Evaluation of inter- and intrafractional motion of liver tumors using interstitial markers and implantable electromagnetic radiotransmitters in the context of image-guided radiotherapy (IGRT) – the ESMERALDA trial
Habermehl et al. Radiation Oncology
Evaluation of inter- and intrafractional motion of liver tumors using interstitial markers and implantable electromagnetic radiotransmitters in the context of image-guided radiotherapy (IGRT) - the ESMERALDA trial
Daniel Habermehl 0 4
Patrick Naumann 3
Rolf Bendl 1 2
Uwe Oelfke 5
Simeon Nill 5
Jürgen Debus 3
Stephanie E. Combs 0 4
0 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Ismaninger Str. 22, 81675 Munich , Germany
1 Medical Informatics, Heilbronn University , Heilbronn , Germany
2 Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ) , Heidelberg , Germany
3 Department of Radiation Oncology, University Hospital of Heidelberg , Im Neuenheimer Feld 400, 69120 Heidelberg , Germany
4 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Ismaninger Str. 22, 81675 Munich , Germany
5 Joint Department of Physics at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust , London , UK
Background: With the development of more conformal and precise radiation techniques such as Intensity-Modulated Radiotherapy (IMRT), Stereotactic Body Radiotherapy (SBRT) and Image-Guided Radiotherapy (IGRT), patients with hepatic tumors could be treated with high local doses by sparing normal liver tissue. However, frequently occurring large HCC tumors are still a dosimetric challenge in spite of modern high sophisticated RT modalities. This interventional clinical study has been set up to evaluate the value of different fiducial markers, and to use the modern imaging methods for further treatment optimization using physical and informatics approaches. Methods and design: Surgically implanted radioopaque or electromagnetic markers are used to detect tumor local-ization during radiotherapy. The required markers for targeting and observation during RT can be implanted in a previously defined optimal position during the oncologically indicated operation. If there is no indication for a surgical resection or open biopsy, markers may be inserted into the liver or tumor tissue by using ultrasound-guidance. Primary study aim is the detection of the patients´ anatomy at the time of RT by observation of the marker position during the indicated irradiation (IGRT). Secondary study aims comprise detection and recording of 3D liver and tumor motion during RT. Furthermore, the study will help to develop technical strategies and mechanisms based on the recorded information on organ motion to avoid inaccurate dose application resulting from fast organ motion and deformation. Discussion: This is an open monocentric non-randomized, prospective study for the evaluation of organ motion using interstitial markers or implantable radiotransmitter. The trial will evaluate the full potential of different fiducial markers to further optimize treatment of moving targets, with a special focus on liver lesions.
Image-guided radiotherapy; IGRT; Fiducial marker; Fiducials; Organ motion management; Organ motion
Primary liver tumors (PLC) represent a great challenge in
radiooncology because tumor sizes are often large and
represent a relatively high proportion of liver tissue .
Furthermore, high radiation doses are needed for
longterm control of primary liver cancer. Incidence of
hepatocellular carcinoma (HCC) is raising in western countries
mostly due to increasing hepatitis c infections. Current
therapeutic approaches for HCC and other PLC are
complete surgical resection, liver transplantation and
locoregional ablative therapies including radiofrequency
ablation and chemoembolization. In case of locally
advanced or metastasized tumors the multi-kinase inhibitor
Sorafenib (Nexavar®) has proven efficacy and leads to
prolonged overall survival compared to placebo .
Radiation therapy has failed to show promising results
in the past because conventional photon techniques lead
to a high dose deposition in the normal liver which can
potentially cause Radiation-Induced Liver Disease (RILD)
. With the development of more conformal and precise
radiation techniques such as Intensity-Modulated
Radiotherapy (IMRT), Stereotactic Body Radiotherapy (SBRT)
and Image-Guided Radiotherapy (IGRT) over the last two
decades, patients with hepatic tumors (mainly not suitable
for standard therapies) could be treated with high local
doses by sparing normal liver tissue and showed good
short- and long-term responses [4–7]. However,
frequently occurring large HCC tumors are still a
dosimetric challenge in spite of modern high sophisticated RT
modalities due to the limited hepatic tolerance and
limited hepatic function in this patient subgroup with a
high frequency of liver cirrhosis [4, 8].
Treatment of PLC and liver metastases is an
interdisciplinary challenge for all involved clinical disciplines.
While multiple liver metastases are treated with systemic
therapies, oligometastatic patients can undergo local
ablative treatment approaches, e. g. surgical resection, RFA
and radiotherapy (RT) [5, 9]. Every local ablative
approach has pros and cons and clinical decision finding
depends on tumor localization, size, proximity to greater
vessels and multifocality. In many cases different therapy
modalities have to be combined to achieve optimal
results. Radiotherapy may play a more important role in
centrally located tumors near the porta hepatica, in case
of close proximity to the portal or hepatic vein, local
relapses or medically inoperable patients.
There are numerous studies on the characterization of
respiration-induced tumor motion [10–13]. Attempts to
detect tumor motion through the analysis of easily
observable surrogate signals (e. g. Anzai-belt, lung volume)
finally showed a relatively high grade of uncertainty.
Several feasibility studies focused on fiducial- or
imagebased recognition of organ and tumor motion [14, 15].
These publications showed that the use of radioopaque
fiducial markers can successfully minimize margins,
increase dose to tumor volume and finally improve clinical
Dynamic adaptation of dose application due to
detection of real-time organ motion requires the
prediction of organ motion during time latency of the
individual system. A further unsolved problem is the
prediction of organs at risk (OARs) during therapy. To
compensate for inaccurate irradiation due to organ
motion during therapy with a conventional linear
accelerator (LINAC) mainly two strategies are possible:
adaptation of tumor position through dynamic couch
shifting and automatic adaptation of the multi-leaf
collimator (MLC). None of these strategies has been
successfully integrated in clinical routine. Besides the
prediction of respiratory-induced motion another
unresolved issue is the secure integration of a real-time
motion sensor with an automatic, dynamic MLC
conformation into one system.
Surgically implanted radioopaque or electromagnetic
markers are used to detect tumor localization during
radiotherapy. Radioopaque markers are commercially
available and approved as medical product. The
electromagnetic markers of the CALYPSO system in the
U.S. are approved by the Federal Drug Administration
(FDA). The surgical implantation follows a preceding
interdisciplinary discussion for the definition of an
oncological therapy concept with the aim of
extracting a biopsy or a surgical resection of the tumor in
one session. The required markers for targeting and
observation during RT can be implanted in a
previously defined optimal position during the
oncologically indicated operation. If there is no indication for
a surgical resection or biopsy (open biopsy), markers
may be inserted into the liver/tumor tissue by using
Thus, the present study concept has been set up to
evaluate the value of different fiducial markers, and to use
the aquired imaging for further treatment optimization
using physical and informatics approaches.
Secondary study aims
– Detection and recording of 3D organ motion of the
liver during RT
– Development of technical strategies and
mechanisms based on the recorded information on
organ motion to avoid inaccurate dose application
resulting from fast organ motion and deformation
Therapeutic advantages for patients included in the
clinical trial and treatment
The immediate advantage for all patients who will
participate in the present trial consists in the procedure of
marker implantation for the detection of organ motion
before radiotherapy. The radioopaque marker material
allows correlation of IGRT generated kV- or MV-based
cone-beam-CTs with pretherapeutic treatment planning
CT scans and thus provides additional information that
improves the accuracy of patient positioning and dose
application. For this purpose medically approved interstitial
fiducial markers (CE labeled) are applied for clinical use,
and furthermore the electromagnetic CALYPSO marker
system has FDA approval for comparable indications.
For local ablative treatments a three to eight
fraction regimen, e.g. 3×20 Gy (primarily liver tumors) or
8×7.5 Gy(centrally located lung tumors) prescribed to
the 65- or 80 %-isodose will be performed.
Conventional doses are not planned for patients included in
the ESMERALDA-trial. Currently, patients are
immobilized using a customized vacuum pillow and an
abdominal compression. However, if patients don´t
tolerate the compression a free-breathing radiotherapy
will be performed, e.g. with a gating technique.
Treatment planning will be performed using a 4D-CT scan
and free breathing; breath-hold techniques are not
establied at our institution. Fiducial marker (except
the Calypso system) motion will be analyzed by
information derived from the 4D computed tomography of
the treatment planning imaging, fluoroscopic imaging
in the treatment position/setup and the sequential
and interfractional kV-CBCT imaging.
Toxicity and additional radiation exposure for patients
Implanted markers are approved for clinical use in this
setting. There will be no toxicities that exceed the
known toxicities resulting from the implantation
procedure. In the context of IGRT portal images will be taken
regularly and no additional radiation exposure will
occur. Through the observation of the marker position
and the installation of the monitor system (e.g. Calypso
system), there will be an additional time effort of about
15-20 minutes for the patient.
This is an open monocentric non-randomized, prospective
study for the evaluation of organ motion using interstitial
Indication for high precision radiotherapy of
primary and secondary liver tumors using IGRT
Age ≥ 18 years of age
ability of subject to understand character and
individual consequences of the clinical trial
written informed consent (must be available before
enrolment in the trial)
refusal of the patients to take part in the study
medical reasons impeding marker implantation or
IGRT for treatment of liver tumors.
non-compliance of patients
Study plan and duration of regular study participation
1. Interdisciplinary consent for the indication of high
precision RT of primary or secondary liver tumors
2. Information about the ESMERALDA study with a
focus on trial sequence, risks and adverse events
3. Submission of the written informed consent
4. Implantation of the required fiducial markers for
IGRT in the context of an oncologically indicated
operation or during an ultrasound-guided procedure
5. Imaging studies for radiotherapy treatment planning
6. Radiotherapy treatment planning
7. Radiotherapy with daily IGRT and/or the CALYPSO system
8. Planned study end: 6-8 weeks after the end of RT (first oncolgical follow-up) Acquired data will be pseudonymised for further technical examinations and computations.
Statistical design and analysis
This prospective, non-randomized clinical trial is planned
to include 50 patients with primary (n = 25) or secondary
(n = 25) liver tumors. The proposed number of patients is
an approximated estimation for a sufficient investigation
of parameters in both groups which allows a finalization
during the mentioned timeline. A dedicated power
calculation is not adequate and was therefore not performed.
Motion data of the initial 4D treatment planning CT will
be correlated with on-board fluoroscopic and
CBCTbased motion and calculated shift vectors. Intrafraction as
well as interfraction motion will be measured.
Furthermore, putative fiducial migration will be analyzed. In
summary, the study will help to establish a
motionmanagement strategy, also including the significance of
the number of markers and their spatial correlation.
The study protocol as well as the patients´ informed
consent and the patient information were submitted to the
Ethical Commission of the University of Heidelberg for
appraisal. The assigned in-house number is S-112/2012.
All changes of the study protocol, especially those
concerning patient safety, will be communicated to the study
committee of the Ethical Commission.
Patients´ informed consent
Only those patients who agreed to participate in the
study after detailed oral and written information will be
included. Study participation is voluntary and can be
withdrawn at any time by the patients´ choice without
From a radiation oncology perspective, optimization of
dose distributions as well as motion management in
moving targets is of utmost priority. For the latter,
motion surrogates can be implemented, such as fiducial
markers placed into the tumor or into its surrounding
tissue. The present one-armed non-randomized trial will
evaluate the full potential of different fiducial markers to
further optimize treatment of moving targets, with
special focus on liver lesions.
SEC, DH and JD wrote the study protocol and helped obtain the required
votes of the relevant authorities. SEC, DH, PN, SN, JD, RB and UOE provided
considerations on design and realization and will follow the study and
evaluation. DH, PN, JD and SEC will provide patient care. DH, PN, SN, UOE,
RB and SEC will perform data analysis. DH, PN, UOE, RB, JD and SE will
implement the protocol and oversee data collection. All authors contributed
to and approved the final manuscript version.
The project is funded by the Sonderforschungsbereich SFB/TRR 125 of the
German Research Foundation. We acknowledge the financial support of the
German Research Foundation and Ruprecht-Karls-Universität Heidelberg
within the funding programme Open Access Publishing.
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