ongoing as exemplified by ERCC1
in the case of Cisplatin and for hypoxia, the description of
hypoxia gene signatures is undergoing validation in the
context of prognostic and predictive impact and the pre-
therapeutic value of identifying those who may benefit
from hypoxic modification of RT. An additional adverse
biological modifier of RT outcome is represented by
smoking exposure which confers adverse survival outcome
overall within a complicated matrix of activity including
adverse influence on the host through additional co-
morbidity, causation of the cancer that may be adversely
effected as a function of the intensity of tobacco
exposure, or may influence the response to RT in current
smokers who continue to smoke during RT. Finally,
beyond smoking, other tumor-host microenvironment
interaction exists. The most significant interest in this
area today is the emergence of programmed death-ligand
1 (PD-L1)/programmed death-1 (PD-1) interaction in
inhibiting anticancer T-cell immunity with the possibility
of generating durable responses and extended overall
survival using targeted therapy. Much interest has been
generated for a range of possible HNC scenarios in the
context of RT. Approaches under consideration include
modification of RT volumes, RT and CTx interaction with
immune check point inhibitors and application of these
combinations in different risk subsets, and the continued
search for ways to exploit the rare instance of RT induced
immune-mediated systemic response, a phenomenon
termed the ‘
abscopal effect’
. For the latter, local RT may
induce regression of metastatic cancer at distant sites
which have not been irradiated through induction of
adaptive immune responses. This effect governs such
clinical trial questions as reduction of the intensity of
treatment to regions that traditionally have been
managed with conventional elective doses of RT or for the
management of oligometastases. Also, elderly patients
require novel approaches and there is considerable
evidence that aging affects the immune system and anti-
tumor response in the elderly, particularly through T cell
function. Combining standard RT with immune
modulation is an attractive strategy in the elderly due to
their poorer anti-tumor T cell function and the favorable
toxicity
profile
of
emerging
immunotherapy
approaches. Trials addressing these approaches are
currently in design.
SP-0398 Novel developments in the radiobiology of
HPV-positive head and neck tumours
S. Nuyts
1
1
University Hospital Gasthuisberg, Leuven, Belgium
Head and neck squamous cell carcinoma (HNSCC) is a
highly heterogeneous disease that is often the result of
tobacco and/or alcohol abuse or infection with high-risk
Human papillomaviruses (HPV). Worldwide, an increase in
HPV related oropharyngeal carcinoma’s is seen. Despite
the fact that the HPV positive HNSCC form a distinct
clinical entity with better treatment outcome, all HNSCC
are currently treated uniformly with the same treatment
modality. However, it is expected that the results of
ongoing randomized studies will reshape radio-
chemotherapy schedules for this tumour group.
At present, biologic basis of these different outcomes and
their therapeutic influence are an area of intense
investigation.
The radiobiological differences between HPV+ and HPV−
head and neck tumours and resulting treatment
possibilities will be discussed from the perspective of the
5 Rs.
Over the last couple of years several hypotheses have been
put forward correlating radiotherapy response to micro–
environmental (immune system and hypoxia) and tumour
intrinsic factors. It has been hypothesized that the
immune system plays a more important role in clearance
of HPV related HNSCC compared to HPV- HNSCC due to the
expression of viral proteins. On the other hand the
presence of high-titer serum antibodies to these viral
proteins indicates the presence of immune tolerance and
opportunities for immunotherapeutic approaches. One of
the most studied environmental factors in relation
to radiotherapy response is hypoxia, which is known to
result in radiation resistance. Some studies suggest a
possible influence of hypoxia in radiation sensitization in
HPV+ HNSCC, whilst others suggest a more ambiguous role
for tumour hypoxia. Moreover, factors influencing the
intrinsic radiotherapy response such as the role of cancer
stem cells, differences in DNA repair capacity and
influence of HPV on cell cycle and cell death pathways will
be discussed. In this presentation, we will thus summarize
the molecular basis for different radiotherapy response
based on HPV status, novel treatment opportunities and
possible biomarkers for HPV positive HNSCC.
OC-0399 Transcriptome analyses of the radiation
response in HNSCC cells with different radiation
sensitivity
J. Heß
1,2
, A. Michna
1
, U. Schötz
2,3
, M. Selmansberger
1
, H.
Zitzelsberger
1,2
, K. Unger
1,2
, K. Lauber
2,3
1
Helmholtz Zentrum Muenchen - German Research
Center for Environmental Health, Research Unit
Radiation Cytogenetics, Muenchen, Germany
2
Helmholtz Zentrum Muenchen - German Research
Center for Environmental Health, Clinical Cooperation
Group "Personalized Radiotherapy in Head and Neck
Cancer", Neuherberg, Germany
3
Ludwig-Maximilians-University, Department of
Radiotherapy and Radiation Oncology, Muenchen,
Germany