Bone Metastases Kenneth Rankin Orthopaedic Postgraduate Teaching 22nd November 2010.

Bone Metastases

Kenneth RankinOrthopaedic Postgraduate Teaching

22nd November 2010

Overview

• Molecular mechanisms• Origin & distribution• Clinical features• Medical management• Surgical management• Cases

Molecular mechanisms of metastasis

• Analysis of 735 autopsy records of breast cancer patients

• Identified a non-random pattern of metastases• The Lancet 1889 : ‘seed and soil hypothesis’

Dr Stephen PagetSurgeon & pathologist1855-1926

Integrin

Extracellular matrix

Cadherin

Dysregulation of these allows cancer cells to breakaway from the ECM and other cells

Loss of adhesion↓E-Cadherin expression

VEGFNeoangiogenesis

Resident blood vessel

Primary site

Zone of severehypoxia

HIF

Intravasation (Interaction with Endothelial cells)

HIF= Hypoxia inducible factor

VEGF= Vascular endothelial growth factor

Mineralised Bone

Unmineralised Bone

StimulatesVia RANK/RANKL & VEGF

Hypoxia pathway activatedwhich facilitates invasion via MMP-1 expression

Bone absorption

Bone proteins/factors (e.g. TGFβ, IGF, PDGF & BMPs) act as chemoattractants

Extravasation

ZONE OF HYPOXIA

Bone marrow sinusoid

Cancer cell

Osteoclast

Mineralised Bone

Unmineralised Bone

Stimulates via TGFβand FGF

Hypoxia pathway activatedwhich facilitates invasion

Bone sclerosis

Bone proteins/factors (e.g. TGFβ, IGF, PDGF & BMPs) act as chemoattractants

Extravasation

ZONE OF HYPOXIA

Bone marrow sinusoid

Prostate ca cell

Osteoblast

Metastatic cells

• Small aggressive population• Not all circulating cancer cells form a

metastasis• Animal models show that 100s of cells detach

and circulate each day• 0.1% are viable 24 hours later• 0.01% form a metastasis

MCF-7 less aggressive breast cancer cells: PolyHEMA Concentration 0.3mg

Oestrogen receptor +ve

Day 1: MDA-MB-231 (more aggressive breast cancer cells):PolyHEMA concentration 0.3mg/ml

Oestrogen receptor -ve

Day 7: MDA-MB-231 (more aggressive breast cancer cells):PolyHEMA concentration 0.3mg/ml

Origin & distribution

• Types of tumour spread to boneo Breasto Prostateo Lungo Kidneyo Thyroid

• Differential: myeloma and lymphoma• Skeleton is ⅓ most favoured site for metastasis

of solid tumours (after liver and lung)

Frequency of skeletal metastases at autopsy

Tumour Bone metastases (%)

Breast

Prostate

Thyroid

Kidney

Lung

Oesophagus

GI tract/colon

Rectum

Bladder

Uterine/cervix

Ovaries

Liver

Melanoma

50-85

60-85

28-60

33-6032-64

6

3-10

8-60

42

50

9

16

7

Frequency of skeletal metastases as detected by bone scan

Primary site % with metastases

Breast

Prostate

Thyroid

KidneyLung

Rectum

Uterine/cervix

84

70

43

6064

61

56

Breast

6059

38

32

Spine

Ribs

Pelvis

Appendicularskeleton

28 Skull

Prostate

6050

57

38

Spine

Ribs

Pelvis


28 Skull

Lung

4365

25

27

Spine

Ribs

Pelvis


16 Skull

Kidney

4248

48

23

Spine

Ribs

Pelvis


10 Skull

Bladder

4753

47

7

Spine

Ribs

Pelvis


13 Skull

Cervix

2622

43

43

Spine

Ribs

Pelvis


26 Skull

Rectum

3629

43

43

Spine

Ribs

Pelvis


21 Skull

Clinical features of bony metastases

• Bone pain• Pathological fracture• Nerve compression• Hypercalcaemia

Bone pain

• Frequent in all lesion types• Exact mechanisms unclear• Remissions and exacerbations

– No obvious change in lesions

Pathological fractures

• Trivial injury• Associated with lytic lesions• Sites: Vertebral bodies & proximal long bones

Nerve compression

• Vertebral # and deformity• Direct pressure on spinal cord by metastasis• Osteoblastic lesion overgrowth• Skull lesion- impingement on foramina

Hypercalcaemia• Common: particularly osteolytic metastases• Less common in prostate cancer• 30% breast cancer patients at some point during

illness course (usually late on)• Causes:

– Excessive bone resorption– Impairment renal calcium excretion

• CHECK PTH before treatment if originating cause unknown

• Treat with i.v. bisphosphonate

Evaluation of bone metastases with unknown origin

History and examination

Serum biochemistry: FBC/U&E/LFTs/Bone PSA Serum/urine electrophoresis

ImagingCXR & Skeletal surveyBone scan

Chest and/or abdominal CT

Biopsy

Normal in 92%

Normal

90% patients are over 40 years old

InvestigationsMyeloma Breast Prostate

Lymphoma (particularly Hodgkins) may have osteolytic or osteoblastic lesions

Rarely, myeloma may be osteoblastic

X-rays Osteolytic Osteolytic or mixed Osteoblastic

Serum alkalinephosphatase

Normal ↑

↑

↑↑ +↑PSA

↑↑NormalBone scan

Histology ↑Osteoclast↓Osteoblasts

Mixed osteoclasts &osteoblasts

↑Osteoblasts

Always be alert for primary bone tumours

SCORE

VARIABLE 1 2 3

Site

Lesion

Upper limb Lower limb Pertrochanteric

Mild Moderate Functional

Blastic Mixed Lytic

<⅓ <⅓-⅔ >⅔

Pain

Size 81% #rate

100% #rate

0% 32% 48%

10% # rate

35% 31% 36%

Total of 7 or less: no fixation (4% risk)

Total of 9: fixation required (33% risk)

Total of 8: dilemma (15% risk)

Determination of requirement for prophylactic fixation of long bones

MIRELS Score

Score predicts risk of # over subsequent 6 months




Go the Boks

CriticismsSite n

Breast 50

Myeloma 11

Prostate 6

Lung 5

Cervix 3

Occult 3

Total 78

Small sample size: mainly breast carcinoma.

Definition of pain was not clear

Medical management

• Breast cancer• Prostate cancer• Radiotherapy

Breast cancer

• Hormonal• Chemotherapy• Newer inhibitors

Hormonal

Premenopausal Postmenopausal

Ovarian ablation (surgical or chemical)

Aromatase inhibitors

Antioestrogens

Progestins

Must be oestrogen or progesterone receptor positive

e.g. Tamoxifen

e.g. Megestrol

Chemotherapy

• For hormone receptor negative patients• Numerous different agents

Inhibitors

• Human epidermal receptor overexpression– Amenable to the inhibitor Tratuzumab (Herceptin)

• Avastin (VEGF inhibitor)

Breast cancer bone metastases medical management

• Bisphosphonates• Zolendronate shown to perform better than

Pamidronate in some studies

Prostate

• Androgen deprivation therapy (ADT) is mainstay

• Bisphosphonates – Offset osteoporosis due to ADT– Effective for ADT non-responders

Radiotherapy

• Major role in therapy for bone metastases• Pain relief in 70%• Reduce neurological complications• Recommended after internal fixation

– ↓ revisional surgery– Improved functional outcomes

Surgical management

• Approx 1.5% of patients with bone metastases require surgery (pre or post #)

• Stabilise long bones prior to #• Spine

– Cord compression– Instability– Occasionally amenable to

vertebroplasty/kyphoplasty• Radiofrequency ablation increasing in use

Urgent decompression & stabilisation

Indications

• Mirel score of 9+• Individualise for Mirel score of 8• Painful lytic lesion unresponsive to

radiotherapy• Avulsion of lesser trochanter

Relative Contraindications

• Moribund patient• Infected wound in surgical region• Acute DVT, especially if accompanying PE• Extensive neurovascular encasement by soft

tissue tumour extension• Severe malnutrition• Short expected survival

Planning surgery• CT useful for pre-op planning• Goal is early return to reasonable function/weight bearing• Reconstruction nail for femur (pertrochanteric and shaft)• No indication for standard femoral nail• Bipolar for neck/head metastases (ensure no significant acetabular

metastases)• Retrograde nail only if adjacent previous THR• Various i.m. nails for humerus• Cement (with antibiotics and anticancer agents) to fill large defects• Massive endoprostheses or arthroplasty

– Large diffuse areas of destruction (usually already fractured)– Lesions affecting adjacent joints

• Minimal role for plates and screws

Surgically treated bone metastases (excludes spine)

Site Number %

Scapula 10 3

Humerus 64 20

Pelvis/acetabulum 28 9

Femur 182 56

Tibia/fibula 18 6

Other 21 7

Total 323 100

From Ward et al: Clinical Orthopaedics and Related Research October 2003

Tumour originAll sites Femur

Primary Number % Number %

Lung 57 18 41 23

Breast 41 13 39 21

Myeloma 44 14 28 15

Renal 54 17 16 9

Prostate 21 7 17 9

Lymphoma 24 8 9 5

GI 9 3 3 2

Other 46 15 23 13

Unknown 18 6 3 2

Endometrial 3 1 3 2

Total 317 182

Procedure Number %

Amputation 0 0

Allograft 0 0

ORIF

Cannulated screws 3 2

Standard plates 2 1

DHS 13 7

DCS 2 1

Combination/complex 2 2

Intramedullary nail

Standard 14 8

Recon 89 49

Retrograde (adjacent THR only) 2 1

Enders 1 1

Arthroplasty

Hemi (head and neck lesions) 22 12

THR 5 3

Proximal femoral (extensive diffuse disease) megaprosthesis

19 10

Distal femoral (extensive supracondylar disease) megaprosthesis

5 3

Intercalary 1 1

Total femur 2 1

TOTAL 182 100

Final points

• Does IM nailing embolise metastases?– No evidence in animal models– No clear evidence that unreamed nailing is safer

• There is a significant risk of intra and postoperative PE – Surgical & anaesthetic team must be on the alert– Pulse lavage in between reaming may reduce the

risk– Venting reduces pressure (cadaver study)

CLINICAL CASES

Score 1 2 3

Pain Mild Moderate Functional

Site Upper limb Lower limb Per troch

Size ⅓ ⅓-⅔ >⅔

Type Blastic Mixed Lytic

Score=8

6 month # risk 15%

72 year old lady with known breast cancer

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score 10

6 month # risk 72%

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=8

6 month # risk 15%

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=10

6 month # risk 72%

54 year old with known breast ca

77 year old with breast cancer : 6 years bony mets (refused all treatment)

Score=10

6 month # risk 72%

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Palliative care

64 year old breast ca 8 years previously: mastectomy & good response to treatment

Referred to orthopaedic clinic with thoracic back pain: bone scan requested

Developed neurological symptoms 2 weeks later

66 year old male with Multiple Myeloma

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=8

6 month # risk 15%

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=10

6 month # risk 72%

2 months later

Destruction to acromium

Not reconstructable- radiotherapy only

48 year old lady with known breast ca

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=11

6 month # risk 96%

Already fractured

71 year old female, breast ca 1977 & 2003, 2 years elbow pain & stiffness

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=7

6 month # risk 4%

Lung ca

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=9

6 month # risk 33%

81 year old gentlemanwith known prostate ca

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=7

6 month # risk 4%

Spinal involvement in 80% of advanced prostate carcinoma patients & 6% develop cord compression

58 year old gentleman- fatigue & lower leg pain & swelling several months

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=10

6 month # risk 72%

Feeding vessel

REFERRED FOR EMBOLISATION

Renal carcinoma cells express large amounts of HIF and VEGF-results highly vascular bony metastases

61 year old gentleman- fatigue & lower leg pain & swelling several months

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=10

6 month # risk 72%

Renal ca treated with chemotherapy: too advanced for excision

Score 1 2 3



Size ⅓ ⅓-⅔ >⅔


Score=8

6 month # risk 15%

61 year oldunknown primary

2 weeks later

A further few days later

Further Reading

Clinical Orthopaedics and Related ResearchSupplement October 2003

QUESTIONS?

Bone Metastases Kenneth Rankin Orthopaedic Postgraduate Teaching 22nd November 2010.

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