Several options are available for
detecting, characterizing, and
treating metastases to the bone.
Snowy Egrets in the Mangroves_5033. Photograph courtesy of
Henry Domke, MD. www.henrydomke.com
Diagnostic Imaging and Image-Guided Therapy of
Skeletal Metastases
Junsung Choi, MD, and Meera Raghavan, MD
Background: The high incidence of skeletal metastases in cancer patients warrants careful detection with
imaging and follow-up. Efforts are needed to manage pain associated with skeletal metastases as part of
overall patient management.
Methods: This article reviews the current methods of diagnostic imaging in the evaluation of skeletal metastases
and image-guided treatment of bone metastases for the palliation of pain based primarily on the assessment
of imaging and interventional radiologic literature.
Results: Approaches to diagnostic imaging of skeletal metastases are summarized. Skeletal scintigraphy provides
high sensitivity for detecting skeletal metastases, but targeted computed tomography (CT) or magnetic resonance
imaging (MRI) may be needed to increase specificity. Newer imaging modalities, such as positron emission
tomography (PET)/CT, improve detection of both lytic and blastic metastases. Minimally invasive percutaneous
ablative treatment techniques, including radiofrequency ablation, microwave ablation, and cryoablation,
are examined. They provide alternative approaches to radiation therapy to effectively palliate pain of bone
metastases. Preliminary results of MR-guided focused ultrasound surgery (MRgFUS) demonstrate its effectiveness
in palliating pain from skeletal metastases.
Conclusions: Skeletal scintigraphy is the most common imaging modality for detecting skeletal metastases.
Additional imaging may be required based on the type of tumor, the disease state, or treatment options.
External-beam radiation therapy remains the mainstay for palliation of pain from bone metastases. Alternative
minimally invasive and noninvasive image-guided treatment options can provide effective pain palliation.
Introduction
From the Department of Diagnostic Imaging and Interventional
Radiology at the H. Lee Moffitt Cancer Center & Research Institute,
Tampa, Florida.
Submitted May 2, 2011; accepted July 26, 2011.
Address correspondence to Junsung Choi, MD, Department of
Diagnostic Imaging, Interventional Radiology, WCB-RAD OPI,
Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
E-mail: Junsung.Choi@moffitt.org
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
102 Cancer Control
Skeletal metastases are the most common malignant
bone tumors, occurring in 30% to 70% of all cancer
patients.1 Breast, prostate, and lung cancers are the major sources of bone metastases, with prostate and lung
cancers most common in males and breast cancer in
females.2 Less frequent sources of bone metastases include bladder cancer in men and uterine malignancies
in females.2
Detection of bone metastases is essential for accurate staging and optimal treatment. The goals of imaging
are to identify sites of metastasis and to evaluate them
April 2012, Vol. 19, No. 2
for the presence of, or potential for, complications such
as pathological fractures and spinal cord compression.1
Imaging is also used to guide biopsy and assess response
to treatment.
there are some features typical of different tumors.
Metastases of lung, kidney, and thyroid cancers are invariably lytic. Blastic lesions are usually seen in prostate (Fig 1A-C) and breast cancers. Mixed lesions are
frequently seen in breast carcinoma.1
Mechanism
Bone undergoes constant remodeling, maintaining a
dynamic balance between osteoclastic (resorptive) and
osteoblastic (bone-forming) activity.1,2 As a metastatic
lesion in the marrow enlarges, osteoclastic and osteoblastic reactive changes occur simultaneously.1 The simultaneous presence of both cell types explains why bone
metastases can be lytic, blastic, or mixed.1,3 The osteoblastic component of a lytic metastasis represents the
reaction of normal bone to the metastatic process.1 The
radiographic appearance of the lesion can vary, depending on the balance between bone-forming and resorptive
processes. Aggressive metastases tend be lytic, whereas
sclerosis indicates a slower, more indolent course.1
Metastases can occur by one of three routes: hematogenous, lymphangitic, and direct extension. Bone
metastases occur most commonly by hematogenous
spread.1,2,4 Both arterial and venous routes of dissemination are possible, but the venous paravertebral plexus of
Batson appears more important in osseous metastases.
Batson’s paravertebral plexus consists of an intercommunicating system of thin-walled vessels with low intraluminal pressure and without valves, allowing for
variability in the direction of flow.2 They lie outside
the thoracoabdominal cavity and are therefore not subject to direct pressure by the abdominal musculature.
These factors allow retrograde dissemination of tumor
cells through the vessels.4 The veins of the plexus also
have extensive communication with veins in the spinal
canal, explaining the tendency of osseous metastasis to
involve the spine.
Diagnostic Imaging Modalities
Skeletal metastases can be evaluated by four clinical
imaging modalities: plain film radiography, computed
tomography (CT), magnetic resonance imaging (MRI),
and skeletal scintigraphy.
Plain Film Radiography
Plain film radiographs are commonly used to evaluate
symptomatic areas and to confirm fi ndings seen with
other imaging modalities. Because of its poor sensitivity
A
Distribution
The distribution of osseous metastases is influenced by
the specific type of primary malignancy; however, there
is predominant involvement of the axial skeleton, an
area rich in red bone marrow.2,4 Red marrow is mostly
found in the axial skeleton, while fatty marrow is mostly
found in the appendicular bones (eg, long bones). The
vertebral column, sacrum, pelvis, and proximal femora
are the most common locations for metastatic disease.
Within the spine, the lumbar segment is most frequently
involved, followed by the thoracic and cervical segments. Infrequent sites of disease include the mandible,
patella, and bones of the extremities below the knee
and elbow.2 In most cases, metastases in the peripheral bones are due to bronchogenic lung carcinoma
and occur most often in the phalanges of the hand and
scaphoid and lunate bones of the wrist.2
Metastatic lesions can present with any appearance
(lytic, blastic, or mixed), regardless of tumor type, but
April 2012, Vol. 19, No. 2
B
C
Fig 1A-C. — (A) Anteroposterior radiograph of the pelvis in a patient
with prostate carcinoma. Multiple sclerotic foci (arrows) are seen
throughout the pelvis, compatible with blastic metastatic disease. (B)
Anteroposterior radiograph of the lumbar spine in the same patient
with prostate carcinoma. As seen in radiograph A, there are multiple
sclerotic lesions throughout the pelvis and proximal femora, as well as
ivory vertebral bodies (arrows). (C) 99mTc-MDP anterior and posterior
planar bone scanin the same patient. There are multiple areas of increased tracer accumulation corresponding to the sclerotic lesions seen
on radiographs A and B.
Cancer Control 103
(ie, 44% to 50% less sensitive than scintigraphy in detecting breast cancer metastases3), it is generally not used as
a screening method.3-5 Considerable bone destruction
must be present before a bone metastasis is evident radiographically. An estimated 30% to 75% reduction in
bone density is required for a lesion to be visualized on
radiographs.1 Moreover, the radiographic bone survey
remains useful in the event of a “skeletal emergency,”
such as an impending pathological fracture, particularly
of weight-bearing bones (Fig 2A). Radiography is invaluable for assessing the extent of cortical compromise and
the risk of pathological fracture in tubular bones.6 For
example, lytic lesions that destroy 50% or more of the
diaphyseal cortex can result in a 60% to 90% reduction
in bone strength, significantly increasing the risk of frac-
ture.6 Radiographs are recommended for patients with
symptoms of pain or tenderness that might be related
to a weight-bearing bone (eg, femur or tibia).6 The radiographic bone survey, however, remains important in
staging of multiple myeloma due to poor sensitivity of
scintigraphy in this condition.4,6
Bone lesions can appear as areas of faint or absent
density (osteolytic), as disrupted or absent trabecular
structure, or as sclerotic lesions or rims (osteoblastic).3
The limited contrast in trabecular bone makes radiographic detection of lesions more difficult than that in
cortical bone.3
Computed Tomography
CT demonstrates superior bony detail and distinguishes between different densities, allowing detection of
metastases within the bone marrow before destruction occurs.5 The sensitivity of CT for the diagnosis of
bone metastases ranges from 71% to 100%.2 CT is also
superior to radiography and skeletal scintigraphy for
identifying lesions in the spine and calvarium and for
detecting radiographically occult pathological fractures
(Fig 2B). The main limitation of CT is that only limited
areas can be scanned at a time and thus cannot be used
for whole-body screening.
CT can be useful for the assessment of bone tumor
response to treatment and is better than radiography
for delineating changes in attenuation and size of lesions. Image-guided biopsy is easily performed with
CT. This technique can also be used to identify the
unknown primary tumor in patients who first present
with skeletal metastasis.
Magnetic Resonance Imaging
A
B
Fig 2A-B. — (A) Anteroposterior radiograph of the right femur in a
patient with lung carcinoma. A lytic lesion in the proximal femur (arrow) is compatible with a metastasis. There is no obvious fracture. (B)
Noncontrast axial CT image from the same patient. CT confirms the
presence of a slightly expansile, lytic lesion involving nearly the entire
cross-sectional area of the proximal right femur. Furthermore, not seen
on the radiographs, CT demonstrates signifi cant cortical thinning with
a focal cortical break (arrow) compatible with pathological fracture.
104 Cancer Control
MRI can provide detailed imaging of the bone and bone
marrow. It is highly sensitive (with a sensitivity ranging from 82% to 100%3) for the detection of metastasis
because of its ability to demonstrate marrow abnormalities. Normal bone marrow contains a high percentage
of fat and demonstrates high signal intensity on T1weighted sequences. Metastatic lesions typically appear
as areas of decreased signal on T1-weighted sequences,
reflecting the replacement of normal marrow fat cells
by tumor. On T2-weighted images, metastases usually
have a higher signal than normal bone marrow due
to high water content4,6 and demonstrate gadolinium
enhancement (Fig 3A-C).
MRI is less sensitive than CT for the detection of
cortical bone destruction because cortical bone demonstrates a dark signal on both T1- and T2-weighted
sequences.1,4,5 On the other hand, this technique is
more effective than CT for elucidating spinal cord compression in patients presenting with spinal symptoms.
Due to superior soft-tissue contrast seen with MRI, it
can better distinguish benign from malignant vertebral
compression fractures.1,2
April 2012, Vol. 19, No. 2
A
B
C
Fig 3A-C. — (A) Coronal T1-weighted MRI in a patient with breast carcinoma. A well-defined lesion is present in the right proximal femur (arrow)
that demonstrates low signal intensity, reflecting replacement of normal marrow by tumor. (B) Coronal T2-weighted image in the same patient
demonstrates the lesion (arrow) to be high signal intensity, reflecting higher water content. Mild perilesional edema is present. (C) Coronal contrastenhanced, T1-weighted, fat-suppressed image. The lesion (arrow) demonstrates solid diffuse enhancement.
Skeletal Scintigraphy
Skeletal scintigraphy, generally referred to as bone scan,
is the most widely used method of detecting bone metastasis because it provides visualization of the entire
skeleton within a reasonable amount of time and at a
reasonable cost.1 99mTc-methylene diphosphonate (99mTcMDP) is the most commonly used tracer. It accumulates
in areas of increased osteoblastic activity and increased
blood flow, and it is reliable for detecting osteoblastic
metastases seen in breast and prostate cancers. The
method is less sensitive for detecting tumors that have
little or no osteoblastic reaction (such as those in multiple myeloma) or aggressive lesions with rapid bone
destruction.1 Lytic lesions can appear as “cold” defects
but are frequently overlooked.1
In contrast to plain fi lms, as little as 5% to 10%
change in the ratio of lesion to normal bone is required
to detect an abnormality on bone scan, and it is estimated
that bone scan can detect malignant bone lesions 2 to 18
months earlier than radiographs can.1 Therefore, skeletal
scintigraphy is the preferred initial imaging modality in
cancer patients at high risk of bone metastases.1 Bone
scan has published sensitivity rates between 62% and
100%, with a specificity of 78% to 100%.1 However,
tracer accumulation can occur in any area of high bone
turnover related to trauma, infection, or arthropathy.1,2,4
To overcome lack of specificity, correlative imaging with
radiographs, CT, or MRI is recommended, especially in
the context of equivocal findings (single “hot spot” or
few lesions). The presence of multiple lesions in patients
with a known malignancy is more suggestive of metastatic disease, although other nonneoplastic conditions
can also have multifocal areas of uptake.
Monitoring Treatment Response
Response of skeletal lesions to treatment may result in
reactive bone formation, or sclerosis. Sclerosis tends to
progress from the periphery toward the center.4 ProApril 2012, Vol. 19, No. 2
gressive sclerosis can make areas subtly more visible,
giving a false impression of disease progression. Sclerosis of a lytic component usually suggests a positive
response to treatment, while advanced or new lysis
within a sclerotic or mixed area, or an increase in the
size of a blastic lesion, may reflect actual disease progression.2 Determining response can be difficult as it is not
always possible to differentiate residual tumor from the
repair process. No consensus has been reached on the
type of study to be used or the criteria to be applied for
assessing response to treatment. Newer techniques are
targeted at improving the distinction between viable
tumor and necrotic tissue and the effects of treatment.
Scintigraphic uptake usually decreases following
treatment.4 However, early in the course of treatment,
particularly in patients receiving hormonal therapy, a
flare phenomenon can occur. This is characterized by
increase in uptake as a result of the stimulation of osteoblastic activity during the repair process.1
Adjunct Imaging Modalities
Positron Emission Tomography
Positron emission tomography (PET) has been found to
be superior to bone scan in detecting bone involvement
in various malignancies.1 Two radiopharmaceuticals
can be used, 18F-fluorodeoxyglucose (18F-FDG) or 18Ffluoride.3 18F-fluoride is administered intravenously as
Na (sodium) 18F.
FDG is a glucose analog that is taken up by tumor
cells and phosphorylated and becomes trapped within
the cells. Cells with high glucose consumption, such as
tumors, are FDG-avid and therefore uptake is an indicator of metabolic activity. Since uptake is not restricted
to skeletal metastases, FDG-PET is a mainstay of staging
in many malignancies.
Although 18F FDG-PET has been reported to detect
lytic, blastic, and mixed lesions, the data suggest that
it is more sensitive for detecting lytic metastases (Fig
4A-B). In particular, 18F FDG-PET is more sensitive in
Cancer Control 105
detection of skeletal metastases than conventional bone
scintigraphy with 99mTc-MDP in tumors such as renal
cell carcinoma and plasmacytoma/myeloma, which
tend to be predominantly osteolytic with little or no
local osteoblastic reaction.7 A recent meta-analysis by
Chang et al8 demonstrated increased sensitivity of 93%
A
B
Fig 4A-B. — (A) Axial PET image from the patient with breast carcinoma
illustrated in Fig 3. There is a focal area of increased activity (arrow) in
the subtrochanteric right femur. This lesion was radio-graphically occult (radiograph B). (B) Anteroposterior radiograph of the right femur
in the same patient with breast carcinoma. A subtle lucency can be
seen, but no definite lesion is identified.
106 Cancer Control
and specificity of 95% with FDG-PET in the detection
of bone metastasis from lung cancer compared with
conventional bone scintigraphy, which demonstrated
sensitivity and specificity of 87% and 82%, respectively.
The mechanism of 18F-fluoride is similar to 99mTcMDP, with its accumulation similarly dependent on
bone deposition and blood flow. Fluoride deposition accompanies the osteoblastic mineralization of
new bony matrix by depositing fluorapatite in place
of the common bone mineral hydroxyapatite.9 Similar to 99mTc-MDP bone scintigraphy, 18F-fluoride PET
demonstrates uptake in areas of osteoblastic activity.
However, 18F-fluoride PET achieves good skeletal-tobackground ratio as quickly as 1 hour after injection
compared with 2 to 4 hours with conventional bone
scan.7,10,11 18F-fluoride PET images also produce higher
spatial resolution compared to conventional bone scan
(Fig 5A-B).11 Several studies have shown better metastatic lesion detection with 18F-fluoride PET than with
a 99mTc-MDP bone scan.
Although only a few studies comparing 18F-fluoride
PET/CT and bone scan with 99mTc-MDP exist, 18F-fluoride PET seems to be more sensitive for evaluation
and characterization of bone metastases.11 18F-fluoride
PET was more sensitive in detecting skeletal metastases
than was planar 99mTc-MDP scintigraphy either alone or
in combination with 99mTc-MDP SPECT. In one study,
18F-fluoride PET detected skeletal metastases in all patients, whereas 99mTc-MDP bone scan detected lesions
in 18 of 23 patients.11 Anatomic correlation with CT
also increases the specificity of 18F-fluoride PET.12 18Ffluoride PET offers the additional advantages of faster
A
B
Fig 5A-B. — (A) Whole-body methylene diphosphonate (MDP) bone
scan and (B) 18F-Na PET scan done 1 year later in a 61-year-old man
with prostate cancer. 18F-Na PET demonstrates better spatial resolution
compared to conventional bone scan as well as multiple new areas of
increased uptake in the lumbar spine, which were proven metastases.
Uptake in the cervical spine and left shoulder were degenerative in
nature. Fig 5A-B images courtesy of Jaime L. Montilla-Soler, MD.
April 2012, Vol. 19, No. 2
study times, improved workflow, and increased convenience to the patient and referring physician. However,
widespread use of 18F-NaF as a bone-imaging agent has
been limited by familiarity with 99mTc-MDP scintigraphy
and by issues related to insurance reimbursement for
18F-fluoride PET.11
Single Photon Emission
Computed Tomography
Single photon emission computed tomography (SPECT)
uses the same radionuclide as conventional bone scan,
but images are acquired in a cross-sectional rather
than planar method, thus providing better anatomic
localization of lesions.5 SPECT and bone scan may
not detect purely lytic lesions, but this limitation is
minimized by combining SPECT with CT.1,5 Due to its
limited availability, SPECT/CT is not typically used for
fi rst detection of metastatic disease, but it can be used
to evaluate indeterminate fi ndings on whole-body bone
scans.5 Currently, the main drawback of SPECT is that
the data are obtained for only a limited skeletal region.
In busy routine practice, it is not possible to perform
several SPECT acquisitions to tomographically assess
the entire skeleton.
Novel/Evolving Imaging Modalities
Whole-Body MRI
Whole-body MRI uses fast pulse sequences over multiple anatomic regions to achieve a survey of the entire body.6 It is currently being used as an adjunct or
alternative to established multimodality approaches
for tumor staging or for screening for recurrence after
curative therapy.13 For MRI bone screening, the combination of unenhanced T1-weighted spin echo and
turbo-short tau inversion recovery (STIR) sequences
proved to be highly sensitive in discriminating benign
from malignant marrow disorders.13 Promising results
have been reported for detection of metastases in bone,
liver, and brain; whole-body MRI has also been proposed as an application for integrated assessment of
multiple myeloma.13
In addition, whole-body diffusion-weighted imaging
(WB-DWI) is an evolving application. While WB-DWI
is being used for detection of lymphadenopathy as well
as tumors in the abdomen and peritoneum,14 it has potential skeletal applications as well.
Diffusion-Weighted Imaging
Diffusion-weighted MRI (DWI) is being added to standard musculoskeletal MRI sequences at many institutions. DWI is based on the motion of water molecules.
Water molecules outside the body demonstrate random
Brownian motion.14 Extracellular water has more freedom, or is less impeded in its motion, in comparison to
intracellular water molecules, which are limited in their
motion by intracellular organelles, macromolecules, and
April 2012, Vol. 19, No. 2
cell membranes.15 The degree of restriction to water
diffusion in biological tissue is inversely correlated
to cellularity and the integrity of cell membranes.14
The water molecules are more restricted in tissues with a high cellular density associated with numerous intact cell membranes (eg, tumor tissue).
In contrast, in areas of low cellularity or where the cellular membrane has been breached (eg, necrosis), the
motion of water molecules is less restricted.14,15 Based
on the DWI sequences, the apparent diffusion coefficient (ADC) is calculated. The ADC is independent of
the magnetic field strength and can overcome a pitfall of
DWI known as “T2 shine-through.”14 Areas of restricted
diffusion in highly cellular areas show low ADC values compared with less cellular areas that demonstrate
higher ADC values.14
DWI has been shown to differentiate between areas of treatment-induced necrosis from highly cellular
residual tumor. Additionally, DWI is being applied for
monitoring response to chemotherapy and radiation,
and appears to have the ability to predict treatment
response.14
PET Radiotracers
Many recently published reports have emphasized the
potential advantages of PET using new radiotracers such
as 11C acetate, 11C and 18F-labeled fluoroethylcholine, and
18F-fluorocholine (FCH) in assessing skeletal metastases
in prostate cancer patients.12 Increased cell proliferation
in tumors and upregulation of choline kinase in cancer
cells are suggested as two possible mechanisms for increased choline uptake, particularly in prostate cancer
cells.12 Beheshti et al16 reported that 18F-FCH PET/CT
showed promising results in early detection of metastatic bone disease and monitoring response to therapy.
Summary
Bone scintigraphy remains the most common method
for detecting osseous metastasis since it is a whole-body
imaging modality. However, the lack of specificity of
scintigraphy usually requires additional evaluation with
a cross-sectional modality such as MRI or CT. Although
those can elucidate only a single or limited area, they
allow better lesion characterization. CT offers high
bony detail, and it is also used to perform image-guided
interventions. MRI has superior soft-tissue contrast and
can clarify overall marrow involvement. Plain film radiography is a mainstay in the evaluation of osseous
lesions and is important for assessing complications
such as pathological fracture.
Monitoring response of osseous metastases can be
difficult, and there is no established consensus on the
type of study or criteria to be used. PET/CT has become
a mainstay in the staging of many malignancies and
is also useful in the evaluation of osseous metastasis.
18F-fluoride PET is being used for evaluation of blastic
Cancer Control 107
metastasis, but widespread use is limited. Newer modalities such as WB-MRI and DWI as well as PET radiotracers show promise but continue to evolve.
patients may not be able to receive recurrent treatment
because of toxicity or limited tolerance of normal tissue
for additional radiation.
Management of Painful Skeletal Metastases
Percutaneous Ablation
The increasing longevity of the population and the
advances in the management of cancer patients have
contributed to an increasing number of individuals
living with metastatic bone disease. The majority of
patients who develop bone metastases will suffer from
significant bone pain. In addition to potentially intractable pain, complications of skeletal metastases include
fracture, decreased mobility, reduced performance,
and poorer quality of life.8 Beyond proper diagnosis
of skeletal metastases, management of bone pain is an
important component in the overall management of
patients with metastatic bone disease.9 Current treatment options include analgesic medications, systemic
chemotherapy, bisphosphonates, hormonal therapy,
radiation therapy, radionuclides, localized ablation techniques (radiofrequency, cryoablation, microwave, and
laser), and surgical stabilization.
Targeted pharmacologic therapy for pain control,
including chemotherapy, hormonal therapy, and narcotic analgesic medications, have limitations in the treatment of most painful bone metastases. Many medical
therapies do not achieve durable pain relief, and most
require chronic administration. Chemotherapy may be
ineffective, having either no response or toxicity that
limits the treatment dose. Bisphosphonate therapy is
used for decreasing and delaying the complications of
bone metastases and for pain relief. Although there is
evidence to support its effectiveness in providing pain
relief, it is not recommended as fi rst-line treatment.
Risks associated with bisphosphonates include renal
impairment and osteonecrosis of the jaw.19 Analgesics
often become the default therapeutic choice, even with
their potential side effects that may include drowsiness,
dizziness, headaches, nausea or vomiting, and development of dependence.
Percutaneous ablation for the palliation of painful bone
metastasis has developed into an effective, minimally
invasive alternative to the more established practices of
EBRT and systemic therapy.
Radiofrequency Ablation
Radiofrequency (RF) ablation is the most widely adopted
method of percutaneous ablation for the treatment of
soft-tissue tumors. The first application of its use in bone
was described by Rosenthal et al23 in the treatment of an
osteoid osteoma. RF ablation is performed by delivering
RF energy with one or more needle electrodes placed
directly into the treatment site under sonographic or CT
guidance (Fig 6). High-frequency alternating current
passes into the tissue, causing frictional heat that extends further into the surrounding tissue as conductive
heat, inducing cell death through coagulation necrosis.
Several clinical trials have demonstrated the effectiveness of RF ablation for palliation of pain from
bone metastases.24-26 In a recent multicenter American College of Radiology Imaging Network trial of 55
patients treated with RF ablation to palliate pain from
bone metastases, a decrease in pain severity was seen
at 1 month and 3 months following treatment.24 Based
on a 100-point pain scale, the average decrease in pain
intensity was 26.9 at 1 month and 14.2 at 3 months.
Patients also had a statistically significant improvement
in mood. Grade 3 toxicity occurred in 3 patients (5%).
In another multicenter trial of 43 patients with painful
osteolytic bone metastases, the mean score for worst
pain prior to treatment was 7.9 on a 10-point pain scale.26
This decreased to 4.5, 3.0, and 1.4 at 4, 12, and 24 weeks,
External-Beam Radiation Therapy
External-beam radiation therapy (EBRT), with or without systemic chemotherapy or hormonal therapy, is the
standard of care for the alleviation of pain caused by
skeletal metastases. Prospective randomized trials comparing single- vs multiple-fraction radiotherapy regimens
resulted in overall pain relief in 53% to 86% of patients
with uncomplicated bone metastases. Complete response varied from 15% to 58%.20 A higher response rate
was seen for patients with breast cancer and prostate
cancer than for those with lung cancer.21 A higher incidence of re-treatment occurred with the single-fraction
treatment (18% to 35%) than with a 10-fraction treatment
(8% to 9%).21,22 Although re-treatment of nonresponders
and those with disease progression can be successful,
108 Cancer Control
Fig 6. — Percutaneous radiofrequency ablation of an osteolytic bone
metastasis for pain palliation. Axial CT scan of the pelvis demonstrates
tines from a radiofrequency needle probe (arrow) extending into the lytic
bone tumor.
April 2012, Vol. 19, No. 2
respectively, following RF ablation. Opioid analgesic
usage decreased significantly at 8 and 12 weeks after
treatment. Adverse events were seen in 3 patients.
Cryoablation
Percutaneous cryoablation is performed in a fashion
similar to that of RF ablation. Insulated cryoprobes of
1.2 to 2.4 mm in diameter are utilized. These applicators
use high-pressure argon gas that expands within the
distal noninsulated segment of the cryoprobe, causing
rapid cooling (the Joule-Thomson effect) to temperatures as low as –100° C (Fig 7). Following the freeze
cycle, helium is introduced, which generates heat with
expansion within the cryoprobe and allows thawing of
the ice ball for probe removal. Cryoablation has certain
advantages over RF ablation. The ablation margin is
readily visible on CT imaging during treatment, due to
the low attenuation of the ice ball, allowing for more
precise targeting of the treatment field. Patients experience reduced pain during treatment and immediately
thereafter. Compared with RF energy, deeper penetration of ice into bone is seen, which may allow more effective treatment of osteoblastic bone lesions. Interim
results from single-center prospective clinical trials have
been encouraging.27,28 In their study involving 14 patients, Callstrom et al27 reported a decrease in the mean
score for worst pain in a 24-hour period, from 6.7 before
treatment to 3.8 (P = .003) at 4 weeks after treatment,
based on a 10-point pain scale. All 8 patients who were
taking narcotic medications prior to treatment reported
reduced medication use after cryoablation. Pain control
appeared durable, with 4 of 5 patients in the 24-week
follow-up interview reporting excellent pain relief. No
serious complications were reported.27
Microwave Ablation
Microwave ablation utilizes a thin antenna (14.5 gauge)
placed, under imaging guidance, in the treatment site.
A microwave generator emits an electromagnetic wave
through the noninsulated portion of the antenna, causing agitation of water molecules in the surrounding tissue. The agitation produces heat, resulting in cell death
via coagulation necrosis.29 Microwaves travel through
all types of tissue, including those with high impedance, such as lung or bone. Microwaves also have less
susceptibility to the heat sink effect in adjacent larger
vessels, thereby reducing possible distortion of the ablation zone. The heat sink effect is more problematic with
other thermal ablative techniques, leading to regions of
incomplete ablation.30 The benefits of microwave ablation also include higher intratumoral temperature, larger
and more uniform ablation volume, and faster ablation
time. The use of microwave ablation for treating patients with bone metastases has been limited, but early
results are promising.31,32 Other ablative techniques are
available, such as laser ablation and a new, nonthermal,
ablative modality known as irreversible electroporation
(IRE), which uses high-voltage direct current to irreversibly open nanopores of cell membranes to induce
cell death. However, little data are available, especially
for IRE, regarding treatment of patients with bone metastases. Clinical trials are necessary to determine the
efficacy of these procedures for the palliation of pain
from metastatic bone lesions.33-35
Summary
All of the percutaneous ablative techniques described
here have some limitations or disadvantages. Although
minimally invasive, they require skilled interventionalists to place needle probes or applicators into the accessible target. Probe placement into osteoblastic metastases with preserved cortical bone may be difficult.
The proximity of critical normal structures, including
nerves, major blood vessels, bowel, and bladder, must be
considered to prevent injury, and this influences patient
selection. Treatment also requires regional anesthesia,
moderate sedation, or general anesthesia for adequate
intraprocedural pain control.
MR-Guided Focused Ultrasound Surgery
Fig 7. — A cryoprobe being tested with sterile water prior to the cryoablation procedure. A small ice ball has formed around the noninsulated tip
of the cryoprobe following introduction of argon gas through the probe
while it is submersed in water.
April 2012, Vol. 19, No. 2
MR-guided focused ultrasound surgery (MRgFUS) is a
noninvasive thermal ablation technique that combines
high-intensity focused ultrasound tissue ablation with
MRI for imaging guidance. MRI is used for treatment
planning as well as for monitoring actual treatment. T2weighted images are used to evaluate the tumor and surrounding anatomic structures and to define treatment volume and treatment path. MR thermometry is performed
with phase map imaging, which relies on subtle changes
in resonance frequency of tissue at different temperatures, thus providing real-time temperature feedback during treatment. The focused ultrasound energy elevates
temperature sufficiently to cause protein denaturation
and cell death via coagulation necrosis. Immediately folCancer Control 109
lowing treatment, contrast-enhanced MRI is performed
to evaluate results. Since the concept of MRgFUS was
introduced in 1992 by Cline et al,36 its clinical safety and
effectiveness have been established for the treatment of
symptomatic uterine fibroids. Clinical investigations are
currently being conducted for breast, liver, brain, and
prostate tumors, and preliminary results for the treatment
of metastatic bone tumors have been encouraging.37-39
Treatment of Bone Metastases With MRgFUS
Treatment of bone metastases with focused ultrasound
has advantages over treatment of soft tissue, due to
higher absorption of acoustic energy (up to 50 times
that of soft-tissue tumors) and lower thermal conductivity of bone tissue, leading to reduced penetration
of energy into the bone.40,41 The treatment is targeted
to heat the cortical margin of the bone lesion. This
allows for a wider zone of coverage at the bone surface with each delivery of focused ultrasound energy
(termed sonication) and the need for fewer sonications,
resulting in faster treatment time. Although the relationship between bone invasion by tumor and bone
pain is unclear, it has been postulated that stimulation
of nerve endings in the endosteum and stretching of
the periosteum by increasing size of the tumor are
contributing factors.17
MRgFUS Procedure
MRgFUS treatment of bone metastasis is performed
under conscious sedation and involves a focused ultrasound phased array system integrated with a clinical
MRI system. The procedure described is based on a current commercially available MRgFUS system (ExAblate
2000 system; InSightec Ltd, Haifa, Israel).
Pretreatment MRI localizes the painful bone lesion.
The targeted lesion is positioned directly above a water
bath within the MR table that contains the phased array
transducer. Acoustic coupling is accomplished by placing a coupling gel pad with degassed water between the
patient and the chamber containing the transducer. The
skeletal structure in the treatment region is evaluated to
identify any abnormalities that may prevent safe treatment. Adjacent organs such as bowel, lung, or major
nerves are evaluated to ensure that they are not in the
path of the ultrasound treatment beam. If the bone metastasis is identifiable on the MR images, the contour of
the bone cortex in the targeted area is traced, followed
by an estimation of the treatment volume. If the bone
is not well visualized, CT images can be overlaid on the
MR images to better define the cortical margin that is
drawn. Based on the treatment volume and the defined
cortical margin, the total number of planned sonications and their locations are determined. Pretreatment
A
C
B
D
Fig 8A-D. — (A) CT scan demonstrating a solitary osteoblastic metastasis located in the right iliac bone adjacent to the sacroiliac junction (arrow). (B)
MRgFUS planning image for a sonication. Axial MRI scan shows the targeting of the bone lesion, with the beam bath for acoustic energy seen in light
blue. The focal point (cross hairs) is placed deep to the cortical bone. The blue oval is the actual target for heat deposition. The green line represents
the contour of the bone cortex. (C) Phase map image of a sonication treatment. The arrow points to the temperature history curser on a phase map
image (temperature map) at the site of sonication. The curser can be moved within the image to evaluate temperature rise. (D) A temperature history
graph demonstrating the measured temperature over time at the specified position of the cursor in image C.
110 Cancer Control
April 2012, Vol. 19, No. 2
verification of planning accuracy
is performed with subtherapeutic sonications. When a mild increase in temperature is observed
at the exact intended target (geometric and thermal-dose verification), then the actual treatment is
started, using therapeutic energy
levels. Sonications are performed
on each successive planned sonication site, while temperature rise
is monitored with MR phase map
imaging (Fig 8A-D). For each seA
B
lected treatment location, sonicaFig 9A-B. — (A) PET/CT scan demonstrating a painful PET-avid bone metastasis to the medial left
tion parameters, including acousscapula. (B) Posttreatment with MRgFUS. MRI with contrast demonstrates the site of treatment
tic energy, sonication duration,
(arrow) with cetral area of low signal and rim of tissue enhancement. The arrowhead indicates the
coupling gel pad, and (p) shows the phased array transducer.
and acoustic power, are evaluated
and adjusted. Acoustic power is
adjusted during the entire treatment to not exceed the
treatment. No severe adverse events were reported. A
thermal-dose threshold between 65° C and 85° C, with
phase III multicenter randomized prospective trial is in
maximum acoustic energy reaching 2,000 joules. The
progress to evaluate the efficacy of MRgFUS for the palsonication duration is approximately 30 seconds, with
liation of pain from bone metastases or multiple myeloma
a cool-down duration of 90 seconds between sonicain patients who have failed or are not candidates for
tions. They are continued until the prescribed target
radiation therapy. This trial is nearing completion of its
area has been treated. Posttreatment diagnostic MRI
targeted accrual of 150 patients. The results, which may
is conducted, including T2-weighted sequences and
become available by the time of this publication, should
contrast-enhanced T1-weighted images, to evaluate the
provide more support for the efficacy of this therapy
extent of the ablated area (Fig 9A-B).
(J.C., unpublished data, 2012). Another multicenter prospective randomized trial has been started in Europe (not
MRgFUS Treatment Results
in the United States) comparing MRgFUS with EBRT for
The initial evaluation of safety and effectiveness of MRgthe palliation of pain from skeletal metastases.
FUS in pain palliation was shown in two feasibility studThe advantages of MRgFUS treatment for the palliaies.39,42 In the first study,39 12 patients of 13 with a mean
tion of bone pain include a noninvasive approach with
follow-up of 59 days received adequate treatment and
a short recovery time, and without the need for interfollow-up. One patient’s treatment was prematurely terventional expertise. Osteoblastic as well as osteolytic
minated due to intolerance of pain related to sonication.
lesions can be treated similarly. Unlike conventional
A total of 10 patients reported prolonged improvement
multifractionated radiation therapy, treatment is perin pain and reduction in analgesic medication usage.
formed in one session, without ionizing radiation and
No severe adverse events were recorded.39 In the secwith the possibility of repeat treatment for symptom
ond single-center study,42 which included 11 patients,
recurrence or new tumors.
12 metastatic lesions were treated. In these patients the
There are limitations to use of the procedure as
mean visual analog pain score (VAS), on a 10-point scale,
well. The location of the lesion might prevent treatment
was reduced from 6.0 before treatment to 0.5 at 3 months
since the targeted lesion needs to be coupled to the array
posttreatment. All patients reported decreased intake of
transducer without intervening air bubbles or vital strucpain medication, including 7 patients who ceased taking
tures. This problem may be diminished with the use of
all pain medication. No adverse events were reported.
a mobile conformal array transducer, which is presently
In the most recent multicenter prospective trial, Liberbeing investigated. The use of MRgFUS for metastases
man et al43 performed 36 treatments on 32 bone lesions
in the skull and the spine, except the posterior elements
in 31 patients. Of the 25 patients with a follow-up of
of the lower lumbar spine, is limited; before applying
3 months or longer, 18 (72%) reported significant imMRgFUS to lesions in the spine, additional investigation
provement in pain, and their average VAS rating reduced
is necessary to determine the safety of the nearby spinal
from 5.9 before treatment to 1.8 at 3 months after treatcord and nerve roots during treatment. Patients who
ment. Nine patients had a complete response, 6 had no
cannot undergo MRgFUS are those with metal orthoperesponse, and 1 reported an increase in pain. Of the 9
dic hardware near the treatment field and those with
patients who were prescribed opioid pain medications
cardiac pacemakers or other contraindications to MRI.
prior to treatment, 67% reported reduction in usage postFinally, fracture risk assessment in weight-bearing long
April 2012, Vol. 19, No. 2
Cancer Control 111
bones is necessary prior to treatment, in order to reduce
the potential for pathological fractures.
Conclusions
Skeletal scintigraphy remains the most commonly used
diagnostic imaging modality for the evaluation of skeletal metastases. More sensitive imaging modalities are
available to better define metastatic lesions and possibly alter patient management. Further investigation is
needed, based on the primary tumor, disease state, patient symptoms, and available treatment options. Newer
imaging modalities such as 18F-Na PET and whole-body
MRI are not routinely available, but they may be more
widely used in the future as treatment modalities evolve.
Treatment of painful bone metastases requires a
multifaceted approach. Radiotherapy continues to be
the mainstay for palliation of bone pain. Image-guided
percutaneous ablation of skeletal metastases provides a
minimally invasive treatment option that appears to be
safe, effective, and durable. Local ablative treatments
require appropriate patient selection, and anatomic considerations are critical to successful outcomes. MRgFUS
provides a noninvasive alternative to local ablative
methods. Preliminary investigations show promise,
and further data supporting the efficacy and validity of
this treatment are anticipated.
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