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METASTATIC BONE DISEASE

Hanif Andhika W
METASTATIC BONE DISEASE

Primary Bone Tumors :


W.H.O (2002) : Very rare : 0,2 % overall
human tumor burden
National Central General Hospital Jakarta
(1995 1999) : 1,2%

Secondary Bone Tumors :


USA : 2001 : 1.3 million cases of cancer
50% potential to spread to musculo-
skeletal system
Post mortem : 30 85%, die of cancer
occult meta in bone

Secondary >> Primary 70% malignant


bone tumors are metastatic
METASTATIC BONE DISEASE

Bone is 3rd most common site of


metastatic after lung and liver

Metastatic bone tumors : 80% caused by


Ca of Breast, Prostate, Lung, and
Kidney (in order of incidence)

Other CA : Thyroid, Gaster, Colon


Children : Neuroblastoma
METASTATIC BONE DISEASE

Site of meta : Spine (thoraco lumbar),


Pelvis, Ribs, Skull and Proximal
Limb Girdle

Meta to distal knee and elbow (Acral


metastasis) uncommon

50% Acral meta are due to Ca lung and


breast
Incidence of cancer to MBD

Lipton, Allan. Pathophysiology of Bone Metastases: How This Knowledge


May Lead to Therapeutic Intervention. 2004
Pathogenesis
Seed and soil hypothesis (Paget) 1889 :
Cell movement to distant sites is NOT random. Organ
spesific metastase is influenced by homing
mechanism (chemoattractant & adhesion molecule
meet the tumor receptor)

local factors (IGF I-II, FGF, PDGF, BMP etc)


provide optimal environments (soil) for specific
cell cancers (seed) to grow tumor

Circulation (Filter & Flow) theory (Ewing 1928) :


metastasis occurs purely by anatomic and
mechanical routes.
METASTATIC BONE DISEASE

Biology of Bone Metastases :

Cell adhesion molecules : Laminin


metastatic cell attach to basement
membrane

Once meta cell had skeletal attachment


interacts with extracell matrix
produce : Proteases (metalloproteinase /
MMP) involved in bone matrix turn
over and stimulate prolif tumor cells
METASTATIC BONE DISEASE

Produce : - Urokinase Plasminogen Activator


(uPA) important pathway in
development of meta Breast,
Lung and Prostate

- Cytokine : Interleukin (IL-1, IL-6,


IL-8) and TNF (Tumor Necrosis
Factor Alfa)

Stimulation of osteoclast
Formation and Activation of
Osteoclasts Molecular insights
RANK/RANKL/Osteoprotegerin (members of TNF family)

Receptor activator of NF-kB


Receptor expressed on mature
RANK Osteoclasts and precursors

RANK Ligand Cytokine expressed by osteoblasts, stromal cells,


some tumour cells leading to osteoclastic activation

Natural antagonist of RANKL secreted by bone


Osteoprotegerin lining cells (decoy/scavenger receptor)
Cancer cells

Most of osteolytic
factors act via
Bone-derived
osteoblast
growth factors Osteolytic factors
production
IGF, TGFof PTHrP, IL-11
RANKL

Osteoblasts
Osteoclasts Mineralised bone matrix
RANKL
The Soil and Seed Theory
Tumour cell Bone microenvironment Interactions:
the Vicious Circle in Prostate Cancer

Cancer cells

Osteoblastic
factors
Adrenomedullin
Bone-derived
ET-1,
growth factors Osteolytic factors
IGF, TGF PTHrP,RANKL, IL-11

New bone

Osteoblasts
Osteoclasts Mineralised
RANKL bone matrix

The Soil and Seed Theory


RANKL and Chemotactic Migration of Circulating Cancer Cells to Bone
Tumour Cell / Bone Microenvironment Interactions
Circulating Cancer cells
expressing RANK
RANKL may act as a
RANK chemotactic factor which
attracts circulating cancer
cells expressing RANK to
migrate into the bone

Osteoblasts
Bone matrix
RANKL
Adapted by Hamdy Azim from Armstrong AP, et al. Prostate 2008; 68:92-104.
METASTATIC BONE DISEASE

Effect on skelet : Osteolytic

Biology of osteoblastic bone meta is


less well understood
METASTATIC BONE DISEASE

Lytic or blastic appearance depends on


relative of osteoclast and osteoblast
activity and degree of coupled bone
turn over at site

Mostly : mixed appearance


METASTATIC BONE DISEASE

Diff. Diagnosis for destructive lesion


of the bone in patients > 40 years :

- Metastatic
- Myeloma
- Lymphoma
- Chondro Sa / Fibro Sa /
Malignant Fibrous
Histiocytoma
(MFH)
METASTATIC BONE DISEASE

Work up : Medical History, Physical Exam,


lab. exam (Ca !!), X-ray of involved
Bone and Chest, Bone survey
Bone Scan
Lab : ESR > 100 mm/H Myeloma, CEA
(GI tract, HC Ca), PSA
If necessary for unknown / unidentified origin
additional CT of chest, abdomen and
pelvis
With above strategy 85% primary tumor were
identified
METASTATIC BONE DISEASE

Positron Emission Tomography (PET) :


metabolic imaging for identifying site
of primary
Tumor Marker :
Currently no reliable marker to predict
which primary tumor will spread to bone
New biochemical marker of bone turn
over N-telopeptide (NTX) and C-telopeptide
(ICTP) for detecting bone metastases /
disease progressive combined with
serial bone survey / bone scan
METASTATIC BONE DISEASE

Prostate Cancer Predictive marker :


Transforming Growth Factor (TGF-)

TGF- and no known meta likelihood


of subsequent disease progression
METASTATIC BONE DISEASE

Effect of meta in bone


Disturbance to :

- Structural support
- Hematopoeitic system
- Mineral metabolism
METASTATIC BONE DISEASE

Structural Support :
Causes Impending Fx : Fx likely to occur
with physiologic loading / ADL
Risk of pathologic fx in Weight Bearing
Bone 50% cortical destruction
Diaphysis Femur : Long permeative lytic
METASTATIC BONE DISEASE

Hematopoiesis :
Suppresion due marrow replacement
with tumor cell (Ca Breast, Prostate,
Lung, Thyroid) anemia normo
chronic / cytic
METASTATIC BONE DISEASE

Mineral metabolism Hypercalcemia


due to extensive bone destruction
symptom : anorexia, weakness, nausea/
vomiting, polydipsia / uria
Flu like symptom
Incidence : up to 30%
Most common in : Ca Lung, Breast,
Myeloma, Lymphoma
METASTATIC BONE DISEASE

Treatment : MULTIDISCIPLINARY APPROACH


Medical oncologist, Radiotherapist,
Orthopaedic surgeon and Rehab.

Medical :
- Once meta (+) prognosis poor
- Prognosis : Median survival : 6 48 mos
(Lung < 6, thyroid 48)

- Yamashita: Ca breast : osseous meta : 35 mos;


( Ref: Menendez) extraosseous meta (Lung and Liver)
only 5 mos !
METASTATIC BONE DISEASE

Medical th/ :

- Chemotherapy, endocrine treatment


- Therapy for bone lesions : Bisphosphonate
inhibit osteoclastic bone resorption, do not
have direct affect in tumor growth
Bone meta (+) : combined chemo tx and
bisphosphonate
- Hypercalcemia : Hydration / saline diuresis +
bisphosphonate
Effect of Bisphosphonate after binding to the
matrix :

Blocks attachment of osteoclast precursor cells to the


bone
Inhibits osteoclast functions
Inhibits osteoblast mediated osteoclast activation
METASTATIC BONE DISEASE

Radiation : External Beam Radiation Therapy


(EBRT)
for preventing progression also for pain
Early radiation tx of painful lytic lesions may
avoid surgical intervention
For lesions NOT with impending fx.
Most common meta are Radiosensitive
palliative effects in 80% of patient for up to
1 year
METASTATIC BONE DISEASE

Recalcification of lytic areas begin


3 6 weeks post radiation
To decrease pain adm. of radioisotope :
Strontium 89, Samarium
Effect : improved mobility, narcotic
analgetic , performance status ,
quality of life
Some report : improved survival
METASTATIC BONE DISEASE

Surgical :
Indications for operative treatment
- Established pathologic fracture
- Lesions 2,5 cm in the femur Impending fx
Prophylactic int.
- Lytic lesions 50% cortical
fixation
involvement/(cross section)
- Risk of Fx determined by CT-Scan
- After fixation Radio th/
METASTATIC BONE DISEASE

Implant : Intramedullary devices


mainstay of treatment for diaphyseal
lesion in upper and lower extremities

Proximal Femur : Prosthetic replacement,


standard or long stem
as indicated

Bone cement : Extremely useful adjunct for


fixation enhancement
METASTATIC BONE DISEASE

Criteria for open fx. fixation / prosthetic


replacement :
Life expectancy at least 2 mos and
general condition good enough
Will expedite mobilization and facilitate
general care
Quality of bone proximal and distal of fx.
site is adequate to support metallic
fixation
METASTATIC BONE DISEASE

Stable fixation is imperative because of low


rate of union

Delayed / non union caused by : Pre-op


chemo/radio th, interposition of bone
cement, viable tumor cell on fx site

Bone graft : effective if at least 6 mos


after radiation
METASTATIC BONE DISEASE

Survival expectancy should NOT be the


sole determinant for surgical
intervention because often
inaccurate

Potential benefit of surgery >< patients


overall condition and survivability

Need thorough pre-op evaluation and


planning TEAM approach decision !