Review Article · Übersichtsarbeit
Onkologie 2004;27:304–309
DOI: 10.1159/000077983
Magnetic Resonance Spectroscopy in Clinical Oncology
W. Golder
Institut für Klinische Radiologie, DRK Kliniken Berlin Westend, Germany
Key Words
Magnetic resonance spectroscopy · Tumor metabolism ·
Neurotoxicity · 5-Fluorouracil
Summary
The combination of magnetic resonance spectroscopy
(MRS) and imaging (MRI) has led to mapping metabo-
lites from normal and neoplastic tissue within the time
limits of a routine study. MRSI (magnetic resonance
spectroscopy imaging) detects metabolites that contain
protons, phosphorus, fluorine, or other nuclei. The
uniqueness of the information available in vivo and in a
non-invasive manner encouraged radiologists and oncol-
ogists to apply MRSI in research and clinical practice.
Both 1H- and 31P-MRS have revealed significant distur-
bances in amino acids, lipids, and phosphorus-contain-
ing metabolites within tumors. Phosphocreatine is often
diminished in neoplasms compared to their primary host
or surrounding tissues. However, the reduction of the
compound does not appear to be closely correlated to
the degree of malignancy. Moreover, abnormalities in 31P
spectra from neoplasms are shared by other disorders.
Changes in high-energy phosphate levels almost invari-
ably occur with radio- and chemotherapy of tumors. The
spectroscopic alterations are often seen before any vari-
ations in tumor size and shape can be detected. Howev-
er, opposite responses can be associated with the same
clinical outcome. 1H-MRS has been successfully used to
quantify the extent of neuronal cell loss imposed on the
brain during radiotherapy. Recently, MRSI was success-
fully integrated into radiotherapy planning in prostate
cancer patients. 19F-MRS opens access to artificially in-
duced fluorocompounds such as 5-fluorouracil and its
metabolites.
© 2004 S. Karger GmbH, Freiburg
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Schlüsselwörter
Magnetresonanzspektroskopie · Tumorstoffwechsel ·
Neurotoxizität · 5-Fluorouracil
Zusammenfassung
Die Verknüpfung von Magnetresonanzspektroskopie
(MRS) und -tomographie (MRT) bietet die Möglichkeit,
den Stoffwechsel gesunden und neoplastischen Gewe-
bes im Rahmen einer einzigen Untersuchung bildlich
darzustellen. Das Kombinationsverfahren erfasst Stoff-
wechselprodukte, die Wasserstoff, Phosphor, Fluor oder
andere resonanzfähige Kerne enthalten. Die Aussicht,
derartige Informationen in vivo und nicht-invasiv zu ge-
winnen, macht die spektroskopische Bildgebung auch für
die onkologische Forschung und Praxis zu einer wertvol-
len Technik. Sowohl die Protonen- als auch die Phos-
phor-Spektroskopie haben bedeutende Veränderungen
im Aminosäuren-, Lipid- und Phosphorstoffwechsel von
Tumoren aufgedeckt. Kreatinphosphat liegt in Neoplas-
men häufig in geringerer Konzentration vor als im ge-
sunden Parenchym. Eine enge Korrelation zum Grad der
Malignität des Tumors fehlt allerdings. Außerdem wer-
den ähnliche Normabweichungen im Phosphorstoff-
wechsel auch bei nicht-neoplastischen Erkrankungen be-
obachtet. Radio- und Chemotherapie führen nahezu obli-
gat zu Änderungen im Metabolismus der energiereichen
Phosphate. Die Verschiebungen im Spektrogramm wer-
den oft bereits sichtbar, bevor sich Form und Größe des
Tumors ändern. Allerdings kann das klinische Ergebnis
trotz divergierender Trends im Resonanzbild identisch
sein. Die Protonen-Spektroskopie eignet sich zur Quanti-
fizierung des Verlusts von Nervenzellen während und
nach Strahlentherapie des Gehirns. Jüngst hat man das
Verfahren erfolgreich in die Planung der Strahlentherapie
des Prostatakarzinoms einbezogen. Die Fluor-Spektros-
kopie schafft einen nicht-invasiven Zugang zur Beobach-
tung des Metabolismus fluorhaltiger zytotoxischer Sub-
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stanzen wie 5-Fluorouracil in Tumoren.
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Prof. Dr. Werner Golder
Institut für Klinische Radiologie
DRK Kliniken Berlin Westend
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Spandauer Damm 130, D-14050 Berlin
Tel. +49 30 3035-4100, Fax -4109
E-mail radiologie@drk-kliniken-westend.de
Introduction Table 1. Tissue metabolites identified by 1H-MRS [37]

Magnetic resonance spectroscopy (MRS) offers unique possi- Compound Peak position, Change with
ppm malignancies (organ)
bilities for the non-invasive evaluation of biochemical process-
es in vitro and in vivo. In vitro MRS of body fluids, biopsy Creatine +4.0, +3.1 ↓ (brain)
samples and surgical specimens provides metabolic informa- Myo-inositol +3.6 ↑ (prostate)
tion when other sensitive and specific disease markers are Choline +3.3 ↑ (brain)
lacking. In vivo MRS may detect biochemical alterations in Citrate + 2.6 ↓ (prostate)
Glutamine, glutamate +2.3 ↑ (brain)
the absence of morphologic lesions. MRS obtains signals from
N-acetyl-aspartate +2.0 ↓ (brain)
a wide variety of molecules which are present in tissue at Lactate +1.2 ↑ (brain)
much lower concentrations than water and fat. Each chemical- Lipids +1.0 ↑ (brain)
ly distinct nucleus of a given species resonates at a slightly dif-
ferent frequency, resulting in different MR peaks. The crucial
point is the spatial resolution obtainable by MRS which is in-
ferior compared to that usually achieved by MRI [1]. Table 2. Tissue metabolites identified by 31P-MRS [37]

Compound Peak position, Change with

ppm malignancies (organ)
Localized Biochemical Information
Phosphomonoesters +8.0 ↑ (bone and soft tissue)
By providing localized biochemical information in vivo, MRS Inorganic phosphate +5.0 ↑ (brain, mammary gland)
Phosphodiesters +3.0 ↓ (brain, mammary gland)
offers unequalled chances to characterize and distinguish dis-
Phosphocreatine 0.0 ↓ (brain)
ease and nondisease states. Although it is well accepted that γ-ATP

higher field strength is superior because of improved sensitivi-
ty and chemical shift dispersion, other factors like relaxation
time differences, line broadening due to magnetic susceptibili-
ty effects, and radiofrequency coil efficiency potentially affect
the expected improvement. Barker et al. [2] report a 20% im-
provement in sensitivity and a 28% increase in signal-to-noise
ratio at 3.0 T compared to 1.5 T. An exceptionally high field
strength (4.0 T) may overcome current limitations of quantifi-
cation of human proton spectra [3]. Maximal homogeneity of
the magnetic field is another absolute prerequisite to satisfac-
tory MRS results.
Chemical shift (CS) is defined as the frequency shift relative
to some reference chemical, divided by the resonance fre-
quency of the reference chemical. Nuclei in different chemical
environments experience different fields and hence produce
signals at different frequencies. If one nucleus is more shield-
ed than another, its signal will be shifted to low frequency. By
convention, it will have a more negative chemical shift and
will appear further towards the right-hand side of the spec-
trum. The amount of the shift is specified in parts per million
(ppm) of the resonance frequency relative to a standard.
Another important parameter arising from interactions with
the bonding electrons is the spin-spin or J coupling. J coupling
is an interaction between nuclear spins within a molecule and
provides a direct spectral manifestation of the chemical bond.
The effect is transmitted via the electrons in orbit around the
nuclei and two spins have measurable J coupling only if they
are linked together through a small number of chemical
bonds, including hydrogen bonds. The behavior of an individ-
ual spin is influenced by other coupled nuclei. Thus, what
would otherwise be a single resonance, is split into two or
more distinct frequencies, depending on the state of the cou-
↔↔ ↔
–3.0 (brain)
α−ATP –8.0 (brain)
β-ATP –17.0 (brain)
pled spin. In proton-proton coupling, the effect is advanta-
geous in aiding the identification of particular species.
For deep organs some effort is required to localize the spectra
to a specific region of the target organ. The respective tech-
niques fall into several groups [4]. Those that use pulsed spa-
tial gradients at audio frequencies (e.g. DRESS, ISIS) have
proven especially valuable. To acquire long and short TE
(echo time) spectra within the sampling volume, point-re-
solved spectroscopy (PRESS) and stimulated-echo acquisition
mode (STEAM) technique are applied.
1H-MRS is used to visualize amino acids, lactate, and lipids.
The main problem with 1H-MRS is the large signal from water
in tissue. The metabolites are quantified by using the target
organ water concentration as internal reference. The concen-
tration of a metabolite detected is proportional to the area
under the peak and not just the peak height. So a tall, narrow
peak does not necessarily reflect a higher concentration than a
short, broad peak.
1H-MRS of the brain can detect a number of amino acids as
well as choline, phosphocreatine (PCr), creatine (Cr), and lac-
tate (table 1). N-acetyl-aspartate (NAA), the marker molecule
for normally functioning neurons, forms the highest peak. In
disease, signals from lactate and mobile lipids may frequently
be observed. The metabolites that are typically seen in 31P-
MRS are phosphomonoesters (PME), inorganic phosphate
(Pi), phosphodiesters (PDE), PCr and ATP (table 2). Pi is
composed of mono- and divalent phosphate with a pK of 6.75.
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MRS in Clinical Oncology Onkologie 2004;27:304–309 305

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Selecting TE for 1H-MRS should be based on the metabolites
sought [5]. Generally, short TE (20–60 msec) is applied to di-
minish signal loss due to T2 relaxation. Another advantage of
short echo delays is the ability to detect resonances from cou-
pled spin protons (e.g. glutamate, glutamine, inositol) whose
apparent transverse relaxation times are too short to permit
detection at larger echo delays. The peaks for lipids are gener-
ally evaluated at short TE, those for NAA-, creatine- and
choline-containing compounds are assessed at long TE. With
short TE (30 msec), resonances of macromolecular com-
pounds, which overlap the spectra of (mobile) lipids and low-
molecular substances, are observed as well. In order to sepa-
rate the compounds, MRS is repeated with an echo time of
136 msec. Thus, the lactate peak is inverted, whereas the lipid
peak will remain in phase.
Changes in the chemical shift of inorganic phosphate can be
used to determine intracellular pH noninvasively [6]. Acidosis
shifts the Pi peak to the right, whereas alkalosis shifts it to the
left. Changes in the chemical shift of Pi are usually referenced
to PCr. However, several problems arise with this approach.
Factors other than pH, especially ionic strength, metal ion
binding, and temperature affect the chemical shift of mono-
and dibasic phosphate.
Applications in Oncologic Diagnosis
With the development of spatial localization and mapping
techniques, MRS has adopted promising applications in
human cancer biology as well as in clinical oncology. Using
MRS, the chemical composition of tumors can be analyzed
and compared with the biochemical characteristics of adjacent
tissues. Cancers display typical metabolic alterations and an
intracellular pH more alkaline than the extracellular one [6].
1H- and 31P-MRS are of value in observing metabolic path-
ways of both neoplasms and intact parenchyma [7].
Brain
MRS of the brain is a protean tool. Early studies held out
hope that analysis of metabolite composition might improve
differential diagnosis of intracranial lesions. Recent findings
have cast doubt on the ability of 1H-MRS to play such a role
[8]. Nevertheless, MRS may contribute to the characterization
of brain neoplasms, as tumor spectra differ considerably from
those obtained in intact brain parenchyma.
Negendank et al. [9] and Kaminogo et al. [10] applied in vivo
1H-MRS to characterize brain tumors of the glial type in
adults. NAA signal intensities were decreased compared to
brain, regardless of the grade of malignancy. Choline signal
was highest in astrocytomas, creatine signal was lowest in
glioblastomas. New and recidivant astrocytic tumors had iden-
tical mean NAA/creatine and choline/creatine ratios. Mobile
lipids turned up in 41% of high-grade tumors with higher
mean amounts detectable in glioblastomas [9].
306 Onkologie 2004;27:304–309
To clarify the efficacy of 1H-MRS in differentiating high-grade
glioma from metastasis, 1H-MRS using PRESS with TE of
both 136 and 30 msec was used by Ishimaru et al. [11]. A defi-
nite intratumoral creatine signal was strongly associated with
the diagnosis of glioma, whereas 21 of 25 metastases showed
no creatine peak. Inversely, a definite lipid signal was ob-
served in all metastases and glioblastomas, but not in anaplas-
tic gliomas. In abscesses, resonances from cytosolic amino
acids, lactate, alanine, and acetate can be found [12]. In child-
hood cancer, the choline/NAA ratio seems to be predictive of
clinical outcome [13].
Overall, 1H-MRS may be used to confirm that a lesion is neo-
plastic before biopsy or to demonstrate a low likelihood of
malignancy. It can also serve to identify the portion of a tumor
that will most likely yield a positive result at histologic exami-
nation [14].
Mammary Gland
The potential of ex vivo 31P-MRS to differentiate between ma-
lignant, benign and non-involved breast parenchyma has been
shown by Merchant et al. [15]. The PME peak is constantly al-
tered in neoplastic tissues relative to the surrounding
parenchyma. PCr has been found to be elevated only in speci-
mens of benign tumors. Still more interesting are the phos-
pholipid profile data. Lysophosphatidylcholine is decreased in
malignant compared to non-involved, but also in benign com-
pared to normal breast tissues.
Uterus
1H-MRS of the cervix uteri demonstrates reproducible spec-
tral differences between normal and neoplastic tissue in vivo
[16]. Spectra from women with cervical cancer reveal strong
resonances for choline. In healthy volunteers the spectra are
dominated by resonances corresponding to creatine and lipids
without detection of a choline peak.
Prostate
1H-MRS has also proven useful for the non-invasive discrimi-
nation between benign prostatic hyperplasia and prostate car-
cinoma [17]. Apart from the typical citrate, creatine, and
choline signals of prostate spectra, both entities showed a
peak centered at 3.6 ppm that was assigned to myo-inositol.
The intensity of this compound was found significantly in-
creased in carcinoma compared to hyperplasia.
Bone and Soft Tissue
Tumors can be distinguished from normal muscle and soft tis-
sue by examining the low-energy phosphate resonance peaks
of the spectrum and inorganic phosphate. Malignant lesions
are distinguishable from benign ones on the basis of higher
mean peak ratios of PME and PDE to β-nucleoside triphos-
phates (NTP), a lower mean peak area ratio of PCr to NTP
and a higher mean pH. Early treatment-induced changes in
the PME peak predict sensitivity of a sarcoma to continued
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Golder
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therapy [18]. Furthermore, a relationship exists between intra-
tumoral pH and the degree of necrosis induced by radio- and
thermotherapy [19]. A decrease in the ATP/PME ratio from
the pretreatment to the first post hyperthermia scan is associ-
ated with a chance of 95% necrosis in surgically resected soft
tissue sarcomas [20].
Therapy Monitoring
Several spectroscopically demonstrable metabolic characteris-
tics of solid tumors appear to be of prognostic value. This
is especially true for radiotherapy. Metabolic trends after
chemotherapy were observed from several groups within
hours or days after cytotoxic drug application. Since there is
very little natural mobile fluorine in the body, in vivo 19F-MRS
is a powerful technique for monitoring intratumoral metabo-
lism and modulation of fluorine-containing anticancer drugs,
thus enabling prediction of tumor response.
Radiotherapy (Brain, Prostate)
The spectra of brain tumors during extended irradiation indi-
cate clear, but inconsistent influence of therapy. None of the
metabolites may serve as a firm indicator due to the complex-
ity of tumor tissue metabolism. More telling are the metabo-
lite ratios as they are consistently affected in the course of
time. In studies of early irradiation sequelae, an increase of
choline-related ratios is more symptomatic of cell prolifera-
tion than of cell injury, whereas the myo-inositol/creatine ratio
is one of the first indicators of local irradiation damage [21].
Tarnawski et al. [22] prospectively analyzed the prognostic sig-
nificance of 1H-MRS from the tumor bed of patients after
surgery for malignant glioma. They found a significant de-
crease in the NAA/Cr ratio and a significant increase in the
Choline/Cr, Choline/NAA and myo-inositol/Cr ratios after re-
section and external radiation. Metabolic information provid-
ed by proton MRS is likewise useful for the differentiation of
neoplastic and non-neoplastic lesions after stereotactic radio-
therapy of brain tumors [23].
1H-MRS has also been used to quantify the extent of neuronal
cell loss imposed on the brain during and after post-surgical
radiotherapy in regions adjacent to and more distant from the
tumor bed [21, 24, 25]. The myo-inositol/Cr ratio appears to be
one of the first indicators of local radiation injury. There were
no significant differences in whole-brain NAA between pro-
phylactic and therapeutic radiotherapy.
Assessing the impact MRS might have on the target vol-
umes used for radiotherapy planning, Pirzkall et al. [26]
arranged the levels of NAA and choline in line with MR
images of the neoplasms. T2-weighted images estimated the
region at risk of microscopic damage as being as much as
50% greater than MRS. Nevertheless, metabolically active
tumor still extended the T2-region in 88% of patients with
high-grade gliomas.
MRS in Clinical Oncology
Kristjansen et al. [27] assessed the value of MRS for the radio-
therapy of bronchogenic neoplasms in a pilot study. Following
5 Gy irradiation, a reversible increase in the ATP/Pi ratio was
observed. 20 Gy induced a reversible decrease.
DiBiase et al. [28] reported a remarkable approach to inte-
grating MRS into radiotherapy of the prostate. In prostate
brachytherapy, typically the target volume encompasses the
entire gland because of the inability to exactly localize the
often multifocal tumor. To assign cancerous areas a higher
dose of irradiation, the authors prescribed a dose of 130% of
the entire target volume to the abnormal citrate regions, thus
escalating dose in the metabolically active regions and re-
specting the normal radiation tolerances of the adjacent areas.
Similarly promising experience has been gained with the inte-
gration of MRS data into a planning system for prostate can-
cer patients who underwent implantation of permanent inter-
stitial 125I seeds [29].
Chemotherapy Monitoring (Methotrexate, 5-Fluorouracil)
Intravenous methotrexate has found increasing use as a means
of preventing the development of central nervous system dis-
ease in childhood acute leukemia [30]. However, pediatricians
are anxious about acute and chronic neurotoxicity following
high-dose methotrexate therapy. Davidson et al. [31] studied
children undergoing high-dose methotrexate therapy for
leukemia by 1H-MRS. All patients had a low choline/water
ratio compared to controls. The authors conclude that choline
depletion in the brain of these children reflects subclinical dis-
turbances of myelin metabolism as the result of methotrexate
therapy.
To understand the effectiveness of 5-fluorouracil (5-FU) in the
treatment of colorectal cancer, 19F-MRS has been used to
monitor the presence of the drug and a number of its anabo-
lites and catabolites in tumor tissue. Glaholm et al. [32] com-
pared hepatic 5-FU pharmacokinetics following intravenous
and intraperitoneal administration. Intravenously adminis-
tered 5-FU decayed with half lifes ranging from 5 to 17 min.
Following intraperitoneal application, 5-FU pharmacokinetics
varied still more intensely. Another group monitored 5-FU
and its modulation by interferon-α in patients with liver
metastases of colorectal cancers [33]. In patients observed by
MRS during the first 2 months of treatment, those with a visi-
ble 5-FU signal were likely to respond to therapy. When inter-
feron-α was added, 19F-MRS demonstrated in 7 of 15 patients
increased or newly developed signals. These patients were
more likely to subsequently respond to interferon-α.
Schlemmer et al. [34] studied the kinetics of 5-FU uptake and
metabolism in patients with neck tumors during radio-
chemotherapy. Serial 19F-MR spectra were obtained from cer-
vical lymph node metastases. The median of 5-FU was more
than twofold higher after the first therapy cycle compared to
the pre-treatment assessment. This and other findings indicate
that 19F-MRS is a powerful method to modify and optimize
schemes and doses in synchronous therapy regimens.
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Onkologie 2004;27:304–309 307
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Isolated Limb Perfusion
In patients with unresectable soft tissue sarcoma of the ex-
tremities, isolated limb perfusion (ILP) has become a promis-
ing therapeutic modality. However, the decrease in tumor size
is frequently only small even when the lesions show extensive
necrosis. Complete remissions might be missed and inade-
quate decisions made if the dimensions of a tumor at cross-
sectional imaging are the sole criterion to assess the efficacy of
the procedure. To fill the diagnostic gap in a non-invasive
manner, Kettelhack et al. [35] performed spectroscopic imag-
ing of soft tissue neoplasms prior to ILP and at regular inter-
vals after local therapy until definite tumor resection. The
PME/PCr and PME/β-ATP ratios decreased significantly after
ILP in comparison to preoperative values. Moreover, the
changes in the PME/β-ATP ratio were significantly different
between clinical responders and nonresponders and strongly
correlated to histologic response. Moreover, 31P-MRS pro-
vides information facilitating the decision on when to remove
the tumor or its residue and, in the case where the tumor re-
mains inoperable, whether or not to apply additional therapy
[36].
Perspective
MRS is a potent instrument to analyze and monitor tissue me-
tabolism non-invasively. However, not all expectations have
come true. The disappointment of some clinical oncologists is
due to its inability to clearly distinguish between benign and
malignant lesions and to differentiate between in situ and in-
vasive carcinomas. Ambiguity of spectroscopic findings has its
origin in biologic diversity and spatial variations in grading
within a tumor. Of equal importance are persisting methodic
inadequacies like different acquisition parameters, nonunifor-
mity of techniques used to localize spectra to the region of in-
terest and variable success of avoiding contamination of spec-
tra by metabolites from necrotic tumor and surrounding
edema [8]. More trials in well-defined clinical settings and new
techniques (e.g. 3D-chemical shift imaging, ultra-high whole-
body scanners, post-processing of data, quantification of spec-
tral data and metabolic concentrations) will clarify if MRS can
provide independent prognostic indices useful in cancer sur-
veillance.

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