7.14 (13.2) Cancer induced bone pain

Question 1

List the three most common sites of metastatic disease

Answer 1

• lung
• liver
• bone

Question 2

List the two types of nerves that carry nociceptive information

Answer 2

a-delta and c fibres

Question 3

List the three predominant types of stimuli that result in nociception

Answer 3

• mechanical
• thermal
• chemical

Question 4

Where do nociception carrying neurons synapse?

Provide 4 examples of neurotransmitters that modulate second order neurons at the level of the spinal cord

Answer 4

Laminae I and II in the superficial dorsal horn of spinal cord

NTs - glutamate, GABA, glycine

FS: glutamate, GABA, opioid, substance P, serotonin (GGOSS)

Question 5

Where do the ascending noiceptive spinal tracts cross over? What tract do these nerves travel in? Where do they synapse?

Answer 5

They crossover after synapsing in the spinal cord (anterior white commissure) –> travel superiorly in spinothalamic tract –> synapse in thalamus

FS:
Second order neurons cross at the anterior white commissure

Question 6

List three factors that interact to create the experience of cancer induced bone pain (CIBP)

Answer 6

• tumor type
• malignancy site
• degree of bony destruction*
• local changes in sensory nerves*
• inflammation*
• bone microenvironment

Question 7

List 2 higher brain areas that act as the origins of descending pathways to modulate nociception at the level of the spinal cord

Answer 7

Nucleus raphe magnus (medulla)
Rostral ventromedial medulla

Fs: Nu Ra Ma - RUM… sorry this is so bad

Question 8

What is the proposed role of osteoprotegrin (OPG) in the pathology of cancer induced bone pain

Answer 8

OPG acts by sequestering RANKL, preventing osteoclast activation and reducing bone resorption

This feedback loop is disrupted in CIBP, with a marked osteoblastic inflammatory response, increased secretion of a range of cytokines increasing osteoclast activity, and an increased ratio of RANKL to OPG

FS:
- RANKL binds to RANK which activates osteoclasts
- OPG binds to RANKL so that it can’t bind to RANK
- PTHrp (cancer) increases osteoblastic inflammatory response = RANKL > OPG —-> osteoclast activation —-> bone resorption

FS: denosumab mimics OPG

Question 9

How does gabapentin work to reduce CIBP

Answer 9

It reduces activity of dorsal horn neuron wide dynamic range (WDR) neurons.

WDR neurons appear to alter in CIBP, with increased responsiveness to mechanical and thermal stimuli in addition to ongoing spontaneous activity

Question 10

CIBP treatments

Medication - list 4
Cancer treatment - list 2
Intervention - list 4

Answer 10

XRT, radioisotopes, hemibody XRT
TENS
complementary tx (acupuncture)
bisphosphonates
surgery
anesthetic interventions (they put vertebroplasty here)
PT, OT
WHO analgesic ladder
topical tx (lidocaine)
tumoricidal agents
new emerging tx (gabapentin and other glumate inhibitors
)
5th Ed. Figure 13.2.3

FS:

Medications
- opioids
- steroid
- nsaids
- bisphosphonate
- gabapentin
- topical

Cancer treatment
- radiation
- systemic treatment

Interventions
- Kyphoplasty
- Surgery
- PT/OT
- TENS

Question 11

List 3 characteristics of pain associated with CIBP

Answer 11

tonic background pain
spontaneous pain at rest
movement-related pain
incident pain (related to event other than movement)

Question 12

What are the three most common sites of bone mets

Answer 12

vertebral
Chest wall
pelvis and long bones

Question 13

What is the most common individual site of bone mets with the following malignancies:

• head and neck
• breast
• lung
• upper GI
• lower GI
• prostate

Answer 13

head and neck - skull

breast - vertebral (!!!)

lung - chest wall

upper GI - vertebral (!!!)

lower GI - pelvis / long bones

prostate - pelvis/ long bones

Question 14

What is the most common type of pain syndrome seen in breast, prostate and hematlogic ca

Answer 14

generalized bone pain

Question 15

List two consequences of breakthrough pain in CIBP

Answer 15

increased anxiety and depression
greater functional impairment

Question 16

List five symptoms of opioid toxicity

Answer 16

hallucinations
confusion
agitation
sleepiness
poor concentration
vivid dreams
hyperalgesia

FS: allodynia, hyperalgesia, myoclonus, delirium, seizure (OIN)

Question 17

What is the gold standard treatment for CIBP?

Answer 17

radiotherapy

Question 18

What are three strategies for treating breakthrough pain in CIBP?

Answer 18

treat underlying cause of pain

optimizing around the clock analgesia

Specific pharm or non-pharm interventions for BT pain

Question 19

List three mechanisms through which bisphosphonates treat CIBP

Answer 19

inhibit the differentiation of stem cells into osteoclasts*

cause apoptosis of osteoclasts*

affect interaction between osteoclasts and blasts via OPG RANKL and RANKL axis

inhibit growth of some tumor cells
stimulate immune system against tumor

cause apoptosis of tumor cells

delay development of skeletal events*

FS: bisphosphonate increase bone density by interfering with osteoclasts:

• affect interaction of osteoclast and blast via RANKL (produced by osteoblast) RANK axis
• prevent osteoclast differentiation
• cause osteoclast apoptosis

Question 20

List three side effects of bisphosphonates

Answer 20

flu like syndrome
injection site reaction
renal toxicity*
osteonecrosis of the jaw*
Hypocalcemia*

Question 21

List three risk factors for osteonecrosis of the jaw in the setting of bisphosphonate use

Answer 21

dental extraction
local trauma
local infection
systemic chemo

FS:
Poor dental health
Gingivitis
Dental procedure
Poor healing (chemo, radiation, steroid)

Question 22

What is the most common radiation modality used for CIBP? What two other mechanisms can be used

Answer 22

external beam XRT , local field - most common

wide field XRT

radioisotope treatment (internal, can be PO or IV)

Question 23

List four pathology-related factors that are taken into account when deciding if an impending pathological fracture should be operated on

Answer 23

Lesion:
- size and involvement (maximum amount of cortex destroyed)
- location
- type: blastic, lytic, combo

degree of pain

Question 24

What are two complications that can occur in cementoplasty

Answer 24

cement leak that can cause chemical damage in epidural space and cord/nerve root compression

cement embolization

Question 25

Briefly describe the pathophys of met bone pain in relation to osteoclast activation.

Answer 25

◆ Tumour cells stimulate osteoclast activation through a series of cytokine mechanisms
◆ in doing so promote bone damage which leads to a compensatory but often inefficient osteoblast response.

FS:
Cancer release PTHrp -> osteoblast to release RANKL-> bind to RANK and activate osteoclast -> bone resorption

Question 26

Role of denosumab

What is the main effect re bone?

How does it compare to pamidronate and ZA?

Answer 26

◆ Denosumab is a monoclonal antibody which targets and inhibits RANKL***

◆ main effect is delay onset of pain (vs analgesia) (!!!)

◆ was associated with a statistically sig improvement vs placebo for:
- time to first on-study skeletal-related event
- risk of first and subsequent skeletal-related events
- skeletal morbidity rate (RR 0.47, 95% CI 0.25–0.67)

◆ superior to pamidronate & zoledronic acid in time to fisrt skeletal-related event

Question 27

Name THREE fracture assessment from met disease tools.*

Answer 27

◆ Mirels’ Score
◆ Dutch Bone Metastasis study
◆ CT structural rigidity analysis
◆ Spinal Instability Neoplastic Score (SINS)

Question 28

Solitary or oligo-bone mets are most commonly seen in which malignancies?

Answer 28

◆ Prostate
◆ Breast