Palliation of brain, spinal cord compression and bone metastasis. A review of Guidelines

1. Palliation of Brain, Spinal Cord
and
Bone Metastases
By
Dr. Ayush Garg
Senior Resident

2. Palliation of Brain Metastases

3. Introduction
• Most common intracranial lesion in adults, occurring
at a median time of 8.5 to 12 months from primary
diagnosis.
• The heterogeneity of patients with brain metastases
and evolving treatment approaches, their
management is complex, evolving, and controversial.
• As a result, a number of clinical trials are ongoing to
determine the optimal treatment strategy for these
patients.

4. Epidemiology
It develops in nearly 30% of cancer patients
20%–50% 5%–20%
7%–10%2%–5%4%–6%

5. Clinical Presentation

6. Pathophysiology
Arterial
Circulation
Arrest
in the
capillar
y bed
Crosses
BBB
Crosses
BBB
A
B
C
D
E
F
G
Peritumoral
edema

7. Diagnosis
Imaging modality of choice is an MRI
Cerebral hemispheres (80%)
Cerebellum (15%)
Brain stem (<5%)

9. • Typically they are solid or ring-enhancing
lesions and pseudospherical in shape at the
junction of gray-white matter.
• Generally they are T1 iso- or hypointense, T2
hyperintense and enhance with contrast
administration

13. Role of Whole Brain Radiation
Therapy
Question
Should whole brain radiation therapy (WBRT) be
used as the sole therapy in patients with newly-
diagnosed, surgically accessible, single brain
metastases, compared with WBRT plus surgical
resection, and in what clinical settings?

14. Recommendation
Surgical resection plus WBRT versus WBRT
alone
• Level 1 Class I evidence supports
surgical resection plus post-operative WBRT,
as compared to WBRT alone, in patients with:
– Good performance status
– Limited extracranial disease.
• Patients with poor performance scores,
advanced systemic disease, or multiple brain
metastases- Limited data

15. If WBRT is used, is there an optimal dosing/
fractionation schedule?
Recommendation
• Level 1 Class I evidence- altered dose/
fractionation schedules of WBRT do not result
in significant differences in median survival,
local control or neurocognitive outcomes
when compared with “standard” WBRT
dose/fractionation.
• 30 Gy in 10 fractions or a biologically
effective dose (BED) of 39 Gy

16. If WBRT is used, what impact does tumor
histopathology have on treatment outcomes?
Recommendation
• Insufficient evidence to support the choice of
any particular dose/fractionation regimen
based on histopathology.

17. Question
Does the addition of WBRT after surgical
resection improve outcomes when compared
with surgical resection alone?
Recommendation
Surgical resection plus WBRT versus surgical
resection alone
• Level 1 Surgical resection followed by WBRT
represents a superior treatment modality, in
terms of improving tumor control at the
original site

18. Role of Surgical Resection
Question
Should patients with newly-diagnosed
metastatic brain tumors undergo open surgical
resection versus whole brain radiation therapy
(WBRT) and/or other treatment modalities such
as radiosurgery, and in what clinical settings?

19. Surgical resection plus WBRT versus SRS ±
WBRT
• Level 2 Sx plus WBRT, versus SRS plus WBRT,
both represent effective treatment strategies,
resulting in relatively equal survival rates
• SRS is unsuitable for larger lesions (>3 cm) or
for those causing >1 cm midline shift
• Level 3 Class I suggests SRS alone may provide
equivalent functional and survival outcomes
compared with Sx + WBRT for patients with
single brain metastases

20. Question
• Does surgical resection in addition to WBRT
improve outcomes when compared with WBRT
alone?
• Target population
• This recommendation applies to adults with a
newly diagnosed single brain metastasis
amenable to surgical resection
• The recommedation does not apply to relatively
radiosensitive tumors histologies (i.e., small cell
lung cancer, leukemia, lymphoma, germ cell
tumors and multiple myeloma).

21. Recommendation
Surgical resection plus WBRT versus WBRT
alone
• Level 1 Class I evidence supports
surgical resection plus post-operative WBRT,
as compared to WBRT alone, in patients with:
– Good performance status
– Limited extracranial disease.
• Patients with poor performance scores,
advanced systemic disease, or multiple brain
metastases- Limited data

22. Role of Radiosurgery
Question
• Should patients with newly-diagnosed metastatic brain
tumors undergo stereotactic radiosurgery (SRS)
compared with other treatment modalities?
• Target population
• These recommendations apply to adults with newly
diagnosed solid brain metastases amenable to SRS;
• Lesions measuring less than 3 cm in maximum
diameter
• Less than 1 cm of midline shift

23. Recommendations
SRS plus WBRT vs. WBRT alone
• Level 1 Single-dose SRS + WBRT  significant
longer survival compared with WBRT alone for
patients with single metastatic brain tumors
who have a KPS ≥ 70.
• Level 2 Single-dose SRS + WBRT is superior in
terms of local tumor control and maintaining
functional status when compared to WBRT
alone for patients with 1–4 metastatic brain
tumors who have a KPS ≥ 70.

24. • Level 3 Single-dose SRS + WBRT may lead to
significantly longer patient survival than WBRT
alone for patients with 2–3 metastatic brain
tumors.
• Level 4 There is class III evidence that single-
dose SRS + WBRT is superior to WBRT alone
for improving patient survival for patients with
single or multiple brain metastases and a KPS
< 70.

25. SRS plus WBRT vs. SRS alone
• Level 2 Single-dose SRS alone may provide an
equivalent survival advantage for patients
with brain metastases compared with WBRT +
single-dose SRS.
SRS alone vs. WBRT alone
• Level 3 Single-dose SRS alone appears to be
superior to WBRT alone for patients with up
to three metastatic brain tumors in terms of
patient survival advantage.

26. Question
• What is the role of SRS alone in the
management of patients with 1 to 4 brain
metastases?
• Level 3: For patients with solitary brain
metastasis, SRS should be given to decrease
the risk of local progression.
• Level 3: For patients with 2 to 4 brain
metastases, SRS is recommended for local
tumor control, instead of whole brain
radiotherapy, when their cumulative volume is
< 7 mL.

27. Question
• What is the role of SRS alone in the
management of patients with more than 4
brain metastases?
• Level 3: The use of stereotactic radiosurgery
alone is recommended to improve median
overall survival for patients with more than 4
metastases having a cumulative volume <7 mL

28. Role of Chemotherapy
Question
• Should patients with brain metastases receive
chemotherapy in addition to whole brain
radiotherapy (WBRT)?
• Target population
• This recommendation applies to adults with
newly diagnosed brain metastases;
• However, the recommendation below does not
apply to the exquisitely chemosensitive tumors,
such as germinomas metastatic to the brain.

29. Recommendation
• Level 1 Routine use of chemotherapy
following WBRT for brain metastases has not
been shown to increase survival and is not
recommended.
• Four class I studies examined the role of
carboplatin, chloroethyl nitrosoureas, tegafur
and temozolomide, and all resulted in no
survival benefit.

30. Recurrent/Progressive
Brain Metastases
Question
• What evidence is available regarding the use of
whole brain radiation therapy (WBRT),
stereotactic radiosurgery (SRS), surgical resection
or chemotherapy for the treatment of
recurrent/progressive brain metastases?
• Target population
• This recommendation applies to adults with
recurrent/progressive brain metastases who have
previously been treated with WBRT, surgical
resection and/or radiosurgery.

31. Recommendation
• Level 3 There is insufficient evidence to make
definitive treatment recommendations
• Treatment should be individualized based on
– Patient’s functional status
– Extent of disease
– Volume/number of metastases
– Recurrence or progression at original versus non-
original site
– Previous treatment and type of primary cancer

32. • In this context, the following can be
recommended depending on a patient’s
specific condition:
– No further treatment (supportive care),
– Re-irradiation (either WBRT and/or SRS),
– Surgical excision
– Chemotherapy

33. Question
If WBRT is used in the setting of
recurrent/progressive brain metastases, what
impact does tumor histopathology have on
treatment outcomes?
• No studies were identified that met the
eligibility criteria for this question.

34. The Role of Anticonvulsants
Question
• Do prophylactic anticonvulsants decrease the
risk of seizure in patients with metastatic brain
tumors compared with no treatment?
• Target population
• These recommendations apply to adults with
solid brain metastases who have not
experienced a seizure due to their metastatic
brain disease.

35. Recommendation
• Routine prophylactic use of anticonvulsants is
not recommended

36. The Role of Steroids
Question
• Do steroids improve neurologic symptoms in patients
with metastatic brain tumors compared to no
treatment? If steroids are given, what dose should be
used?
• Comparisons include:
– Steroid therapy versus none
– Comparison of different doses of steroid therapy.
• Target population
• These recommendations apply to adults diagnosed
with brain metastases.

37. Recommendations
Steroid therapy versus no steroid therapy
• Asymptomatic brain metastases patients
without mass effect Insufficient evidence
exists to make a treatment recommendation
for this clinical scenario.

38. Brain metastases patients with mild symptoms
related to mass effect
• Level 3 Corticosteroids are recommended to
provide temporary symptomatic relief of
symptoms related to increased intracranial
pressure and edema secondary to brain
metastases.
• It is recommended for patients who are
symptomatic from metastatic disease to the
brain that a starting dose of 4–8 mg/day of
dexamethasone be considered.

39. Brain metastases patients with moderate to
severe symptoms related to mass effect
• If patients exhibit severe symptoms consistent
with increased intracranial pressure, it is
recommended that higher doses such as 16
mg/day or more be considered.

40. Choice of Steroid
• Level 3 If corticosteroids are given,
dexamethasone is the best drug choice given
the available evidence.
Duration of Corticosteroid Administration
• Level 3 Corticosteroids, if given, should be
tapered slowly over a 2 week time period

41. New and Emerging Therapies
Question
• What evidence is available regarding the
emerging and investigational therapies for the
treatment of metastatic brain tumors?
• Target population
• These recommendations apply to adults with
brain metastases.

42. Recommendations
New radiation sensitizers
• Level 2 A RCT suggested a prolongation of
time to neurological progression with the
early use of motexafin-gadolinium (MGd).
Interstitial modalities
• There is no evidence to support the routine
use of new or existing interstitial radiation or
chemotherapy

43. New chemotherapeutic agents
• Level 2 Treatment of melanoma brain
metastases with concurrent temozolomide
(Class II)
• Level 3 Fotemustine is used in certain studies
Molecular targeted agents
• Level 3 The use of EGFR inhibitors may be of
use in the management of brain metastases
from NSCLC

44. • RPA
(Recursive Partition Analysis)
• GPA
(Graded Prognostic Assessment)
Prognosis

45. Disease Specific GPA

46. Symptom Management
• Corticosteroids-
– To decrease peritumoral edema
– Dexamethasone 16mg no advantage over 4-8mg/day
– More side effects with high dose
– Should be tapered within 1-2 weeks
– Concurrent with PPIs (Pantoprazole/ Rabiprazole)
• Anticonvulsants-
– No benefit of prophylactic use of AEDs in patients without a
previous history of seizures
– Preferable agents that do not interact with hepatic cytochrome
P450 (e.g., levetiracetam)
• Venous Thromboembolism- Anticoagulants
• Inferior Vena Cava filters can be used

47. Whole Brain RT
• Whole Brain Radiotherapy is gold standard
• Extended or hypofractionated WBRT has
shown no survival benefit
• RTOG 0933 and 0614 is evaluating the role of
hippocampal avoidance WBRT (HA-WBRT) and
use of WBRT + memantine
• Role of PCI only in SCLC
FACT

48. VARIOUS FRACTIONATION SCHEDULES FOR BRAIN METASTASIS

49. RT Fields
• Parallel opposed lateral portals used
• The inferior field border should be inferior to
the cribriform plate, the middle cranial fossa,
and the foramen magnum
• The safety margin depends on
penumbra width, head fixation,
and anatomic factors but
should be at least 1 cm, even
under optimal conditions.

50. Surgery
• Surgery provides immediate and effective relief
from symptomatic mass effect and can confirm or
establish the diagnosis
• Three trials by Patchell et al, Noordijk et al and
Mintz et al concluded that suggest that surgical
resection should be reserved for lesions:
– Causing life-threatening complications,
– Requiring pathologic confirmation or
– In patients with KPS ≥ 70
– Controlled extracranial disease burden

52. Stereotactic Surgery
• No randomized trials compare surgery with SRS, SRS
boost appears to provide comparable local control
rates (80% to 90% when combined with WBRT)
• Ideal candidate for SRS:
– Patients with controlled or absence of extracranial
metastases
– Excellent KPS
– Lesion less than 4 cm size
• Historically, the number (one to four) of brain
metastases was considered a general contraindication,
although recent publications refute this.

53. • RTOG 9005 Dose Prescription:
≤2cm- 24Gy
>2 to 3cm- 18Gy
>3 to 4cm- 15Gy
• In conclusion, although SRS boost is indicated
in patients with a single metastasis
• It is difficult to justify its routine use in
patients with multiple metastases sue to
equivocal phase III trials.

54. Comparison of the Advantages of Surgery and Stereotactic
Radiosurgery
Surgery Stereotactic Surgery
• Treatment of larger lesion(s)
(>4 cm diameter)
• Immediate removal of mass
effect and edema
• Histologic confirmation
• Rapid taper of steroids for
symptomatic lesions
• Removal of cancer
• Minimal risk for radiation
necrosis
• Less intensive follow-up
• Less long-term dependency on
steroids
• Treatment of small deep
lesion(s) or eloquent areas
• Minimally invasive
• No general anesthesia use
• Outpatient procedure
• Treatment of multiple lesions at
same session
• Short recovery time (<1 wk)
• Potentially avoid whole-brain
radiation therapy
• Rapid initiation of systemic
therapies
• Fewer immediate complications

55. Chemotherapy & Targeted Therapy

56. Concurrent Radiosensitizers
No trial has demonstrated a survival advantage

57. Re-Irradiation
• Wong et al and Son et al did a study to check
for adequate doses for Re Irradiation.
• A minimum of 20Gy in 1.8-2Gy per fraction
should be given.

58. Palliation of Spinal Cord
Metastases

60. Continued growth
& expansion of
vertebral bone
mets into the
epidural space
Neural foramina
extension by a
paraspinal mass
Destruction of
vertebral cortical
bone
Vetebral body
collapse
Displacement of
bony fragments
into epidural space
Continued
growth and
expansion of
vertebral bony
mets into the
epidural space
Epidural venous
plexus
compression

62. Spinal cord
edema
Increased pressure
on small arteries
White matter
ischemia
White matter
infarctionPermanent
cord damage

63. • Most common primary sites include:
– Breast Cancer
– Lung Cancer
– Prostate Cancer
• Most commonly involved vertebrae:
– Thoracic (60-80%)
– Lumbar (15-30%)
– Cervical (<10%)

64. • Clinical Features:
– Back pain (70-94%)
– Weakness (61-91%)
– Sensory Deficits (46-90%)
– Autonomic Dysfunction (40-57%)
• MRI is gold standard
• CT Myelogram can be
performed for patients who
are contraindicated to MRI

65. Lancet Oncol 2017; 18: e720–30

66. Initial assessment algorithm for patients with spinal metastases

67. MNOP algorithm for spinal metastasis management

68. Confusion?
When not to Treat?
• KPS ≤ 40
• Life Expectancy ≤ 2
months
• Extensive, Uncontrolled,
Progressive Primary
• No effective systemic
therapies available
When to Treat?
• KPS > 40
• Life Expectancy > 2
months
• Controlled or stable
disease

69. TREATMENT
• Surgery
• Radiation for non-radiosensitive tumors typically
takes several days to have an effect and does not
stabilize the spine, whereas surgery allows for
immediate cord decompression
• If operable, patients should undergo surgical
decompression and stabilization followed by
radiotherapy.
• Even for radiosensitive tumors, surgery can often
stabilize the spine.
• Therefore, all patients with MSCC should be
evaluated by a surgeon.

70. Kyphoplasty or vertebroplasty and
EBRT
• The updated literature review demonstrates no
prospective data suggesting either kyphoplasty or
vertebroplasty obviate the need for EBRT for
painful bone metastases.
• A new prospective study of 11 patients treated
with vertebroplasty and samarium-153 is under
study.
• However, these limited data do not allow
definitive statements regarding combined
regimens and highlight the importance of future
prospective trials

71. Radiotherapy
• A single fraction of 8Gy should be used in
MSCC patients with limited survival
expectations and that 30Gy in 10 fractions
should be used for all other patients.
• Hypofractionated schedules (8Gy × 1 to 2 or
4Gy × 5) should be routinely avoided.

72. Target volume definition
• The GTV includes vertebral and soft
tissue tumor as seen on CT
planning scan and diagnostic MRI.
• The CTV includes the spinal canal,
the width of the vertebra and one
vertebra above and below the SCC
if the planning is based on MRI, or
• two vertebrae above and below if
based on X-ray or CT to allow for
uncertainty about extent of
microscopic disease.
• The CTV to PTV margin is 1 cm.

73. Bisphosphonates and EBRT
• Literature suggests benefit from bisphosphonates
and similar medications (ie, denosumab) in reducing
skeletal-related events.
• Several prospective trials of Denosumabhave
suggested improved efficacy compared with
bisphosphonates.
• Further studies may further elucidate circumstances
where EBRT may be omitted.

74. Palliation of Bone Metastases

75. Introduction
• The axial skeleton is the most common site for bone
metastasis.
• Most frequest sites are spine, pelvis & rubs.
• Most frequent primary are breast, prostate followed
by lung, melanoma, kidney, gastrointestinal sites &
sometimes myeloma and lymphoma.
• Certain sites give specific types of bone mets:
– Scapula  Renal
– Skull  Breast
– Tibia, Fibula/ Hands  Lungs
– Toes Genitourinary sites

77. Pathophysiology
• There are 3 types of cells within mature bone:
Osteocytes, Osteoblasts and Osteoclasts.
• Metastases to the bone most often occur in
the red marrow, which is found in highest
concentration in the skull, irregular bones of
the axial skeleton, and the medullary portion
of the appendicular skeleton.
• Most often occur by hematogenous spread
but may occur by direct extension as well

78. • Breast and lung cancers more commonly
cause osteolytic-appearing lesions.
• Prostate and thyroid cancers more often have
osteoblastic-appearing lesions.
• Only myeloma is associated with purely
osteolytic lesions.
• Most other tumors have a combination of
osteolytic and osteoblastic components.

79. Diagnosis
• Osteoblastic bone mets can
be detected by Bone Scan.
• Bone scan is the best
method for screening
patients at risk for bone
metastasis who may not
present with bone pain.
• It is also useful to evaluate
the extent of metastatic
disease in the bone.

80. Treatment
• Optimal management requires a multi-
disciplinary team.
• Medical treatment, radiation therapy, surgery,
and bone targeted treatment with the
bisphosphonates and denosumab are
combined depending on the:
– Biology of the disease,
– Extent of the skeletal involvement,
– Life expectancy of the patient

81. Radiopharmaceuticals and EBRT
• Samarium-153 (46.3 hours)
• Strontium-89 (50.6 days)
• Rhenium-186 (3.71 days)
• Radium-223 (11.4 days)
• In patients with bone-only or bone-dominant
disease, these agents may provide benefits beyond
pain relief, including prevention of skeletal-related
events and improved survival

82. • These radionuclides emit beta particles with a
mean range between 0.2 and 3 mm, thereby
minimizing toxicity to surrounding tissue.
• Retention in the areas of bone metastases is
greater than in the normal bone marrow, with
a tumor-to-marrow ratio of 10:1.
• The average time to clinical response is 7 to 14
days.
• Re-treatment time:
– 10 to 12 weeks  Sr 89
– 6 to 10 weeks  Sm 153

83. • A phase 3 RCT of Sm-153 ± EBRT (8 Gy in 1#)
in metastatic prostate cancer with painful
bony metastases demonstrated a significant
improvement in pain relief with addition of
EBRT and no extra toxicity.

84. Received 4 May 2016; revised 15 July 2016; accepted 3 August 2016

85. KQ 1. What fractionation schemes have been
shown to be effective for the treatment of
painful and/or prevention of morbidity from
peripheral bone metastases?
• Studies show pain relief equivalency following
a single 8 Gy fraction, 20 Gy in 5 fractions, 24
Gy in 6 fractions, and 30 Gy in 10 fractions for
patients with previously unirradiated painful
bone metastases.
Agreement:100%, Strength: High

86. KQ 2. When is SF RT appropriate for the
treatment of pain and/or prevention of
morbidity from uncomplicated bone metastasis
involving the spine or other critical structures?
• A single 8 Gy fraction provides noninferior
pain relief.
Agreement:100%, Strength: High

87. KQ 3. Are there long-term side-effect risks that
should limit the use of SF therapy?
• There continues to be no suggestion from
data that SF therapy produces unacceptable
rates of long-term side effects that might limit
its use for patients with painful bone
metastases.
Agreement:100%, Strength: High

88. KQ 4. When should patients receive retreatment
with radiation to peripheral bone metastases?
• Patients with persistent or recurrent pain
more than 1 month following EBRT for
symptomatic, peripheral bone metastases
should be considered for retreatment while
adhering to normal tissue dosing constraints.
Agreement:100%, Strength: High

89. KQ 5. When should patients receive retreatment
with radiation to spine lesions causing recurrent
pain?
• Patients with recurrent spine pain more than
1 month after initial treatment should be
considered for EBRT retreatment while
adhering to normal tissue dosing constraints
Agreement:100%, Strength: High

90. KQ 6. What promise does highly conformal RT
hold for the primary treatment of painful bone
metastasis?
• Advanced RT techniques such as SBRT as the
primary treatment for painful spine bone
lesions or for spinal compression should be
considered in the setting of a clinical trial due
to insufficient data
Agreement:100%, Strength: Moderate

91. KQ 7. When should highly conformal RT be
considered for retreatment of spine lesions
causing recurrent pain?
• Advanced radiation techniques such as SBRT
retreatment for recurrent pain in spine bone
lesions may be feasible, effective, and safe.
• But the panel recommends that this approach
should be limited to clinical trial.
Agreement:100%, Strength: Moderate

92. KQ8. Does the use of surgery, radionuclides,
bisphosphonates, or kyphoplasty/vertebroplasty
obviate the need for palliative RT for painful
bone metastasis?
• The panel reiterates that the use of surgery,
radionuclides, bisphosphonates, or
kyphoplasty/ vertebroplasty does not obviate
the need for EBRT for patients with painful
bone metastases.
Agreement:100%, Strength: Moderate

93. Take Home Message
• Sx + WBRT vs WBRT alone
• Sx + WBRT vs Sx alone
• Sx + WBRT vs SRS ± WBRT
• SRS + WBRT vs SRS alone
• SRS alone vs WBRT alone
• Effective multidisciplinary teamwork is critical
to the rapid evaluation and management of
patients with MSCC