2. Introduction
Bone is the third most common organ affected by metastases, after the lung
and liver.
Can also be extensive in patients with multiple myeloma, and lymphoma.
3. Skeletal related events
Skeletal-related events (SREs) that are due to bone metastases can include
Pain
Pathologic fracture
Hypercalcemia
Spinal cord compression.
Across a wide variety of tumors involving bone, the frequency of SREs can be
reduced through the use of osteoclast inhibitors, such as bisphosphonates
or denosumab.
4. Epidemiology
●At postmortem, 70 to 90 percent of patients with breast or prostate cancer have
some form of skeletal metastases.
●Bone metastases develop in 50, 44, and 37 percent of patients with thyroid, lung,
and renal cancer, respectively .
●Among solid cancers, breast, prostate, lung, thyroid, and kidney cancer account
for 80 percent of all skeletal metastases. However, many other primary malignant
tumors can spread to bone, including, but not limited to, melanoma, lymphoma,
sarcoma, and hepatocellular, as well as uterine carcinomas.
Skeletal lytic lesions are present at the time of diagnosis in approximately 60
percent of patients with multiple myeloma.
Myeloma lesions are rarely sclerotic; when they are, they are often associated with the
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal spike, skin
changes)
5. Clinical presentation
Mostly asymptomatic
There is usually no reason to scan for bone metastases in the absence of symptoms
unless routine laboratory studies indicate an elevated alkaline phosphatase or an
elevated calcium level.
Symptomatic patients
Usually presents with pain
6. Pain
The character of the pain
somatic (ie, achy, sharp, well-localized)
neuropathic (ie, burning, shooting, radiating).
Worse at nights
It may be constant or exacerbated by movement of the joint or involved bone
(so-called "incident" pain).
Sudden severe pain may be caused by a pathologic fracture, and prompt
evaluation, especially in patients with a history of cancer, is necessary.
7. Neurologic symptoms
Neurologic symptoms are not uncommon in patients with vertebral
metastases
causing spinal cord compression or spinal instability.
Symptoms of cord compression range from pain to neurologic deficits, including
motor weakness and paralysis, sensory deficits, bowel and bladder dysfunction,
and ataxia.
Typically, the deficits result from soft tissue tumor compressing the spinal cord or
cauda equina, rather than the pathologic fracture itself.
8. Distribution
Predominantly involves areas of red marrow, such as the skull, axial skeleton,
or the medullary portion of the appendicular skeleton.
Less commonly, metastases can be cortically-based surface lesions, although
this almost always occurs in the appendicular, rather than the axial, skeleton.
The most common locations
the vertebral column, sacrum, pelvis, and proximal femurs
Within the spine, the lumbar, followed by the thoracic and cervical.
Metastatic disease is distinctly unusual in anatomic sites distal to the elbow in
the upper extremity and distal to the knee in the lower extremity (termed
acrometastasis).
Lung and renal cell cancers are the most common primary sites
9. Detection and diagnosis
The choice of imaging should be guided by
The clinical presentation
Underlying histologic type of tumor
Osteoblastic versus osteolytic patterns vary
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14. Extremity pains
Plain radiographs of the affected area for initial evaluation.
If a complete or impending pathologic fracture is suspected
cross-sectional imaging with contrast-enhanced computed tomography (CT) or
magnetic resonance imaging (MRI) can delineate those patients who may require
urgent surgical stabilization.
15. Back pain
Contrast-enhanced spinal MRI is indicated even in the absence of any
neurologic signs
to evaluate bone metastasis,
to rule out epidural extension of tumor and spinal cord compression.
MRI also differentiates between metastasis and spondylodiscitis.
16. Biopsy
For patients with no history of cancer, biopsy of skeletal abnormality is
necessary for diagnosis.
For patients whose cancer is in remission, documentation of a pathologic
diagnosis may be necessary if this is the first evidence of recurrence or
disease progression.
For patients with known history of stage IV malignancy or who were found to
have other visceral metastasis on staging or restaging evaluation, clinical
diagnosis with one or more imaging modalities may be sufficient to make a
presumptive diagnosis of bone metastasis.
17. Choice of skeletal survey
For most patients with a known cancer capable of mixed lytic and blastic
metastasis or pure blastic metastases, skeletal scintigraphy (bone scan) is
indicated.
For pure lytic tumors, such as multiple myeloma, a plain radiographic skeletal
survey is indicated to screen the skeleton.
For patients with lytic primary tumors, including Ewing sarcoma family of
tumors (EFT), 18-labeled fluorodeoxyglucose PET integrated with CT
(integrated 18-FDG-PET/CT) is the recommended initial step.
For patients with sclerotic multiple myeloma (the POEMS syndrome), as well
as EFT with a sclerotic primary tumor and for all other patients with
suspected bone metastases, bone scan is recommended.
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21. Plain radiograph
Generally not used for metastasis screening
However, the radiographic bone survey remains the standard for the initial staging
of multiple myeloma.
Plain radiographs are more sensitive than bone scan for purely lytic metastases
(eg, multiple myeloma, some renal cell metastases)
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25. Plain radiographs
The extent of cortical compromise seen on plain radiographs is an important
indicator of the risk of a pathologic fracture in tubular bones
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27. Cross sectional imaging
Evaluation of suspected complete or impending pathologic fractures
Suspected epidural spinal cord compression
metastatic bone disease involving the shoulder, spine, or pelvis because of the
complex anatomy
if other imaging studies are equivocal and there is a strong clinical suspicion
of bone metastases
28. CT scanning
CT demonstrates superior bony detail and can detect osteolytic and
osteoblastic metastases within the bone marrow before there is sufficient
destruction to become evident on plain radiographs
However, CT is not more sensitive than bone scan.
CT scans are also highly accurate for determining the integrity of the bone
cortex, and this can aid in the diagnosis of a complete pathologic fracture and
in the assessment of fracture risk
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30. MRI
Soft tissue resolution of CT is inferior to MRI.
If spinal cord compression or nerve impingement is suspected, contrast MRI should
be used for evaluation.
MRI is more sensitive than CT to detect small metastases
on a per-lesion basis, the sensitivity and specificity rates for MRI were 90 and 96
for CT were 77 and 83 percent for bone scan, were 75 and 94 percent
Normal bone marrow has high signal intensity on T1-weighted images.
Metastatic lesions Have decreased signal on T1-weighted sequences
On T2-weighted images have a higher signal and they enhance with gadolinium.
MRI with and without contrast is the gold-standard study when spinal cord
compression and/or epiduraldisease/nerve root impingement is suspected
31. MRI
Particularly useful for demonstrating bone marrow lesions at a potential
fracture site to distinguish a pathologic versus insufficiency fracture.
The most sensitive discriminating feature is that of a well-defined, low-signal
T1-weighted abnormality around the fracture, indicating an underlying tumor
34. Bone Scan
The most widely used method to detect bone metastases because it provides
visualization of the entire skeleton within a reasonable timeframe and at a
reasonable cost
Among patients with a variety of malignancies, including breast, lung, and
prostate cancer, bone scan is reasonably sensitive (79 to 86 percent) and
specific (81 to 88 percent) for the diagnosis of bone metastases
However, it is less sensitive for detecting tumors with little to no osteoblastic
activity (such as multiple myeloma)
SPECT can increase the accuracy
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36. 18-F-FDG PET
FDG-PET/CT is clearly superior than bone scan for detection of bone
metastases albeit much more expensive
A major benefit of FDG-PET over bone scan is its ability to screen for distant
metastases at sites other than bone
PET is preferred over Bone scan
rapidly progressive metastases that are associated with minimal reactive bone
formation
for the staging of lymphomas that are routinely avid for radiolabeled glucose (eg,
diffuse large B cell lymphoma, Hodgkin lymphoma
for staging the bone in Ewing sarcoma with a lytic primary tumor.
37. F18-PET
Using (18)-fluorine-labeled sodium fluoride (18F-NaF PET/CT) may offer
increased sensitivity and specificity in evaluating metastatic bone disease
compared with 99mTc-based bone scan in a wide variety of clinical settings
Much more expensive and not yet recommended for routine use
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39. Low-dose, whole-body computed
tomography
one setting in which whole-body, low-dose CT may have utility is in patients
with multiple myeloma as an alternative to skeletal survey
40. Whole-body magnetic resonance
imaging
Whole-body MRI has the potential to detect more destructive bone lesions in
the axial skeleton (particularly the spine) than bone scan or, among patients
with multiple myeloma, whole-body radiographs.
However, on a per-patient basis, whole-body MRI is less sensitive and less
specific than integrated PET/CT and less sensitive than bone scan
In patients with suspected or newly diagnosed myeloma, MRI has become the
gold-standard imaging method for early detection of bone marrow
involvement
Where whole-body MRI is not available, MRI of the spine and pelvis can be used
41. Differential diagnosis
The differential diagnosis of a lytic bone abnormality includes primary
malignant bone tumors, bone metastases from distant primary sites, as well
as several benign bone lesions.
The differential diagnosis of a sclerotic or blastic bone lesion is narrower. A
bone island, calcifying enchondroma, osteoid osteoma, bone infarct, fibrous
dysplasia, and Paget disease of bone.
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53. Diagnostic biopsy
If a primary tumor is known, a skeletal lesion with a typical appearance on
imaging studies (either lytic or osteoblastic) may be presumed to be
metastatic
especially if there are multiple lesions
If a patient has a history of cancer without prior documentation of bone
metastases, and a confirmatory diagnosis of metastatic disease is all that is
required, needle biopsy can be an excellent method
54. Diagnostic biopsy
For patients with an unknown primary cancer who present with a bone
metastasis, and initial staging evaluation fails to delineate the primary
malignancy, a biopsy is generally indicated
Core needle biopsy is recommended
An impending or complete pathologic fracture in a patient with a solitary
bone lesion, with or without a history of cancer, should never be fixed
without a tissue diagnosis.
Should the lesion prove to be a primary mesenchymal malignancy (eg,
osteosarcoma, chondrosarcoma), the surgical repair could jeopardize not only the
opportunity for limb salvage, but also the possibility of cure.
55. Therapeutic options
The goals of management for bone metastases include maximizing pain
control, preserving and restoring function, stabilizing the skeleton, and
enhancing local tumor control.
Observation may be recommended for an asymptomatic bone metastasis with no
significant risk of pathological fracture or spinal instability, especially if life
expectancy is limited
56. Analgesia
The World Health Organization (WHO) analgesic ladder is a widely accepted
approach for managing cancer pain
59. Osteoclast inhibitors
Including bisphosphonates and denosumab
These agents have been shown to reduce the risk of skeletal-related events (SREs,
including pathologic fracture, spinal cord compression, the need for radiotherapy
[RT] or surgery to bone, or malignant hypercalcemia) in patients with a variety of
advanced malignancies, including multiple myeloma, breast, prostate, and lung
cancer.
There are substantial data supporting the analgesic efficacy of all of the
parenteral bisphosphonates, includingpamidronate, zoledronic
acid, ibandronate, and clodronate as well as oral ibandronate and clodronate.
Fewer data are available on the analgesic benefit of denosumab, and its
analgesic superiority over bisphosphonates has not been established.
60. Systemic anti-tumor therapy
Chemotherapy and hormone therapy may contribute to pain relief by reducing
tumor bulk and/or by modulating pain signaling pathways
61. Radiation therapy
External beam radiation therapy — EBRT is a standard approach for
symptomatic skeletal metastases, achieving pain reduction in 50 to 80
percent, which is complete in up to one-third of patients.
Extensive, painful bone metastases may be treated with single-fraction
hemibody irradiation to the upper, lower, or mid-body. Although hemibody
irradiation can provide rapid pain relief when multiple sites of symptomatic
bone metastases are present,
its use has largely been replaced by the administration of bone-seeking
radiopharmaceuticals, which offer a similar degree of pain relief and may be
associated with less toxicity.
62. Bone seeking radiopharmaceuticals
Samarium-153 lexidronam (153Sm) and strontium-89 (89Sr) emit beta
particles and have been shown to be effective for palliation of pain, with
response rates between 40 and 95 percent.
However, the onset of pain relief is slower than with EBRT, taking up to two to four
weeks
patients can have prolonged hematologic toxicity (more prominent with 89Sr than
153Sm)
they do not improve survival.
approved for the relief of pain in patients with confirmed osteoblastic bone
lesions that enhance on radionuclide bone scan,
Both agents are generally reserved for individuals with persistent or
recurrent multifocal bone pain after EBRT and/or other forms of therapy.
63. Bone seeking radiopharmaceuticals
Contra-indications
pregnancy and breast feeding, any evidence of Disseminated Intravascular
Coagulation (DIC), super scan pattern in the latest bone scintigraphy, any
emergency problems such as acute compression on the spinal cord and pathologic
fractures, neurologic origin as the source of bone pain, hemi body radiotherapy
during the last three months and long acting chemotherapy during the last four
weeks.
64. Bone seeking radiopharmaceuticals
Radium 223
223Ra dichloride is an alpha particle emitting radiopharmaceutical that is indicated
for the treatment of patients with castration resistant prostate cancer,
symptomatic bone metastases, and no known visceral metastases.
65. Ra 223
Phase III ALSYMPCA trial
(ALpharadin in SYMPtomatic Prostate CAncer)
●Overall survival, the primary endpoint of the trial, was significantly
prolonged including both those who had and had not received priordocetaxel.
●The time to first symptomatic skeletal event was significantly increased
(median 15.6 versus 9.8 months, HR 0.66, 95% CI 0.52-0.83).
●Was associated with a favorable safety profile, with a lower frequency of all
adverse events compared with placebo;
●In a prespecified subset analysis, radium-223 had similar efficacy in those
who had received prior docetaxel and those who were docetaxel naïve.
● Treatment was well tolerated irrespective of prior docetaxel use
●Treatment with radium-223 was accompanied by a better quality of life
66. Surgery
typically reserved for lesions with a completed or impending pathologic
fracture.
In a systematic review of 45 studies addressing the role of surgical
management of bone metastases involving the humerus, femur,
and pelvis/acetabulum (47 percent of cases with a pathologic fracture),
surgery was associated with significant pain relief in 91 to 93 percent of cases, and
function was maintained or improved in 89 to 94 percent
Prophylactic fixation of an impending pathologic fracture may be considered if an
osteolytic lesion involves more than 50 percent of the cortex circumferentially or if
the metastasis involves the proximal femur with an associated fracture of the
lesser trochanter