Bone is commonly affected by metastasis. Radiation therapy is effective for relieving bone pain from metastases. Shorter fractionation schedules like single 8 Gy fractions provide pain relief but have higher retreatment rates compared to longer schedules like 30 Gy in 10 fractions. Newer techniques like SBRT and hemibody irradiation also effectively palliate bone pain with acceptable toxicity. Bisphosphonates combined with radiation can further improve pain relief and increase bone density. Surgery to stabilize fractures is recommended for high risk or impending fractures to allow early mobility.

1. BONE METASTASIS & ROLE OF RADIATION

2. Introduction
• Bone is the third most common organ affected by
metastasis after liver and lung.
• More frequent in breast and prostate carcinomas
• Others - lung , thyroid and renal carcinomas
• Sites of Metastasis – Spine (Lumbar>Thoracic) >
Pelvis > Ribs > Femur > Skull.
• Cancer cells target bones with extensive blood
supply hence tend not to travel to hands and
feet.

3. Pathophysiology of bone metastasis
• Step I: Disengagement from primary site(loss
of E cadherin)
• Step II: Enter vascular or lymphatic system &
survive immune system
• Step III: Reach final Destination
• Step IV: Adhesions & angiogenesis.

5. Osteolytic metastasis
• The destruction of bone by osteolytic metastases
is mediated by the osteoclasts, not by the tumor
cells.
• Tumor cells produce growth factors that
stimulate bone destruction (i.e. RANK ligand)
• Osteoclasts cannot build bone back fast enough
• Decrease bone density and strength; high risk for
fracture.
• Eg: Multiple myeloma(purely osteolytic), lung
cancer, Breast, renal cancers.

7. Osteoblastic metastasis
• Osteoblasts are stimulated by tumors to lay
down new bone
• Bone become abnormally dense and stiff
• Paradoxically bones are also at risk of
breaking.
• Eg: prostate cancer, Thyroid.
• In Osteoblastic lesions there is also an
associated increase in Osteclastic resorption.

10. Skeletal Related Events-SRE
Morbidities/Symptoms associated with metastatic bone
disease is termed as SRE – skeletal related events.
Commonly observed complications of bone metastases include
 pain (most common)
 impending or pathological fractures
 compression of nerve roots and/or spinal cord
 hypercalcemia

11. Diagnosis
Till date there is no investigation sensitive enough for screening
A)Plain x ray - initial test for bone pain
- can detect lesion only if mineral loss is > 25 to 50%
B)Tc 99 bone scintigraphy – relatively cheaper and provide information about
whole skeleton
- shows osteoblastic lesion
- while pure osteolytic lesions will not be picked up
- poor specificity
- lack of anatomical details ( low spatial resolution)
Shows osteblastic lesion by accumulation in reactive bones with high bone
turnover
False negative bone scan are also possible for highly aggressive and rapidly
growing lytic tumour because of minimal reactive bone formation

12. C)FDG PET scan - can detect both osteoblastic and osteolytic
- can detect tumours that have high glucose metabolism , highly
sensitive for multiple myeloma , breast and lung cancers but less sensitive for prostate
cancers.
D)SPECT (single photon emission CT ) -improves the sensitivity and specificity of Tc99
bone scan for detection of small bone metastasis
E)CT / MRI - used when there is a suspicious lesion in Tc 99 bone scan
- better spatial resolution and anatomical details of bone and soft tissue
CT - shows cortical integrity and structural destruction.
MRI - marrow involvement, vertebral metastasis and extension in spinal cord
-disadv – cannot distinguish changes due to treatment, fracture or tumour
CT is superior to MRI in revealing cortical integrity and extent of structural destruction

13. Choice of treatment depends on
• General condition
• Biology and extent of the disease
• Life expectancy
• Quality of life.

14. Goal
The effectiveness of the treatment also depends
on the goal:
 Achieve maximum pain control.
 Structural and functional preservation and
restoration.
 Prevention of pathologic fracture.
 Local control of the disease.
 Avoidance of future treatments.

15. Treatment options
• Analgesia (First line)
• Radiation therapy
-EBRT
-SBRT
-Wide field/Half-body irradiation
• Systemic therapy
- bone targeted therapy
- chemotherapy
- hormonal therapy
• Surgical
• Radiopharmaceutical Therapy

18. Role of Radiotherapy

19. Radiation therapy common methods
EBRT
Wide field/Half-body irradiation
SBRT

20. EBRT (EXTERNAL BEAM RADIOTHERAPY)

21. EBRT
• External-beam radiation therapy is a common
and highly efficative treatment for local fields
to target painful or involved sites.
• Effect - relieving the bone pain
- prevent bone fracture
- promoting healing of pathological
fracture after surgery

22. • The response to treatment depends on a large
number of factors
a)Sex
b)primary site and histology
c)performance status
d)type of lesion (osteolytic vs. osteoblastic)
e)location of the metastases
f)weight-bearing vs. non–weight-bearing site
g)extent of disease
h)number of painful sites
i)marital status and
j)level of pain prior to treatment.

23. Radiation Therapy Oncology Group (RTOG) 74-02 trial.

24. -Tong et al. (1982)
-No statistically significant difference in response rates between
any of the treatment arms.
-Complete responses in 49% to 61% of patients.
-These results were questioned by Blitzer, who re-analyzed the
data using different criteria for complete response.
a)excluded patients who received repeat treatment, and
b)defined complete response as no pain and no analgesic usage.
-With this adjustment in response definition, there was a
significant difference in response favoring the longer treatment
courses.
1)40.5 Gy in 15 fractions for the solitary metastases and
2)30 Gy in 10 fractions for multiple metastases.

25. • Two randomized studies evaluated single
doses of radiation therapy for palliation of
bone metastases.
-Hoskin et al. randomized patients to 4 versus 8
Gy.
-Jeremic et al. randomized patients to one of
three dose levels, 4 versus 6 versus 8 Gy.
• In both of these studies, the 8-Gy arm was
superior to 4 Gy, indicating that there is a
threshold dose necessary to achieve adequate
palliation.

26. The Dutch trial
• Patients with bone metastases primarily breast (39%), prostate (23%), and lung
(25%) (metastatic melanoma and renal cell carcinomas were excluded)
• Patients-1,171 patients (8 Gy/1# vs 24 Gy/6#).
The spine (36%) and pelvis (30%) were the two most common sites of treatment.
About half of the patient were receiving narcotic pain medications prior to
randomization, and slightly more than half (53%) were receiving systemic therapy.
- Overall survival or response rates -No difference between the two arms.
- Two significant differences between the two treatment groups:
- Retreatment rates -(25%vs7%)
- Pathologic fracture rates -significant difference between the two groups, these
rates are still relatively low. Most of the responses occurred within the first 4 to 6
weeks after treatment.
Complete response rates were higher for patients with breast and prostate
primaries than with lung or other primary sites (44% and 41% vs. 21% and 16%,
respectively).

27. RTOG study 9714 (conducted in the United States and Canada)
• Inclusion criteria:
a)Painful bone metastases from breast or prostate primaries.
b)Up to three painful sites allowed.
c)Minimum pain score of 5 or a high narcotic pain medication requirement of
the equivalent of >60 mg of morphine per day
• Pain was evaluated using the Brief Pain Inventory, an 11-point scale.
• 8 Gy /1# versus 30 Gy /10#.
• The median survival was 9.3 months.
• Complete and partial pain response rates (17% vs 49%)- No significant
differences
• 3-month post treatment evaluation-Complete pain and narcotic response
11%.

28. • Re-treatment - 18% vs 9% (similar to Dutch Trial)
(This disparity in the rate of retreatment occurred despite
nearly identical rates of stable (26% vs. 24%) or
progressive pain scores (9% vs. 10%) and similar rates of
narcotic use between the two groups.)
• Pathologic fractures Rates - 5% vs. 4% (contrast to
Dutch Trial)
• Konski et al. showed that although married men and
single and married women were more likely to receive
retreatment after receiving 8 versus 30 Gy of palliative
radiation therapy, there was no difference in
retreatment rates among single men.

29. Mechanism of Pain Relief
 Lack of a dose–response relationship
-Pain relief is not due to reduction in tumor burden.
-Due to change in the local environment that caused
activation of bone resorption by osteoclasts.
 This explain the higher rates of retreatment after single-
dose 8-Gy treatment because there will be less cell kill with
this dose compared with 30 Gy in 10 fractions.
 Thus, for patients with a longer lifespan, there is a greater
opportunity for regrowth of the tumor, which may again
affect the local milieu, causing osteoclast activation.

30. • Patients with a poor PS
• Difficulty making multiple trips for treatment -Single fraction of 8 Gy.
• Extensive nonosseous metastases
• Short life expectancy
• Patients with a longer life expectancy
• Bone only metastases -30 Gy in 10 fractions
• Good performance status
• The single large-fraction treatment may cause a “flare” reaction, with a
temporary increase in pain at the site of the metastases.
• The retreatment rates are higher after short-course treatment by a factor
of two to three.
• Response rates are lower when scored by the patient instead of by the
treating physician.
• Response rates are better when the initial pain scores are lower, that is,
when the patients are treated for moderate pain rather than severe pain.

31. Reirradiation
• Physician bias
• The assessment of pain was performed by the patients
rather than by physicians or other health care
providers.
• Reirradiation rate – 11 to 42 % in single fraction vs 0 to
24% in multifraction schedule
• Pts who were treated with 8 Gy single fraction and not
responded , 66% of those pts got benefit from
retreatment with compare to 33% of pts who have
received initially multifraction regimen. Dutch bone
mets study

32. Wide field or half body irradiation

33. Wide field or half body irradiation
• Hemibody irradiation (HBI), or wide-field
radiation therapy -Technique of treating a large
portion of the body with external-beam
irradiation.
• The treatment volumes have been divided into
upper, middle, and lower HBI.
-Upper HBI fields- Thorax and abdomen(neck
to the top of the iliac crests).
-Midbody HBI fields-Abdomen and pelvis
(diaphragm to the ischial tuberosities).
-Lower HBI fields-Top of the pelvis to the
inferior portion of the femurs.

34. • RTOG 78-10 was a dose-searching prospective protocol evaluating
the maximum tolerated dose (MTD) for single-dose HBI.
-The MTD for middle and lower hemibody treatment was 8 Gy.
-The MTD for the upper HBI was 6 Gy if the lung dose was
uncorrected and 7 Gy if lung corrections were used.
• Improvement in pain 80%(breast cancer) and 90%(prostate cancer).
• The response rate in terms of pain relief was 73%, with complete
relief of symptoms seen in 19%.
• Pain relief was relatively rapidly
-50% of responses occurring within 2 days
-95% of responses within 2 weeks.

35. The subsequent study RTOG 82-06
• Arms: Local Radiotherapy vs Local Radiotherapy +
HBI
• Aim: To determine whether the HBI would
prevent the development of new sites of disease.
• When compared with single fraction – HBI shows
good pain responses rate (70% vs 15%) with less
retreatment rate in HBI arm ( 13% vs 71%)
• The incidence of severe hematologic toxicity was
low and transitory but was seen only in the group
receiving HBI.

36. Multi-fraction courses of HBI
• The maximum tolerated dose on the RTOG
88–08 study was 17.5 Gy in seven fractions.
• International Atomic Energy Agency study
-3 Gy twice daily for 2 days(12 Gy/4#)
-3 Gy daily for 5 days (15 Gy/5#)
-4 Gy daily for 2 days (8 Gy/2#).
• doses – 15 Gy in 5 frac / 12 Gy in 4 frac / 8 Gy
in 2 frac . Salazar et al.
• pain relief occurs in 70 to 80% of pts within
24- 48 hours

37. • Among all doses 15 gy in 5 frac not only
provides pain relief but also provide longer
survival duration in prostate cancer
• Toxicity – mild bone marrow suppression ,
nausea , vomiting, pulmonary toxicities (less)
• A typical premedication regimen consists of
dexamethasone(8 to 16 mg) and ondansetron
(8 to 16 mg) 1 hour before treatment with
HBI.

38. SBRT (Stereotactic Body Radio Therapy)

39. SBRT (Stereotactic Body Radio Therapy)
• It is a precise delivery of highly conformal and image
guided hypo-fractionated external beam radiotherapy
• Stereotactic radiosurgery has also been evaluated for
the treatment of bone metastasis, particularly in the
spinal region.
• ~ 80% of local pain control with 50% of complete pain
relief
• Use to treat vertebral mets
• Dis adv - pain flare ( 68%)
- radiation myelopathy

40. Gerzsten et al. (2007): (Prospective single arm study)
• 393 patients (500 lesions) 344 lesions had received prior EBRT.
• SBRT (12.5–25 Gy in 1 fxn).
• Long-term improvement in 86% of patients treated for pain.
• For patient treated for imaging progression, LC was 88% for primary
and salvage SBRT.
Sahgal et al. (2009): (Retrospective review of 39 patients-60 mets)
• SBRT (median 24 Gy in 3 fractions).
• 37 mets previously irradiated (median 36 Gy in 14 fractions) with 11
months interim.
• One- and two-year progression-free probability (per met) was 85
and 69%, respectively.
• No difference between primary and salvage.

42. Bone Target Therapy and Radiotherapy
A)Vassiliou et al. (prospective trial)
-Number of Patients -45
-External-beam irradiation and monthly ibandronate for
painful bone metastases from solid tumors.
-All of the patients had improvement in pain, with 57%
complete responses and 43% partial responses
-The average pain score decreased from 6.3 to 0.8.
-Opioid pain medication use decreased from 84% to 24%.
-Bone density in the area of the metastases increased by 73%
by 10 months after treatment.
B) International Union Against Cancer
-women with painful bone metastases from breast cancer
-Pamidronate and 30 Gy of external-beam radiotherapy
-Complete radiographic response -88% patients

43. Pathological and impending fractures

44. High risk patients for pathological
fractures
1. Van der Linden et al. :Axial cortical involvement > 30 mm
and /or circumferential cortical involvement > 50%
predict for high rates of fracture.
2. N- telopeptide of type I collagen – bone resorption marker
3. Mirels system -predicts risk of fracture within 6 months
-Scores of 10-12 have 72-100% chance of fracture.
-Score more than 8 should be treated with surgery.

45. 12 point scoring system estimates risk of pathologic fracture based on the site
of disease, amount of pain, type of lesion and size.

46. Pathological and impending fractures
 Surgery -rapid controls pain and early mobility (90%)
- done by stabilization of the skeleton
- prophylactic fixation reduces the complication rates, hospital stay
and less impact on function outcomes
 Goal - primary – to provide pain relief
- secondary – to achieve stability
 Post op radiation is usually recommended after stabilization of fracture
 As radiation improves the functional outcomes with compare to surgery alone,
post op radiation is indicated in pt without visceral mets and life expectancy more
than 3 months

47. ASTRO GUIDELINES
• External beam radiotherapy has been and continues to be the
mainstay for the treatment of painful, uncomplicated bone
metastases. The longer course has the advantage of a lower
incidence of re-treatment to the same site while the single
fraction proves more convenient for patients and caregivers.
Re-irradiation with EBRT may be safe, effective, and less
commonly necessary in patients with a short life expectancy.
• Bisphosphonates do not obviate the need for external beam
radiotherapy for painful sites of metastases and may indeed
act effectively in combination with EBRT.
• Stereotactic body radiotherapy may be useful for patients
with newly discovered or recurrent tumor in the spinal
column or paraspinal areas.

48. • The use of radionuclides seems most appropriate in circumstances in
which patients have several sites of painful osteoblastic metastases in an
anatomic distribution greater than that which would conveniently or
safely be treated with external beam radiotherapy.
• Hemibody radiotherapy is an option for these patients who reside in
geographic areas where radionuclides are not readily available or when
they are medically contraindicated.
• Surgical decompression and stabilization plus post-operative radiotherapy
should be considered for selected patients with single level spinal cord
compression or spinal instability, unless the patients have too short of an
anticipated life expectancy.
• Kyphoplasty and vertebroplasty may be useful for the treatment of lytic
osteoclastic spine metastases or in cases of spinal instability where
surgery is not feasible or indicated.

49. THANK YOU

51. Radiopharmaceutical Therapy
• Best for patients with multiple lesions that show uptake on bone scan.
• Adv- targeting all bony lesions simultaneously
- outpatient procedure
- less toxicity
• Mechanism – radionuclides reacts with bone minerals and emits beta particles
with a mean range between 0.2 to 3.0mm causing radiation induced apoptosis
• Pain response occurs within 7 to 14 days for 10 to 12 weeks
• Pain reduction rates are comparable with local or HBI
• Strontium- 89, samarium- 153 and radium-223
• Toxicity – reversible myelosuppression specially thrombocytopenia ( after 4 to 6
weeks)
• C/I – PS 3 , life expectancy less then 2 months, extensive soft tissue mets, DIC, low
platelet or WBC, impending or established pathological fracture, spinal cord
compression, nerve root compression, lesions with large extra osseous
component.
• Patients must have adequate blood counts , no myelosuppressive chemotherapy
for 4 weeks before and 6-8 weeks after treatment.

52. • Strontium-89 (beta-emitter) response rates 40-95%, pain relief at 1-4 weeks, lasts
up to 18 months. Improved response rate and duration with low dose platinum.
• Improvement in quality of life and pain response is seen with strontium – 89 with
localised EBRT in a metastatic ca prostate. Even reduction in retreatment rates and
developing new bone mets were seen in the group. TRANS CANADA STUDY
• Samarium-153 (beta and gamma emitter) response rates 70-90%, pain relief at 1-2
weeks, lasts up to 4 months.
• Radium 223- calcium mimetic which targets the bone mets and emits alpha
particles resulting in localised cytotoxic effect with minimal myelosuppression
- inhibits cathepsin K, an osteoclast derived enzyme which is essential
for bone resorption
- in CRPC – it improves OS by 3.6 months and significantly delayed the
first symptomatic skeletal event time

53. Radionuclide therapy
• Sartor et al. (2004): 152 patients with hormone-refractory prostate cancer
randomized 2:1 to 153Sm vs. nonradioactive 152Sm. Better complete
response (38% vs. 18%) with 153Sm. No difference between arms in
transient, mild marrow suppression.
• Oosterhof (Eur Urol 2003): 203 patients with hormone-refractory prostate
cancer randomized to 89Sr vs. EBRT. No difference in subjective response
(~34%), response duration (4.5 months). MS 7.2 vs. 11 months for Sr vs.
EBRT, despite similar toxicity.
• Sciuto et al. (2002): 70 patients with hormone-refractory prostate cancer
randomized to 89Sr±concurrent low-dose cisplatin. Better subjective
response (91% vs. 63%), duration (120 vs. 60 days), survival without new
painful mets (4 vs. 2 months), and less bone disease progression (27% vs.
64%) for cisplatin arm. No difference in toxicity.
• Porter et al. (1993): Randomized local field RT ± strontium 89 in patients
with hormone-refractory prostate cancer. Patients in combined arm
needed lesser analgesics, had fewer sites of new pain, had lower PSA and
alk phos levels, and had better quality of life.

54. Pain
Most common symptom.
Characteristic
 Varies from diffuse dull aching ( pelvic and spine) to severe well localised (extremities).
 worsen at night and during weight bearing activity.
 often not relieved by lying flat or resting.
Mechanism - Physical and functional
Physical:
a) Release of inflammatory mediators- neuropeptides and cytokines.
b) Mass effect of tumour- increased introsseous pressure which irritates the periosteal
nerve endings.
Functional:
Mechanical weakness of bone which can no longer support the normal stress(more
common in lytic lesion).
Development of functional pain is the marker for bone at risk for pathological fracture.

55. Analgesics
Frist line therapy for pain management
World Health Organization analgesic ladder.
• Step I uses non-opioid analgesics such as acetaminophen or non-
steroidal anti-inflammatory drugs.
• step II uses weak opioids such as codeine
• step III uses strong opioids such as morphine.
Adjuvant medications such as gabapentin, pregabalin, or amitriptyline
may be added for neuropathic pain.
Antianxiety or antidepressant medications may also be of benefit in
selected patients.
Combination analgesic therapy is better(good effect with less side
effects).

56. Bone target therapy
• Bisphosphonates
- Analogues of pyrophosphate
- they binds with exposed bone mineral and during bone
resorption they are internalized by the osteoclast and cause
apoptosis of cell
- 25 to 40 % of the injected dose is excreted by kidney
- Poor oral bioavailability ( binds with calicium)
- Optimal duration of the tx not yet determinded
- Ex. Ibandronate (oral) , zolendronic acid and pamidronate
• Binds with calcium hence it has to taken empty stomach

57. • IV drug – delay the onset and lower the incidence of SREs (RCTs)
• Effect – 50 to 75 % pts will have pain relief in one week and last for around
12 months
• Zolendronic acid reduces SREs by 20% more compared to pamidronate in
advanced breast cancer
• In CRPC – zolendronic acid reduces skeletal complication by 36%
• Indication – for widespread diseases and poorly localised pain due to bone
mets
- hypercalcemia
- multiple myeloma ( also improves survival )
• Many rcts shows that iv drugs delays the onset and lower the incidence of
sres
• In hypercalcemia – bisphosphonates with hydration is the standard
treatment

58. Denosumab
 Fully human monoclonal antibody
 Binds and neutralise RANKL with high affinity and specificity to inhibit osteoclast
 Dose – 120 mg subcut 4 weekly
 Causes rapid and sustained suppression of bone turnover in pts with bone mets
 Denosumab is superior to Zolendronic acid in delaying the onset of SREs but no
survival benefit with either of it (RCT)
Adv- does not affect renal function and acute phase reactions are less
Disadv – costly and hypocalcemia
Complication - osteonecrosis of jaw
(Although Denosumab has some adv over Zolendronic it is not cost effective )
 Vit D and calcium supplements should be given to all pts on denosumab

59.  No clear indication for when to start bone targeted therapy
 Development of SRE is not a sign of treatment failure or to stop
treatment
 No agent is superior to another
 Despite of clear benefit of therapy. It is clear that not all events of
SREs can be prevented nor all pts having bone met will develop
SREs therefore till date there is No clear indication for when to start
bone targeted therapy
 Development of SRE is not a sign of treatment failure or to stop
treatment as it can delay 2nd SRE and subsequent complication

60. Surgical management
• Goal of surgery – immediate weight bearing and returning
to function immediately
• Femur at risk – cortical bone destruction > 50%
- lesion > 2.5 cm
- avulsion fracture of lesser trochanter
- persistant pain after radiation
• Options – hemiarthroplasty for head, neck of the femur or
intertrochanteric fracture
- hip screw with side plate with or without PMMA
cement
- intramedullary device for diaphyseal or distal lesion
• Hip arthroplasty with PMMA for acetabular insufficiency

61. • Preop embolization of bone mets – in hypervascular cancer like
RCC to reduce blood loss
- polyvinyl alcohol , coils and gel foams are used
- surgery is done within 48 to 96 hours of embolization
• Spine – most common site
-loss of stability leads to pain and paralysis
- options – decompression, laminectomy , pedicle screw
stabilisation,
- percutaneous vertebroplasty , kyphoplasty – MIS
complication of PV- cement nerve root compression, cement
embolism, spinal cord compression

62. . Two techniques that have been used to treat more diffuse
metastases are hemibody irradiation and intravenous
radiopharmaceuticals.
Hemibody irradiation (HBI), or wide-field radiation therapy
• Hemibody irradiation (HBI), or wide-field radiation therapy, refers to the technique of
treating a large portion of the body with external-beam irradiation. Although the term
hemibody irradiation is used, typically the field does not cover half of the body, but more
accurately treats about one-third of the body.
• The treatment has been used for palliation of symptoms and as an adjuvant to prevent the
development of new bone metastases. The treatment for palliation of pain is most useful in
patients who have diffuse, widespread bone metastases. The treatment volumes have been
divided into upper, middle, and lower HBI. The fields for upper HBI cover the thorax and
abdomen from the neck to the top of the iliac crests. For midbody HBI, the fields include the
abdomen and pelvis from the diaphragm to the ischial tuberosities, and for lower HBI
treatment, the field borders are from the top of the pelvis to the inferior portion of the
femurs. The toxicities from each of the fields depend on the critical structures included. The
most problematic of these is the risk of radiation pneumonitis with upper HBI. This is the
dose-limiting toxicity for upper HBI, and dose-inhomogeneity corrections for the lung are
necessary to minimize the risk of fatal pneumonitis. A lower total dose can be given to the
upper hemibody fields compared with the middle or lower hemibody areas.

63. • RTOG 78-10 was a dose-searching prospective protocol evaluating the maximum tolerated dose (MTD) for
single-dose HBI.The MTD for middle and lower hemibody treatment was 8 Gy. The MTD for the upper HBI
was 6 Gy if the lung dose was uncorrected and 7 Gy if lung corrections were used. Improvement in pain
was noted in 80% of patients with breast cancer and 90% of patients with prostate cancer. Overall, the
response rate in terms of pain relief was 73%, with complete relief of symptoms seen in 19%. Pain relief
was seen relatively rapidly, with 50% of responses occurring within 2 days and 95% of responses within 2
weeks. The subsequent study RTOG 82-06 evaluated the use of HBI in addition to local radiotherapy to
determine whether the HBI would prevent the development of new sites of disease.94 All of the patients
received involved-field irradiation to one or more painful sites, and half of the patients were randomly
assigned to receive single-dose HBI as well. The median time to progression was 6.3 months in the local-
treatment-only group compared with 12.6 months for those receiving HBI. Fewer patients receiving HBI
required additional treatment. The incidence of severe hematologic toxicity was low and transitory but
was seen only in the group receiving HBI.
• Both the RTOG and the International Atomic Energy Agency performed trials evaluating multifraction
courses of HBI.95,96 The doses per fraction ranged from 2.5 to 4 Gy to a total of 8 to 20 Gy. The maximum
tolerated dose on the RTOG 88–08 study was 17.5 Gy in seven fractions. On the International Atomic
Energy Agency study, 3 Gy twice daily for 2 days (12 Gy total) or 3 Gy daily for 5 days (15 Gy total) was
more effective than 4 Gy daily for 2 days. The primary toxicities were hematologic and gastrointestinal.
The rationale for these doses was to decrease the acute toxicity. However, each of these regimens requires
multiple treatments during several days, and the acute toxicities are not appreciably different than the
single-dose treatment. With the use of appropriate antiemetic premedications and with cytokines to aid in
hematologic recovery, there does not appear to be any appreciable benefit to the fractionated HBI
compared with the single dose. Premedication with antiemetics and anti-inflammatory medications
significantly reduce the acute side effects of treatment. Before the development of the 5-HT3 receptor
antagonists, nausea was a significant side effect of treatment, even with pretreatment and posttreatment
use of steroids, prochlorperazine, and intravenous hydration. With the use of ondansetron, granisetron, or
other 5-HT3 receptor antagonists, the incidence of acute nausea and emesis has been minimized and HBI
is well tolerated. 97 A typical premedication regimen consists of dexamethasone, 8 to 16 mg, and
ondansetron, 8 to 16 mg, 1 hour before treatment with HBI.

64. Prognostic factors predicting survival duration of <6 months
include :
1)low performance status such as ECOG <3 or Karnofsky
performance status of <50
2)visceral organ involvement
3)the extent and tempo of bone metastases
4)cachexia
(Falkmer et al. 2003).

65. The Radiation Therapy Oncology Group (RTOG) 0631 phase II/III
study
• Aim: Evaluating the role of stereotactic radiosurgery for patients
with spine metastasis.
• Single-fraction external-beam radiation to 8 Gy Versus single-
fraction image-guided stereotactic radiosurgery to 16 Gy.
• The primary endpoint of this study is assessment of pain control at
the treated site(s), and results of this study are pending.
A prospective, nonrandomized cohort study conducted at the
University of Pittsburgh in 500 cases of spinal metastasis treated with
single-fraction radiosurgery to a maximum intratumor dose of 12.5 to
25 Gy demonstrated long-term pain level improvement in 86% of
cases. Long-term tumor control was demonstrated in 90% of cases
when radiosurgery was used as the primary treatment modality.

66. EBRT dose
• Metaanalysis (Chow et al. 2007) of 16 randomized trials of single fraction vs. multiple fraction
palliative RT regimens. No difference in response rates. Trend for increased risk of pathological
fractures and spinal cord compression with single fraction RT. A 2.5× increased retreatment
rate with single fraction RT.
• Bone Pain Trial Working Party (1999): 761 patients with painful bone mets randomized to 8 Gy
in single fxn vs. 20 Gy in 5 fractions or 30 Gy in 10 fractions. No difference in time to pain relief,
proportion achieving relief, duration of relief, or toxicity. Retreatment given more frequently
after 8 Gy (23% vs. 10%).
• RTOG 9714 (Hartsell, JNCI 2005, Howell et al. 2009): 898 patients with breast or prostate
cancer and KPS ³40 randomized to 8 Gy in 1 fxn vs. 30 Gy in 10 fractions. Higher acute toxicity
with 30 Gy (17% vs. 10%). Pain CR/PR rates at 3 months were equivalent, 15%/50% for 8 Gy
and 18%/48% for 30 Gy, but higher retreatment at 3 years for 8 Gy (18% vs. 9%). Same
conclusions in subgroup of vertebral body mets.
• Tong et al. (1982): Various fractionation schemes evaluated. No differences seen in rates of
pain relief.
• Blitzer (1985): Reanalysis of RTOG data with conclusion that more fractions with higher total
dose were more effective for pain relief.

67. • Studies have shown that 8 Gy has to be
considered as probably the lowest optimal single
fraction although single 4 Gy should be reserved
for specific pts.
• patient with less than 3 month of life expectancy
short course is advisable
• But patient with longer life expectancy , breast
and prostate cancer with bone metastasis only –
protracted schedule can preferred

68. • Patchell et al. (2005): Prospective randomized trial of surgery with post-op
RT to 30 Gy vs. RT alone to 30 Gy. Surgery patients regained ability to walk
more often (62% vs. 19%), retained ability to walk longer (122 vs. 13 days),
and required less steroid and pain medication. Improved survival with
surgery (126vs. 100 days).
• Rades et al. (2009): Prospective nonrandomized trial of 265 patients with
metastatic spinal cord compression treated with short (1 or 5 fxn) vs. long
(10, 15, or 20 fxn) course RT. Longcourse RT achieved higher 1-year LC 61
vs. 81%. Motor function improvement (~35%) and OS (~25%) similar.
Better OS with better KPS, no visceral mets, 1–3 vertebral mets, ability to
ambulate, and use of bisphosphonates.
• Rades et al. (2008): Retrospective review of 124 patients reirradiated for
in-field recurrence of metastatic cord compression. Motor function
improved in 36%, stable in 50%. No radiation myelopathy at 11 months
median follow-up with 24% of patients receiving cumulative BED < 100 Gy,
including both courses of RT. [BED = n*d*(1+d/ab); n = # of fractions;d =
dose per fraction; ab = 2].

69. • Bone metastasis is a devastating condition
that can have a negative impact on the lives of
patients with advanced cancer in many ways.
• Metastatic bone disease is associated with
pain and structural damage, leading to loss of
mobility and social functions, a decrease in
quality of life and an increase in medical costs.
• About two third to three fourth of the patient
with advanced ca breast or prostate will have
bone mets.

70. Posterior and anterior planar bone scans SPECT scan 18F-fluoride PET
Osteoblastic lesions from a man with prostate cancer