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Journal of Medicine, Radiology, Pathology & Surgery (2015), 1, 35–39
REVIEW ARTICLE
A BOLD appraisal of cancer
M. L. Asha, Laboni Ghorai, Basetty Neelakantam Rajarathnam, H.M. Mahesh Kumar,
Srilakshmi Jasti, P. Deepak
Department of Oral Medicine & Radiology, Dr. Syamala Reddy Dental College, Hospital & Research Centre, Bengaluru, Karnataka, India
Keywords
Blood-oxygen-level-dependent magnetic
resonance imaging, functional imaging,
radiosensitizers
Correspondence
Dr. Laboni Ghorai,
Department of Oral Medicine & Radiology,
Dr. Syamala Reddy Dental College, Hospital
& Research Centre, #111/1, SGR College
Main Road, Munnekolala, Marathahalli
(Post), Bengaluru - 560 037, Karnataka, India.
Phone: +91-9035709695.
Email: [email protected]
Received 01 Jun 2015;
Accepted 25 Jul 2015
doi: 10.15713/ins.jmrps.26
Abstract
Tissue hypoxia is a biological condition characterized by oxygen deficiency at the
tissue level. Hypoxia has been seen to play a crucial role in tumor recurrence in head
and neck cancer patients. The detection and assessment of tumor hypoxia plays a
critical role in both validation and development of hypoxia modification therapies.
Hypoxic cancers being more resistant to radiotherapy and chemotherapy, attempts
have been made to improve the response of hypoxic cancers to radiotherapy through
the use of radiosensitizers such as carbogen and others. Several techniques to assess
the status of tumor oxygenation have been developed in the past, among which
functional imaging techniques remain the most validated. Blood-oxygen-leveldependent magnetic resonance imaging (BOLD MRI) is a non-invasive functional
imaging technique that can recognize hypoxic cancers which will respond to
accelerated radiotherapeutic treatment with radiosensitizers. BOLD MRI employs
a T-sensitive sequence which can detect a transient rise in signal during oxygen
inhalation. This increase in signal intensity is caused by the reduced paramagnetic
effect due to a decrease in the blood deoxyhaemoglobin level within cancer. Hence,
BOLD MRI can detect reduced hypoxia in the malignant solid tumors and may
pave the path for more conservative treatment approach for hypoxic head and neck
cancers in future.
Introduction
Pathophysiology of Hypoxia
Tissue hypoxia is a biological condition that is characterized
by oxygen deficiency at the tissue level.[1] Hypoxic
microenvironment is frequently found in solid tumors and
is a well-known factor responsible for poor prognosis in head
and neck squamous cell carcinoma (HNSCC). It indicates an
imbalance between the increased oxygen demand of the rapidly
proliferating cancer cells and the decreased oxygen delivery
due to poor vascularization and blood supply.[2] The resultant
compensatory mechanisms utilized by tumors in response to
hypoxia has an unfavorable impact on the therapeutic response,
irrespective of the treatment modality employed.[1] Hence,
tumor hypoxia has become a central issue in cancer treatment.
The detection and assessment of tumor hypoxia now plays a
critical role in both the validation and development of hypoxia
modification therapies. Functional imaging techniques being
non-invasive are most common used in the field of cancer
research.
Hypoxia is a pathophysiological state that may be classified
as generalized or localized. Localized tissue hypoxia, as it
relates to tumors, can be “acute” which may be a result of
temporary reduction in blood supply or “chronic” which
may be caused by insufficient vascularization impairing the
metabolic needs of the growing tumor. Thomlinson and Gray
were the first to report the presence of tissue hypoxia in the
cancerous tissue. All solid tumors, especially malignant solid
tumors, are subject to hypoxia and often exhibit a decreased
oxygen tension than their tissue of origin.[1] Recurring
tumors most often exhibit a higher hypoxic fraction than
primary tumors.[3,4]
Oxygen diminution in hypoxic tumor brings about
physiological and biochemical changes that aid in tumor growth
and propagation. Increased anaerobic glycolysis causes increased
uptake of glucose, decreased tissue pH and acquisition of more
malignant characteristics. A permanent alteration in the cellular
Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 1:4 ● Jul-Aug 201535
Asha, et al.
composition of tumor cell is brought about by the hypoxiainducible factors (HIFs).[1]
The role of hypoxia in tumor progression is explained in
Flowchart 1.[1]
Effect of Tumor Hypoxia on the Effectiveness of
Curative Treatment of Cancer
1. Accumulation and propagation of cancer stem cells
2. Reduction of the effectiveness of radiotherapy
3. Increased risk of metastasis and reduction of the effectiveness
of surgery
4. Resistance to chemotherapy and chemo-radiation.[1]
Diagnosis of Tissue Hypoxia
Hypoxia or oxygen deprivation is a well-established phenomenon
that plays an important role in tumor progression and is a prime
cause of tumor resistance to therapy.[5] Hence, there has been a
positive incentive to develop various methods to assess the tissue
hypoxia which include.
Direct methods
1.
2.
3.
4.
5.
Oxygen electrode
Phosphorescence quenching
19F-magnetic resonance spectroscopy
Electron paramagnetic resonance
Overhauser-enhanced magnetic resonance imaging (MRI).
BOLD MRI in hypoxic cancer treatment
Endogenous markers of hypoxia
1. HIFs 1α
2. Carbonic anhydrase IX
3.Osteopontin
4. Glucose transporter 1
5. A combined immunohistochemistry panel of protein markers
for hypoxia
6. Comet assay.
Physiologic methods
1. Near-infrared spectroscopy/tomography
2. Photoacoustic tomography
3. Contrast-enhanced color duplex sonography
4. Blood-oxygen-level-dependent MRI (BOLD MRI)
5. EF5 (pentafluorinated etanidazole)
6.Pimonidazole
7. Hypoxia positron emission tomography imaging
a.
18F fluoromisonidazole
b.
18F fluoroazomycinarabinofuranoside
c.
18FEF5 (pentafluorinated etanidazole)
d.
18F flortanidazole
e.
Copper (II) (diacetylbis [N4methylthiosemicar
bazone])
f.
18F Fludeoxyglucose imaging of hypoxia.[1]
Imaging of Tissue Hypoxia
Imaging is an important diagnostic modality that has a
valuable contribution in staging, framing treatment plan and
post-treatment follow-up of the patients with head and neck
cancer.[6] Functional imaging is a method in medical imaging
that can detect or measure changes in metabolism, blood flow,
regional chemical composition, and absorption. Hence, the
functional imaging techniques can predict cancer behavior and
treatment response, can evaluate new anti-angiogenetic agents
and can identify residual or recurrent tumor. With such advanced
hypoxia imaging techniques, spatiotemporal characteristics of
tumor hypoxia and the changes in the tumor microenvironment
can be analyzed.[7]
BOLD MRI
Flowchart 1: Regulation of hypoxia-inducible factors (HIF)-1α and
protein signaling under normoxic and hypoxic conditions (PHD:
Prolyl hydroxylase domain containing protein, FIH-1: Factor
inhibiting HIF-1, VHL: Von Hippel-Lindau tumor suppressor,
HRE: HIF-1 Response element)
36
BOLD effect was first presented by Ogawa et al. in 1990. They
found that the magnetic resonance signal reduces when the
concentration of oxyhemoglobin (HbO) decreases and also
showed that the reduction of signal not only occurs in the blood
but also outside the blood vessels.[8]
BOLD MRI is an MRI technique that can examine the
physiology of tumors without exogenous contrast. BOLD
imaging takes the advantages of subtle differences in magnetic
susceptibility between HbO and deoxy-Hb to assess tissue blood
oxygen levels.[9]
BOLD imaging has been a well-known technique in
performing functional MRI studies of brain activation in
Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 1:4 ● Jul-Aug 2015
Asha, et al.
BOLD MRI in hypoxic cancer treatment
neuroimaging and also been used to evaluate renal perfusion
at high temporal resolution. Now-a-days, BOLD MRI is widely
used for oncologic investigations and has further been extended
for the assessment of the oxygenation status of head and neck
tumors.[9-11]
BOLD contrast principle
The relative decrease in the concentration of paramagnetic
deoxy-Hb can be detected by MRI as a weak transient rise in
the T2 weighted signal. This is known as the BOLD contrast
principle.[12]
Normally, blood contains a mixture of deoxy-Hb and HbO.
Deoxy-Hb is paramagnetic, and HbO is diamagnetic.[10] The
paramagnetic nature of deoxy-Hb (Pauling and Coryell, 1936)[13]
and its influence on the MR signal (Brooks et al. 1975)[14] were
well known before the development of MRI.
BOLD-MRI is sensitive to perivascular bulk microscopic
magnetic field alterations caused by paramagnetic deoxygenated
Hb (Ogawa et al. 1990, Ogawa 2012). The effective transversal
MR relaxation time T2 has been found to be affected by the
changes in the amount of deoxy-Hb per tissue volume element
(voxel).[15] Since BOLD MRI utilizes this paramagnetic deoxyHb as an endogenous contrast agent, this method is sensitive
to the changes in partial pressure of oxygen in and around the
blood vessels.[11] Deoxygenated blood appears darker on T2weighted images compared with oxygenated blood. Any increase
in Hb oxygen saturation would therefore be expected to cause
an increase in the signal and conversely, T2 decreases and signal
attenuation in T2-weighted MR images occur with an increase
in the volume fraction of deoxy-Hb in blood within a tumor.
Thus, the contrast is said to be blood-oxygen-level-dependent
(BOLD).[10]
Henceforth, BOLD MRI may provide complementary
information related to tissue oxygenation that aids in defining
optimal treatment strategies for patients with hypoxic tumors.[1]
The oxygenation status of cancer cells was shown by Gray
et al. in 1953 to affect the outcome of radiotherapy, with
more oxygenated cells being more radiosensitive. Since then,
considerable research has been carried out on techniques that
aim to increase radiosensitivity with the aim of improving the
efficacy of radiation treatment. Increasing the oxygen available
to the cells can be accomplished by inhaling 100% oxygen,[16]
hyperbaric oxygen[17,18] and other high-oxygen gas mixtures
such as carbogen (conventionally 95% O2 and 5% CO2).[16,19-23]
Breathing high concentrations of oxygen should increase blood
oxygen saturation and the measured signal from tissues on
T2-weighted images; however, the inhalation of 100% oxygen
can cause a degree of vasoconstriction within tumor vessels.
The addition of the vasodilator gas carbon dioxide to the oxygen
(forming carbogen) is intended to counter this vasoconstriction.
An additional effect of adding carbon dioxide to oxygen is to shift
the HbO dissociation curve to the right.[10] Compared with air,
both the increased percentage of oxygen in the carbogen and the
shift in the HbO curve will make more oxygen available in the
capillaries. Radiosensitizing agents such as ARCON (Accelerated
Radiotherapy with Carbogen and Nicotinamide)[20,24] which
alleviates acute hypoxia by reducing the intermittent closure
of blood vessels, have also been investigated for their ability to
improve the results of radiotherapy in patients with advanced
HNSCC.[2,10]
The identification of patients who might benefit from the
radiosensitizers is a difficult task, as the hypoxic fraction inside
tumors needs to be assessed. T2-weighted MR techniques show
promise in being able to identify such regions within tumors
non-invasively. Imaging human tumors before and during the
administration of a radiosensitizer and vasodilator such as
carbogen may permit identification of regions with oxygenation
and flow changes, which may in turn indicate regions of reversible
hypoxia.[10] BOLD MRI can successfully detect these regions of
reversible hypoxia within the cancerous tissue through changes
in blood deoxy-Hb level during administration of radiosensitizers
and hence, may pave a path for a more conservative treatment
approach for hypoxic cancers in the future.[6]
MRI protocol
Patient preparation is an important step before the MRI
procedure. The patient should be positioned supine in the body
coil with anesthetic face mask comfortably but securely strapped
in place. The patient’s blood oxygen saturation and pulse rates
should then be continually monitored by a pulse oximeter
attached to a finger and the respiration rate should be recorded
every minute by a radiographer, nurse, or anesthetist present in
the magnet room.
Scout images of the tumor should now be acquired using
a standard steady-state free precession sequence which is an
MRI technique that uses steady states of magnetizations. The
subject should then be brought out of the magnet, and the
mask should be attached to a customized anesthetic circuit
and air cylinders. The gas flow rate should be adjusted to be
comfortable to the patient, who should then be returned back
to the magnet. Now-a-second scout image should be acquired
to check slice position. A delay should be introduced between
acquisitions, calculated to keep the time resolution to one
image per minute.[10]
Gas inhalation protocol
The breathing circuit design should be capable of providing a
flow rate of at least 20 L/min. The gas flow should be continually
modified by trained personnel throughout the examination to
ensure it was sufficient. The mask should have valved inflow/
outflow holes to prevent rebreathing, and to make breathing in
and out equally comfortable.
A careful and complete explanation of the procedure should
be made to each patient, so the hyperventilation does not panic
them. Before the MRI examination, an evaluation for mask
tolerance and gas tolerance should be undertaken, by practicing
with the circuit and those unable to cope with either should not
be allowed to proceed further.
Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 1:4 ● Jul-Aug 201537
Asha, et al.
The effects of breathing carbogen being at a maximum after
5-10 min, the initial imaging protocol used to acquire images
during 5 min of air-breathing, 5 min of carbogen, and 5 min
of air, with a 5 min transition period without imaging between
them. This protocol further evolved into continuous imaging for
30 min: 10 min air, 10 min carbogen, and a further 10 min of air.
However, the final protocol has been accepted to be 5 min air
breathing, followed by 10 min carbogen, and 10 min air.[10]
Image analysis
Regions of interest should be drawn from the T1-weighted scout
image, around the visible limits of the tumor. Color overlays are
being used to help identify regions that increased significantly in
signal intensity with the carbogen breathing.[10]
The response of the hypoxic tumors as interpreted by BOLD
MRI before and during the administration of radiosensitizers has
been summarized in Flowchart 2.
BOLD MRI: Merits and Demerits
BOLD MRI has become a useful tool that can be used to
interrogate the pathophysiology of tumors. Non-invasively, it
can monitor real-time changes of tumor oxygenation during
the administration of pharmacological treatments and can
assess the maturation and the functional state of tumor blood
vessels. It can be repeated whenever necessary and above
BOLD MRI in hypoxic cancer treatment
all it does not require any exogenous contrast medium or
radioisotope.
However, this technique has certain drawbacks. BOLD MRI
is a non-quantitative method for assessing tumor pO2, the rise
in signal is not always the result of oxygenation and the signal
changes are small, short-lived and may pose a challenge in
understanding and interpretation.[6,12] Hence, it alarms a need
for higher level of training in observation and interpretation of
the same.
Conclusion
Tumor hypoxia is a well-known biological entity that is often
present in malignant solid tumors. Hypoxic tumors employ
several different survival mechanisms, which may result in a
loss of apoptotic potential, increased proliferative potential, and
formation of new blood vessels that encourages the evolutionary
selection for a more malignant phenotype. As such, hypoxia
affects the curability of solid tumors, regardless of treatment
modality.
Given the negative treatment and outcome problems
associated with tumor hypoxia, a major goal for clinicians
is to identify hypoxic tumors through a number of different
diagnostic approaches.[1] BOLD MRI is one such robust
technique which is reliable, easy to use and can assess the
tumor oxygenation without the use of any exogenous contrast
agent. Thus, BOLD MRI is a valuable modality that provides
functional and physiological information on tumor hypoxia
which has prognostic and predictive value. Such an assessment
with BOLD MRI will strengthen its valuability to the radiation
oncologists and surgeons, heralding the possibility to implement
this functional imaging technique for the diagnosis of hypoxic
cancer in routine clinical practice.
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Flowchart 2: Schematic representation of method of assessing the
response of hypoxic tumors to radiosensitizer
38
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How to cite this article: Asha ML, Ghorai L, Rajarathnam BN,
Mahesh Kumar HM, Jasti S, Deepak P. A BOLD appraisal of
cancer. J Med Radiol Pathol Surg 2015;1:35-39.
Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 1:4 ● Jul-Aug 201539