Radiation Oncology: A Question-Based Review

Palliative Care: Bone Metastases

Bronwyn R. Stall and William P. O'Meara

image Background

What are the top 3 sites of metastatic Dz?

Top 3 sites of metastatic Dz:

1.     Lung

2.     Liver

3.     Bone

What is the route of spread of cancer cells to the bone?

Most bone mets arise from hematogenous spread of cancer cells.

What part of the skeleton is more commonly affected by bone mets: axial or appendicular?

Bone mets more commonly affect the axial rather than the appendicular skeleton.

What part of the spine is most commonly affected by bone mets?

The thoracic spine is the most common site of bone mets. (Bartels RH et al., CA Cancer J 2008)

What 5 tumors are known to stimulate osteoclast activity?

Tumors known to stimulate osteoclast activity:

1.     Breast

2.     Prostate

3.     Lung

4.     Renal

5.     Thyroid

In decreasing order, what 5 tumors carry the highest risk of bone mets?

Top 5 tumors with regard to the risk of bone mets (in decreasing order):

1.     Prostate

2.     Breast

3.     Kidney

4.     Thyroid

5.     Lung

What is the most common presenting Sx of bone mets?

Most pts with bone mets present with pain.

image Workup/Staging

What is the workup for bone mets?

Bone met workup: H&P, characterization of pain, assessment of fracture risk, assessment for weight-−bearing bone, orthopedic consult as necessary, plain films, and bone scan

What imaging test is 1st line in evaluating bone mets?

Initial imaging of asymptomatic bone mets usually involves a bone scan (skeletal scintigraphy). If −symptomatic, directed plain films and bone scan as well as subsequent clinically directed CT and/or MRI may be beneficial.

When may plain films be useful when evaluating bone mets?

In the setting of bone pain with a positive bone scan, plain films may show an impending fracture or a pathologic fracture.

What cancer is associated with mixed lytic and sclerotic lesions?

Breast cancer is associated with mixed sclerotic and lytic lesions.

What cancers are associated with primarily blastic lesions?

Tumors with predominantly blastic lesions:

1.     Prostate

2.     Small cell lung cancer

3.     Hodgkin lymphoma

What cancers are associated with primarily lytic lesions?

Tumors with predominantly lytic lesions:

1.     Renal cell

2.     Melanoma

3.     Multiple myeloma

4.     Thyroid

5.     Non–small cell lung cancer

6.     Non-Hodgkin lymphoma

What imaging test can help to differentiate degenerative Dz from mets?

CT and/or MRI can help to distinguish between degenerative Dz and bone mets.

When cord compression is suspected, what imaging is indicated?

MRI of the entire spine is indicated if cord compression is suspected.

What scoring system predicts for pathologic fracture?

The Mirels scoring system is a weighted system based on a retrospective review that predicts the risk of pathologic fracture through metastatic lesions in long bones. Score ranges from 4–12. A score <7 can be treated with RT alone, while a score ≥8 requires internal fixation prior to RT. (Mirels H et al., Clin Ortho Res 1989)

What are the components of the Mirels scoring system?

The Mirels scoring system consists of 4 variables:

1.     Site (upper extremity, lower extremity, peritrochanteric)

2.     Pain (mild, moderate, functional)

3.     Lesion (blastic, mixed, lytic)

4.     Size (less than one third, one third to two thirds, or more than two thirds cortex destruction)

Each variable receives 1–3 points for a total of 4–12 points. (Mirels H et al., Clin Ortho Res 1989)

What 2 risk factors predict for pathologic fracture of the femur?

Factors predicting for pathologic fracture of the femur:

1.     Axial cortical involvement >30 mm

2.     Circumferential cortical involvement >50%

(Van der Linden Y et al., J Bone Joint Surg Br 2004)

image Treatment/Prognosis

What is the MS of pts with solitary or multiple bone mets?

RTOG 7402 reported that the MS with multiple bone mets is 24 wks, but 36 wks if there is only 1 met.

Name 6 Tx for bone mets.

Bone met Tx:

1.     Chemo

2.     Radionuclides

3.     Local EBRT

4.     Endocrine therapy

5.     NSAIDs

6.     Narcotics

What supportive measures can be used for pts with painful bone mets?

Supportive care for bone mets may include orthopedic braces such as thoracolumbosacral orthosis (TLSO), canes, walkers, and wheelchairs.

In what cancers may chemo eradicate bone mets?

Chemo can cure bone mets from lymphomas and germ cell tumors.

What is the chief action of bisphosphonates?

Bisphosphonates inhibit osteoclast activity.

What are the ASCO 2003 guidelines for bisphosphonates in the Tx of bone mets from breast cancer?

ASCO 2003 guidelines for bisphosphonate use state that bisphosphonates should be administered q3–4wks to breast cancer pts with destructive bone lesions seen on plain film.

Name 2 bisphosphonates

Pamidronate and zoledronic acid are 2 common bisphosphonates.

Name 3 radionuclides used to treat bone mets.

Radionuclides available in the U.S. for Tx of bone mets:

1.     Strontium-89

2.     Samarium-153

3.     Phosphorus-32

Describe the decay of strontium-89.

Strontium-89 decays by β emission to yttrium-89.

What is the half-life of strontium-89?

The half-life of strontium-89 is 50.6 days.

What is the max decay energy of strontium-89?

The max decay energy of strontium-89 is β 1.4 MeV.

What is the max particle range of strontium-89?

The max particle range of strontium-89 is 7 mm.

Describe the decay of samarium-153.

Samarium-153 decays by β and γ emission.

What is the half-life of samarium-153?

The half-life of samarium-153 is 1.9 days.

What is the max decay energy of samarium-153?

The max decay energy of samarium-153 is β 0.81 MeV.

What is the max particle range of samarium-153?

The max particle range of samarium-153 is 4 mm.

Describe the decay of phosphorus-32.

Phosphorus-32 decays by β emission.

What is the half-life of phosphorus-32?

The half-life of phosphorus-32 is 14.3 days.

What is the max decay energy of phosphorus-32?

The max decay energy of phosphorus-32 is β 1.7 MeV.

What is the max particle range of phosphorus-32?

The max particle range of phosphorus-32 is 8.5 mm.

Describe some differences between strontium-89, samarium-153, and phosphorus-32.

1.     Strontium is naturally occurring and is just below calcium on periodic table with the atomic number 38. It is metabolized like calcium and is incorporated into the bone matrix.

2.     Samarium-153 is produced by neutron bombardment. Its mechanism of action is not fully understood, but it selectively accumulates in bone in association with hydroxyapatite.

3.     Phosphorus-32 is a phosphate. 85% of total body phosphate is held within the skeleton, bound as inorganic phosphate to hydroxyapatite.

Describe the clinical implications of the differences in physical properties between strontium-89, samarium-153, and phosphorus-32.

1.     Both strontium-89 and phosphorus-32 emit β particles with higher energy than those of samarium-153, causing deeper tissue penetration. Though these higher-energy β particles may have a therapeutic benefit, they can also cause greater marrow toxicity.

2.     The half-life of samarium-153 is much shorter than that of strontium-89. Thus, the planned RT dose from samarium-153 is delivered more quickly, leading to faster time to pain relief in many published trials.

3.     As the only gamma emitter, samarium-153 enables posttherapy scintigraphic imaging and dosimetry.

Why is phosphorus-32 seldom used for bone mets?

Phosphorus-32 was the 1st radionuclide to be used for bone mets, but it has greater hematologic toxicity compared to the other 2 agents (strontium-89 and samarium-153) available in the U.S.

When should radionuclides be considered?

Radionuclides should be considered in pts with adequate blood counts and multifocal painful bone mets imaged on bone scan.

What are some contraindications to radionuclides for bone pain?

Contraindications for using radionuclides for bone pain:

1.     Myelosuppression

2.     Impaired renal function

3.     Pregnancy

4.     Cord compression

5.     Nerve root compression

6.     Impending pathologic fracture

7.     Extensive soft tissue component

What randomized data supports the use of samarium-153?

double-blind placebo controlled study of samarium-153 supports its use. 118 pts with symptomatic bone mets were randomized to low-dose samarium-153 (0.5 mCi/kg), high-dose samarium-153 (1 mCi/kg), or placebo. Pts receiving high-dose samarium-153 had significant improvement in pain during the 1st 4 wks per pt and medical evaluation. Relief persisted until at least wk 16 in 43% of pts. There was a significant reduction in the pain score and analgesic use only in pts receiving the high dose. (Serafini A et al., JCO 1998)

What RTOG study originally reported no difference in bone pain relief between different fractionation schemes?

RTOG 7402 randomized 759 pts. Those with solitary bone mets were randomized to 40.5 Gy (270 cGy × 15) vs. 20 Gy (400 cGy × 5). Pts with multiple mets were randomized to 30 Gy (300 cGy × 10), 15 Gy (300 cGy × 5), 20 Gy (400 cGy × 5), or 25 Gy (500 cGy × 5). The initial report revealed that 90% of pts had some pain relief, and 54% had eventual CR of pain. There was no difference between regimens (Tong D et al., Cancer 1982). Reanalysis showed that a higher # of fx correlated with CR of pain, suggesting that a more protracted course was more effective. The analysis was based only on physician assessment of pain (Blitzer P et al., Cancer 1985).

What pts are generally excluded from RCTs of different fractionations for bone-met RT?

RCTs assessing different fractionation schemes for the Tx of bone mets have generally excluded pts with cord compression and pathologic fracture.

Did the study by the Bone Pain Trial Working Party support single- or multi-fx Tx of bone mets?

The Bone Pain Trial Working Party supported −single-fx Tx. The study (UK/NZ) randomized 765 pts with painful bone mets to 8 Gy × 1 vs. a protracted regimen (200 cGy × 5 or 300 cGy × 10). Pain relief was evaluated for up to 1 yr post-Tx by the use of a validated pt questionnaire. There was no −difference in pain control between the arms. Re-Tx was twice as common with single-fx Tx (23% vs. 10%), though this may have been due to a greater willingness to re-treat pts who rcv only 8 Gy × 1. (No author, Radiother Oncol 1999)

Did the Dutch Bone Metastasis Study support single- or multi-fx Tx of bone mets?

The Dutch Bone Metastasis Study supported single-fx Tx. 1,171 pts were randomized to 8 Gy × 1 vs. 4 Gy × 6. Pain relief was evaluated for up to 2 yrs post-Tx by the use of a validated pt questionnaire. No difference was seen with respect to pain relief. However, re-Tx was more common in the single-fx arm (25% vs. 7%) (Steenland E et al, Radiother Oncol 1999). Reanalysis suggested that the higher rate of re-Tx in the single-fx arm may be related to a greater willingness to re-Tx pts who rcv only 8 Gy × 1 (Van der −Linden YM et al., IJROBP 2004).

Did RTOG 9714 support single- or multi-fx Tx of bone mets?

RTOG 9714 supported single-fx Tx. randomized 898 pts with breast or prostate cancer to 8 Gy × 1 vs. 3 Gy × 10. There was no difference in complete pain relief (15% vs. 18%) or partial pain relief (50% vs. 48%), but there was increased acute toxicity in the 3 Gy × 10 arm (10% vs. 17%). The re-Tx rate was significantly greater in the 8 Gy × 1 arm. (Hartsell W et al., JNCI 2005)

What were the results of the Chow et al. meta-analysis of trials comparing single- vs. multi-fx Tx of bone mets?

In a meta-analysis of trials comparing single- vs. multi-fx Tx of bone mets, Chow et al. showed no significant differences between fractionation schemes with respect to pain control. However, re-Tx was more common with single-fx Tx. (JCO 2007)

Is there data supporting 8-Gy single-fx Tx of bone mets rather than 4 Gy?

Yes. A Royal Marsden study randomized 270 pts with painful bone mets to 8 Gy × 1 vs. 4 Gy × 1. Pain was assessed by the pt prior to RT, then at 2, 4, 8, and 12 wks after Tx. The response rate wks was higher for 8 Gy (69% vs. 44%), but there was no difference in CR of pain at 4 wks or a duration of response. It was concluded that 8 Gy has higher probability of pain relief. (Hoskin P et al., Radiother Oncol 1992)

What study supported use of hemibody irradiation (HBI) after focal RT for bone mets?

RTOG 8206 randomized pts treated with focal RT to HBI (8 Gy) vs. no further Tx. HBI increased the time to progression as well as the time to re-Tx. (Poulter C et al., IJROBP 1992)

What are the published response rates of RT for palliation of symptomatic bone mets irrespective of the fractionation scheme?

The published response rates of RT for palliation of symptomatic bone mets are 60%–80%.

What is the benefit of PORT after orthopedic stabilization?

PORT following orthopedic stabilization of impending or pathologic fracture decreases the need for 2nd surgery (2% vs. 15%) and increases the rate of regaining normal function (53% vs. 11.5%) for surgery alone. (Townsend P et al., JCO 1994)

How do NSAIDs alleviate pain from bone mets?

NSAIDS alleviate metastatic bone pain by inhibiting prostaglandins, which are released from osseous mets and can induce osteolysis.

What is the WHO analgesic ladder for cancer pain management?

3-Step WHO analgesic ladder for cancer pain:

1.     Nonopioid (acetaminophen, aspirin, NSAIDs) +/− adj Tx

2.     Opioid for mild to moderate pain (codeine, hydrocodone, oxycodone, propoxyphene) + nonopioid +/− adj Tx

3.     Opioid for moderate to severe pain (morphine, oxycodone, hydromorphone, fentanyl) +/− nonopioid +/− adj Tx

(Levy M et al., NEJM 1996)

What is the relationship between oral, SQ, and intravenous opioid doses?

The oral dose is about one half the SQ dose and one third the intravenous dose.

image Toxicity

What are the expected acute and late RT toxicities associated with Tx of bone mets?

Potential toxicities from focal RT for bone mets:

1.     Acute: skin irritation

2.     Late: fibrosis, nerve damage, fracture, lymphedema

What is the main toxicity of radionuclide Tx?

Radionuclide Tx can cause significant myelosuppression.