Functional magnetic resonance imaging for defining the biological target volume.
ABSTRACT Morphology as demonstrated by CT is the basis for radiotherapy planning. Intensity-modulated and adaptive radiotherapy techniques would greatly benefit from additional functional information allowing for definition of the biological target volume. MRI techniques include several which can characterize and quantify different tissue properties and their tumour-related changes. Results of perfusion MRI represent microvascular density and permeability; MR spectroscopy depicts particular metabolites; diffusion weighted imaging shows tissue at risk and tumour cellularity; while dynamic 3D acquisition (4D MRI) shows organ motion and the mobility of tumours within them.
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ABSTRACT: PURPOSE: With the recent introduction of PET/MRI, we investigated whether diffusion-weighted imaging (DWI) can complement PET for predicting local treatment response in Hodgkin lymphoma. METHODS: This retrospective study included 39 patients selected from a hospital database with a histological diagnosis of Hodgkin lymphoma undergoing whole-body MRI (supplemented by DWI) and PET/CT before and after two cycles of vincristine, etoposide, prednisolone and doxorubicin (OEPA). The pretreatment volume, MRI apparent diffusion coefficient (ADC) and PET maximum standardized uptake value (SUV(max)) of the largest nodal mass were determined quantitatively for evaluation of the local response following two cycles of OEPA. Quantitative pretreatment imaging biomarkers (disease volume, ADC, SUV(max)) were compared between sites with an adequate and those with an inadequate response using Fisher's exact test and Mann Whitney statistics. Multivariate models predictive of an inadequate response based on demographic/clinical features, pretreatment disease volume and SUV(max) without (model 1) and with (model 2) the addition of ADC were derived and crossvalidated. The ROC area under curve (AUC) was calculated for both models using the full dataset (training) and the crossvalidation (test) data. RESULTS: Sites with an adequate response had a significantly lower median pretreatment ADC (1.0 × 10(-3)mm(2)s(-1)) than those with an inadequate response (1.26 × 10(-3)mm(2)s(-1); p < 0.01). There were no significant differences in patient demographic/clinical parameters, pretreatment SUV(max) or pretreatment nodal volume between sites with inadequate and adequate response. The ROC-AUCs for prediction of an inadequate response for the training and test data for model 1 were 0.90 and 0.53, and for model 2 were 0.84 and 0.71, respectively. CONCLUSION: DWI complements PET for prediction of site-specific interim response to chemotherapy.European Journal of Nuclear Medicine 11/2012; · 4.53 Impact Factor
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ABSTRACT: Diffusion-weighted magnetic resonance imaging (dwMRI) is sensitive to tissue microstructure on the cellular level and may therefore help to define biological tumour subvolumes and add complementary information to morphology-based cancer treatment protocols and therapy monitoring. The purpose of this study was therefore to evaluate the potential of dwMRI as compared with morphological MRI (mMRI) for tumour volume delineation using a nude rat human tumour xenograft model. Sixteen tumour-bearing rats (10 H1299, six FaDu) were examined with mMRI (T2-weighted true fast imaging with steady precession (TrueFISP), T1-weighted fast low angle shot (FLASH), T2-weighted dual echo steady state (DESS)) and echo-planar dwMRI in a clinical scanner at 1.5 T. For each method, we compared tumour volume and intra- and inter-observer variability of tumour outer edge delineation (disregarding intra-tumoural structure) as well as tumour signal-to-noise ratio (SNR) and tumour-to-muscle contrast-to-noise ratio (CNR). Tumours were visualised with significantly higher SNR and CNR in dwMRI. Median tumour volumes as measured by dwMRI (3.5 cm(3)) and mMRI (TrueFISP: 3.3 cm(3); FLASH: 3.3 cm(3); DESS: 3.2 cm(3)) were not significantly different and significantly correlated. Related to partial volume effects, the intra- and inter-observer variability of dwMRI (intra/inter: 12%/12%) was larger than for mMRI (TrueFISP: 4%/4%; FLASH: 5%/5%; DESS: 5%/5%). In conclusion, dwMRI allows tumour delineation with overall volume estimation comparable with mMRI approaches but slightly higher observer variability. Thus, besides tumour outline, it may potentially supplement morphology-based therapy planning and monitoring with additional biological information.Journal of Medical Imaging and Radiation Oncology 06/2010; 54(3):194-201. · 0.98 Impact Factor
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ABSTRACT: To evaluate the feasibility, tolerability, and preliminary outcomes in patients with prostate cancer treated according to a hypofractionated dose escalation protocol to boost the dominant tumor-bearing region of the prostate. After conventional fractionated external radiotherapy to 64 to 64.4 Gy, 50 patients with nonmetastatic prostate cancer were treated with an intensity-modulated radiotherapy hypofractionated boost under stereotactic conditions to a reduced prostate volume to the dominant tumor region. A rectal balloon inflated with 60 cc of air was used for internal organ immobilization. Five, 8, and 8 patients were sequentially treated with two fractions of 5, 6, or 7 Gy, respectively (normalized total dose in 2 Gy/fraction [NTD(2 Gy)] < 100 Gy, low-dose group), whereas 29 patients received two fractions of 8 Gy each (NTD(2 Gy) > 100 Gy, high-dose group). Androgen deprivation was given to 33 patients. Acute and late toxicities were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) scoring system. Two patients presented with Grade 3 acute urinary toxicity. The 5-year probabilities of >or=Grade 2 late urinary and late low gastrointestinal (GI) toxicity-free survival were 82.2% +/- 7.4% and 72.2% +/- 7.6%, respectively. The incidence and severity of acute or late toxicities were not correlated with low- vs. high-dose groups, pelvic irradiation, age, or treatment with or without androgen deprivation. The 5-year biochemical disease-free survival (b-DFS) and disease-specific survival were 98% +/- 1.9% and 100%, respectively. Intensity-modulated radiotherapy hypofractionated boost dose escalation under stereotactic conditions was feasible, and showed excellent outcomes with acceptable long-term toxicity. This approach may well be considered an alternative to high-dose-rate brachytherapy.International journal of radiation oncology, biology, physics 11/2009; 78(1):50-7. · 4.59 Impact Factor
Cancer Imaging (2006) 6, 51–55
Functional magnetic resonance imaging for defining the
biological target volume
Hans-Ulrich Kauczor, Christian Zechmann, Bram Stieltjes and Marc-Andre Weber
Department of Radiology, German Cancer Research Center, Heidelberg, Germany
Corresponding address: Prof Hans-Ulrich Kauczor, MD, Department of Radiology, Innovative Cancer Diagnostics
and Therapy, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Date accepted for publication 22 February 2006
Morphology as demonstrated by CT is the basis for radiotherapy planning. Intensity-modulated and adaptive
radiotherapy techniques would greatly benefit from additional functional information allowing for definition of
the biological target volume. MRI techniques include several which can characterize and quantify different
tissue properties and their tumour-related changes. Results of perfusion MRI represent microvascular density and
permeability; MR spectroscopy depicts particular metabolites; diffusion weighted imaging shows tissue at risk and
tumour cellularity; while dynamic 3D acquisition (4D MRI) shows organ motion and the mobility of tumours within
Keywords: Magnetic resonance imaging (MRI); functional imaging; MR perfusion; MR spectroscopy; radiotherapy planning;
biological target volume.
Radiotherapy planning relies on visualization of the
morphology of tumours and the surrounding normal
tissue. The basic workhorse for radiotherapy planning
is CT because of its well-known ability to demonstrate
structure with high spatial resolution and important
information about the radiodensity of the tissues.
Recent and current developments in radiotherapy such
as intensity-modulated and adaptive techniques would
greatly benefit from image-based ‘functional’ informa-
tion of tumour heterogeneity beyond structure. Magnetic
resonance imaging (MRI) provides numerous techniques
for image-based surrogates of different facets of function.
The following pairs of topics and techniques will be
covered in this review: angiogenesis—perfusion MRI;
metabolism—MR spectroscopy; tissue at risk and tumour
cellularity—diffusion weighted imaging; and motion—
Contrast-enhanced dynamic MRI provides information
about tissue perfusion. Such techniques have been
applied to many different tumours, such as cancers of
the breast, prostate, cervix, rectum and liver, as well
as gliomas, pulmonary nodules and multiple myeloma.
From signal intensity time curves descriptive parameters
such as lag time, amplitude, slope and area under the
curve (wash-out) can be calculated. They are determined
by perfusion and flow and related to microvascular
density and permeability. The results can be improved
and perfusion can be quantified by the introduction
of pharmacokinetic compartmental models. The models
provide results for amplitude and exchange rate and
finally lead to quantification for regional blood volume,
regional blood flow and mean transit time. They can
take the different properties of the contrast agents and
the tissue of interest into consideration. Depending
on indication T1- or T2∗-weighted sequences will be
preferred. Some assumptions have to be made to make
This paper is available online at http://www.cancerimaging.org. In the event of a change in the URL address, please use the DOI
provided to locate the paper.
1470-7330/06/010051 + 05
c ? 2006 International Cancer Imaging Society
52 H-U Kauczor et al.
increased values given as light colours representing gross tumour extension at pathology. (b) MR spectroscopy
shows elevated choline and decreased citrate and creatine indicating the adenocarcinoma seen as a hypointense
area in the T2-weighted planning sequences. This area also corresponds to the area of increased perfusion and
Prostate cancer. (a) Parameter image of perfusion and permeability with the cancer showing
(b) Perfusion map obtained by arterial spin labelling, a non-contrast technique, shows tumour blood flow not
elevated compared to grey matter. (c) Single voxel spectroscopy from tumour tissue shows an increase of Cho
indicating increased cellularity and cell membrane synthesis. (d) Colour-coded map of the ratio of N-acetyl-
aspartate (NAA)/creatine superimposed on the T2-weighted TSE image shows reduced NAA signal suggesting
loss of normal neural elements.
Defining the biological target volume 53
weighted imaging and registered on an axial FLAIR image shows the AVM with flow voids (arrow) and fibres of
the corona radiata, including the cortico-spinal tract, which abuts on the AVM. (b) Sagittal view of the complete
result of the tractography which superimposes the AVM (arrow).
Intracerebral arteriovenous malformation (AVM). (a) Tractography calculated from diffusion
the handling of these models feasible. However, in case
of different tissue properties the results might not be
correct. It has been demonstrated that the amplitude of
the signal correlates with the microvascular density of
the tumour whereas the exchange rate points towards
an increased permeability of the tumour vasculature
(Fig. 1)[2,3]. These parameters are also helpful to assess
the angiogenic potential of tumours and are well-suited
to follow-up particular therapies with anti-angiogenic
compounds such as thalidomide for the treatment of
multiple myeloma. Perfusion MRI is also capable of
predicting outcome in patients with cerebral metastases
who have already undergone stereotactic radiotherapy at
6 week follow-up. Perfusion can also be assessed by
non-contrast techniques such as arterial spin labelling
MR spectroscopy (MRS) can provide metabolic infor-
mation about tumour cells and the surrounding tissue.
Shifts in the distribution of certain metabolites provide
important hints towards both differential diagnosis and
the tumour biological behaviour (Fig. 2). Clinical
indications are mainly suspicious intracranial masses
and prostate cancer. In the brain, MRS is an important
adjunct in the diagnosis of gliomas, e.g. separating them
from metastases. After radiotherapy, it is very helpful
in differentiating recurrence from radionecrosis, where
the appearance of lipid peaks is related to necrosis.
In the prostate the cancerous region typically does not
contain citrate which is a metabolic product of the normal
prostate gland. The loss of citrate or an increase in
the choline/citrate ratio is an important indicator for
prostate cancer (Fig. 1). Since citrate is also present
in benign hyperplastic nodules these two entities can be
Tissue at risk and tumour
cellularity—diffusion weighted imaging
Diffusion weighted imaging allows for localization and
visualization of axonal tracts using 3D fibre reconstruc-
tion called tractography. The displacement of impor-
tant neural structures, e.g. the pyramidal tract, by a large
mass can be exactly localized, and taken into account
when the planned target volume is defined (Fig. 3). In a
study involving 20 patients exact knowledge of the course
of the axonal tracts led to a change of radiotherapy plan-
ning in 71%. In this way, the volume receiving less than
15 Gy could be significantly reduced, while the volume
encompassed by the 80% isodose was unchanged.
As an increase in tumour cellularity due to rapid
growth leads to a decrease in apparent diffusion constant
(ADC) 2D depiction of fibre integrity, e.g. fractional
anisotropy, at high b-values can be used to measure tissue
vitality. In primary brain tumours, the delineation of the
target volume is impeded due to incomplete depiction
of the tumour border in conventional MRI. It is known
that these tumours grow along the axonal projections,
in part displacing, in part infiltrating these structures.
Thus, measures from diffusion weighted imaging, such
as fractional anisotropy, can be used to assess fibre
integrity and have been postulated as sensitive markers
for overall tumour extent; however, research has so far
been hampered by limitations in data analysis. Current
research is evaluating the role of DTI in predicting
tumour extent and shows promising initial results for
improved tumour front delineation in patients with
primary brain tumours.
54H-U Kauczor et al.
resolution of three images per second shows the tumour in the right upper lobe with a small clip artifact within
the tumour. (b) Expiratory image from the same series shows the displacement of the tumour and also indicates
the lack of chest wall infiltration.
Lung cancer. (a) Inspiratory image from a dynamic trueFISP sequence obtained with a temporal
Dynamic three-dimensional (4D) MRI is an attractive
means of imaging organ motion and the mobility
of tumours over time. This information is especially
important for respiratory motion and lung tumours when
high precision radiotherapy is used(Fig. 4). Pilot
studies of lung tumour mobility used 2D sequences
with a temporal resolution of approximately 300 ms.
The mobility of lung nodules in X-, Y- and Z-
directions was significantly affected by tumour size
and location. Obviously, mobility was greatest for
small nodules in the caudal lung regions and cranio-
caudal direction during deep breathing[13,15]. However,
even during shallow breathing tumour mobility could
be substantial. Benefiting from new MR developments
such as parallel imaging and view sharing the temporal
resolution of a three-dimensional data set could be
reduced to 1 s. This makes the 3D registration of
lung nodules during continuous breathing feasible.
Theoretical calculations show that the integration of such
information into radiotherapy planning will result in a
substantial increase of the dose that can be delivered
to the planned target volume. Parallel assessment of
chest wall motion detected by external MR markers and
internal tumour motion followed by MRI represents one
way of triggering radiotherapy.
Besides mere volumetric visualization of morphology
and structure, MRI is also capable of providing ‘func-
tional’ information which can be used to define individual
biological target volumes.
 Furman-Haran E, Degani H. Parametric analysis of breast MRI.
J Comput Assist Tomogr 2002; 26: 376–86.
 Kiessling F, Huber PE, Grobholz R, Heilmann M, Meding J,
Lichy MP et al. Dynamic magnetic resonance tomography and
proton magnetic resonance spectroscopy of prostate cancers in
rats treated by radiotherapy. Invest Radiol 2004; 39: 34–44.
 Kiessling F, Farhan N, Lichy MP, Vosseler S, Heilmann M,
Krix M et al. Dynamic contrast-enhanced magnetic resonance
imaging rapidly indicates vessel regression in human squamous
cell carcinomas grown in nude mice caused by VEGF receptor 2
blockade with DC101. Neoplasia 2004; 6: 213–23.
et al. Dynamische MRT des Knochenmarks zum Monitor-
ing des Multiplen Myeloms unter Thalidomid-Monotherapie
oder Kombination mit CED-Chemotherapie. Rofo 2004; 176:
 Weber MA, Thilmann C, Lichy MP, Gunther M, Delorme S,
Zuna I et al. Assessment of irradiated brain metastases by
means of arterial spin-labeling and dynamic susceptibility-
weighted contrast-enhanced perfusion MRI: initial results. Invest
Radiol 2004; 39: 277–87.
 Lichy MP, Plathow C, Schulz-Ertner D, Kauczor HU,
Schlemmer HP. Follow-up gliomas after radiotherapy: (1)H
MR spectroscopic imaging for increasing diagnostic accuracy.
Neuroradiology 2005; 47: 826–34.
 van Dorsten FA, van der Graaf M, Engelbrecht MR, van
Leenders GJ, Verhofstad A, Rijpkema M et al. Combined
quantitative dynamic contrast-enhanced MR imaging and (1)H
MR spectroscopic imaging of human prostate cancer. J Magn
Reson Imaging 2004; 20: 279–87.
 Stieltjes B, Kaufmann WE, van Zijl PC, Fredericksen K,
Pearlson GD, Solaiyappan M et al. Diffusion tensor imaging and
axonal tracking in the human brainstem. Neuroimage 2001; 14:
 Mori S, Kaufmann WE, Davatzikos C, Stieltjes B, Amodei L,
Fredericksen K et al. Imaging cortical association tracts in the
human brain using diffusion-tensor-based axonal tracking. Magn
Reson Med 2002; 47: 215–23.
Defining the biological target volume55
 Aoyama H, Kamada K, Shirato H, Takeuchi F, Kuriki S,
Iwasaki Y et al. Integration of functional brain information
into stereotactic irradiation treatment planning using magne-
toencephalography and magnetic resonance axonography. Int J
Radiat Oncol Biol Phys 2004; 58: 1177–83.
 ProvenzaleJM, McGraw
meningiomas: investigation with isotropic diffusion-weighted
MR imaging and diffusion-tensor MR imaging. Radiology 2004;
 Stieltjes B, Schl¨ uter M, Didinger B, Weber M-A, Hahn HK,
Parzer P et al. Diffusion tensor imaging in primary brain
tumors: reproducible quantitative analysis of corpus callo-
sum infiltration and contralateral involvement using a proba-
bilistic mixture model. Neuroimage (in press). Available online
 Plathow C, Ley S, Fink C, Puderbach M, Hosch W,
Schmahl A et al. Analysis of intrathoracic tumor mobility during
whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol
P, Guo AC,
Phys 2004; 59: 952–9.
 Plathow C, Fink C, Ley S, Puderbach M, Eichinger M, Zuna I
et al. Measurement of tumor diameter-dependent mobility of
lung tumors by dynamic MRI. Radiother Oncol 2004; 73:
 Giraud P, De Rycke Y, Dubray B. Conformal radiotherapy
(CRT) planning for lung cancer: analysis of intrathoracic organ
motion during extreme phases of breathing. Int J Radiat Oncol
Biol Phys 2001; 51: 1081–92.
 Plathow C, Schoebinger M, Fink C, Hof H, Debus J,
Meinzer H et al. Quantification of lung tumor volume
and rotation during respiration using 3D dynamic paral-
lel MRI with view sharing—preliminary results. Radiology
 Plathow C, Zimmermann H, Fink C, Umathum R, Sch¨ obinger M,
Huber P et al. Influence of different breathing manoeuvres on
internal and external organ motion: use of fiducial markers in
dynamic MRI. Int J Radiat Oncol Biol Phys 2005; 62: 238–45.