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Royal Prince Alfred Hospital Missenden Road, CAMPERDOWN NSW 2050.
Incidence, Diagnosis and
Treatment of Bone and Soft
Tissue Sarcoma
Insight to future changes in
Management
Paul Stalley
FRACS Consultant Orthopaedic Oncologist
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Malignant Sarcomas
Of all new cancer notifications each year…
• Multiple Myeloma 0.8 – 1.0 %
• Soft Tissue Sarcomas 0.5 – 0.7 %
• Primary Bone Sarcomas 0.2 – 0.3 %
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Malignant Bone Tumours
Osteosarcoma 22% Leiomyosarcoma
Chondrosarcoma 10% Angiosarcoma
Lymphoma 8% Chordoma
Ewing’s 8% Fibrosarcoma
Giant Cell Tumour Adamantinoma
Clear Cell Sarcoma Hemangiopericytoma
Malignant Fibrous Histocytoma
Mesenchymal chondrosarcoma
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Malignant Soft Tissue Sarcomas
• Liposarcoma
– Myxoid, round cell, pleomorphic, dedifferentiated
• Fibrosarcoma
• Myxofibrosarcoma
• Epithelioid Fibrosarcoma
• MFH
• Leiomyosarcoma
• Rhabdomyosarcoma
• Haemangioendothelioma
• Mesenchymal Chondrosarcoma
• Synovial Sarcoma
• Epithelioid Sarcoma
• Alveolar Soft Part Sarcoma
• Clear Cell Sarcoma of Soft Tissue
• PNET
• Desmoplastic Small Round Cell Tumour
• Malignant Mesenchymoma
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Malignant Sarcomas
Presentation
• Mass 80%
• Discomfort/pain 40%
• Fracture 2%
• Metastases 4%
– Lung symptoms 2%
– Bone pain 2%
• Systemic symptoms 40%
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Management of Malignant
Sarcomas
• Imaging
Surgical Staging
• Biopsy
• Induction Therapy - Chemotherapy or
Radiotherapy
• Surgery - Excision, Amputation or Limb salvage
• Adjuvant Therapy - Chemotherapy and/or Radiotherapy
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Staging Investigations
LOCAL SYSTEMIC BIOPSY
Plain X-ray
CT Scan
MRI
CXR
CT Lungs
PET Scan
Core
Open
Excisional
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Outcome of Therapy for Musculoskeletal
Tumours of Childhood Arndt & Crist. NEJM 341:3429 1998
Type of Tumour Agents Used Duration of Rx LT Survival
Rhabdomyosarcoma
Low Risk
High Risk
Act D, Vcr.
Vcr, ActD, Cyclo.
8-12 mth
8-12 mth
90 - 95%
70 - 80%
Osteosarcoma
Localised
Metastatic
Dox, HDMtx,
CisPL, Ifos.
8-12 mth
8-12 mth
58 - 76%
14 - 50% **
Ewing’s
Localised
Metastatic
Vcr, Dox, ActD,
Cyclo, etopo-ifos.
8-12 mth
8-12 mth
50 - 70%
19 - 30% **
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Surgical Options
• Amputation
• Excision
• Arthrodesis – Autograft
– Vascular Fibula –
Allograft
• Rotationplasty
• Bone Transport –
Ilizarov
• Massive tumour
Prosthesis
• Allograft
• Combined Allograft /
Prosthesis
• Extracorporeal
Irradiation – with
prosthesis – with
vascular fibula
• Pasteurised tumour
• Autoclaved tumour
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Limb Salvage
• 90 – 95% of cases
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Surgical Margins
• Intralesional
• Marginal
• Wide (en block)
– tumour not seen at time of resection
• Radical
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M 35 yr
GCT
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M 35 yr
GCT
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F 13 yr
Osteosarcoma
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F 13 yr
Osteosarcoma
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42 yr M Chondrosarcoma
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42 yr M Chondrosarcoma
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54 F
MFH
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51 F Chondrosarcoma
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51 F Chondrosarcoma
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51 F Chondrosarcoma
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37 yr M GCT
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37 yr M
GCT
1 yr post-op
8 yrs post-op
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13 yr F Ewing’s
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13 yr F
Ewings
5 yrs post-op
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The Ultimate Goal
BIOLOGICAL RECONSTRUCTION
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26 yr M Osteosarcoma
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26 yr M
Osteosarcoma
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26 yr M Osteosarcoma
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26 yr M
Osteosarcoma
2 yrs post-op
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EXTRACORPOREAL
IRRADIATION
FOR LIMB SALVAGE OF
MALIGNANT BONE TUMOURS
“The use of the irradiated segment of
resected bone to achieve limb
reconstruction in a single stage
operation”
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Technique
Multi-layer wrapping
- inner layer moist
- maximum air exclusion
Irradiation to 50Gy
- large specimens linear accelerator
- small specimens blood product irradiator
EXTRACORPOREAL IRRADIATION
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- 50Gy approximately equates to 250Gy
in fractionated dose using
conventional external beam.
- Int. J. Radiation Oncology Vol. 50 No. 2.
Hong, Stalley et al.
EXTRACORPOREAL IRRADIATION
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Rationale for ECI
Use of perfectly fitting graft with soft tissue attachments preserved.
Guaranteed tumour necrosis.
No irradiation of normal surrounding tumour bed tissue.
Preservation, where possible, of adjacent growth plates.
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Pelvic Reconstruction
• THR in skeletally mature patients – Cemented polyethylene acetabulum
– S-ROM femoral stem
• Skeletally immature patients without
total hip replacement- native hip in
acetabulum
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D.B
Male 7 years
Ewing’s Sarcoma
Pre-chemotherapy
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D.B
Male 7 years
Ewing’s Sarcoma
Pre-chemotherapy
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D.B
Male 7 years
Ewing’s Sarcoma
Post-chemotherapy
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D.B
Male 7 years
Ewing’s Sarcoma
Post-chemotherapy
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D.B
6 months post-op
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D.B
5 years post-op
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D.B
5 years post-op
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D.B.
14 years post op
Now aged 21
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N.K.
Female 14 years
Ewing’s
S+I1
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N.K.
23 months
Post-op
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N.K.
Female 14 years
Ewing’s
S+I1
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N.K.
29 months
Post Ewing’s
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N.K.
8 years
Post Ewing’s
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F.G.
Male 39 years
Gd 2 Chondrosarcoma
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F.G.
Male 39 years
Gd 2 Chondrosarcoma
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F.G.
Immediate post-op
F.G.
12 months post-op
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F.G.
10 years post-op
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Femoral Reconstruction
• Intercalary resection performed where
possible, with irradiated graft fixed with nail
and/or plate
• 2/3rds had vascularised fibula graft
augmentation
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R.S.
Female 13 years
Ewing’s Sarcoma
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R.S.
6 months post-op
R.S.
3 years post-op
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R.S.
14 years post-op
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R.S.
14 years post-op
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A.K.
Female 12 years
Osteosarcoma
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A.K.
6 month post-op
A.K.
12 month post-op
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A.K.
4 years post-op
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A.K.
8 years post-op
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Female 12 years
Osteosarcoma
7 years follow-up
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Humeral Reconstruction
• Dissolution of humeral head in first two cases
• Subsequent cases underwent hemiarthroplasty with cemented long
stem Bigliani prosthesis / ECI graft composite.
• One vascularised fibula graft augmentation used
• Results in adults significantly more predictable with use of Bailey-
Walker Reverse Constrained Shoulder Replacement
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A.K.
Male 14 years
Osteosarcoma
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B.S.
6 months post-op
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B.S.
6 months post-op
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AVN head
4 years
Composite
Hemiarthroplasty
plus plate
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Tibial Reconstruction
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Male 65 years
MFH
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Immediate post-op
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8 years post-op
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A.T.
Male 12 years
Osteosarcoma
6 year follow up
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6 months post op 12 months post op
J.W.
Osteosarcoma
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J.W.
Corrective osteotomy
3 years post op
Age 11 years
5 cm short
Skeletal maturity
Age 16 years
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ECI Discussion
• ECI reconstruction demonstrates very good long term
functional outcomes
• Functional scores better in younger age groups and in
femoral tumour sites
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ECI Discussion
• Survival rates (78% at 9.5 years) and complication rates comparable or better than other methods of limb salvage such as allograft or megaprosthesis reconstruction
• Local recurrence occurred with some high grade malignancies, only one of which was extrapelvic
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ECI Discussion
Advantages
– Biological solution, immediately available
– Anatomically matched graft
– Natural joint preservation
– Tendon reattachment
– Preservation of limb length by sparing growth plates
– Minimal cost
– Low infection rate, no risk of viral transmission
– No incidence of radiotherapy-induced sarcoma
– Biological reconstruction which may be lifelong
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ECI Discussion
Disadvantages
– Lack of material for histopathological
analysis
– Potential for avascular necrosis and graft
resorption – augmentation of the
reconstruction with vascularised fibular
graft recommended where possible
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Female 5 yrs - osteosarcoma
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Female 5 yrs - osteosarcoma
Pre-lengthening Post-lengthening
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Male 11 yrs - osteosarcoma
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Current Management of Giant Cell Tumour of Bone
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Definition • Giant Cell Tumour of Bone Primary bone neoplasm
4% all bone tumours (20% China) Female > Male Age 20-50 (70% age 20-40)
• Generally benign
• Potential for :
– Recurrence
– Pulmonary metastasis
– Frank malignancy
Giant cell tumor of bone (GCTB) is a primary osteolytic bone tumor with substantial skeletal morbidity. Occurs the second and third decades of life, causing localized severe and intractable pain and swelling and reduced joint mobility.
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Giant Cell Tumour of Bone
– Long tubular bones distal femur
proximal tibia
distal radius
– Axial skeleton – sacrum (vertebral body v. rare) Female < 20 yrs
– Short tubular bones 3 - 4%
– Flat bones 4% pelvis crest ilium
pubis (acetabulum)
– Craniofacial bones – v. rare (Paget’s, Goltz; sphenoid).
60%
Subchondral bone
Epiphysis, Apophysis
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• GCTB can grow rapidly, completely destroying bone and spreading
into surrounding soft tissues.
• Until recently, there has been no approved or effective chemotherapeutic or medicinal therapy for GCTB.
• Surgery, the definitive therapy for GCT, is often associated with significant morbidity
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Microscopically
– Uniform distribution
– Large, osteoclast like
– 50-100 central nuclei
– Abundant, dense cytoplasm
– +/- vacuolation
Giant cells Stromal cells
round
spindled
Giant cells:
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Microscopically
Giant cells Stromal cells
round
spindled
– Short plump cells
– Elongated fibroblast like
– Small / Intermediate size
– Mitoses common
Stromal cells:
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Behaviour
Locally aggressive:
– Cortical destruction
– Expansion
– Soft tissue involvement
“Metastasis” 1-2%
Malignant transformation v. rare
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PLAIN FILM / CT
Giant Cell Tumour of Bone
Eccentric / lytic lesion
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Giant Cell Tumour of Bone
Eccentric / lytic lesion
Well defined borders
PLAIN FILM / CT
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Giant Cell Tumour of Bone
Eccentric / lytic lesion
Well defined borders
Expansile / remodelling 40%
PLAIN FILM / CT
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Giant Cell Tumour of Bone
Eccentric / lytic lesion
Well defined borders
Expansile / remodelling 40%
PLAIN FILM / CT
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Giant Cell Tumour of Bone
Eccentric / lytic lesion
Well defined borders
Expansile / remodelling 40%
Trabeculae / soap bubble
PLAIN FILM / CT
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Eccentric / lytic lesion
Well defined borders
Expansile / remodelling 40%
Periostitis 10 – 30%
Trabeculae / soap bubble
Septations
Giant Cell Tumour of Bone
PLAIN FILM / CT
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MRI
T1WI
Low / Intermediate SI
Giant Cell Tumour of Bone
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T2WI
Giant Cell Tumour of Bone
MRI
Intermediate/High SI
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Giant Cell Tumour of Bone
MRI
T2WI
Intermediate/High SI
(Soft tissue mass)
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Intermediate/High SI
Fluid / Fluid levels
Assoc ABC component
(Soft tissue mass)
Giant Cell Tumour of Bone
MRI
T2WI
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• Xray
• Ct scan
• MRI scan
• PTH assay
• Biopsy
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Treatment • Traditionally:
– Intralesional curettage / resection & bone graft – Recurrence 35-42% (reported as high as 90% in some studies)
• En Bloc marginal resection
– 5% recurrence – Multiple complications as per limb salvage techniques (mega
endoprosthesis)
• Adjuvant- PMMA Liquid N2 local recurrence 3-6% Phenol CO2 laser
Radiation - ~10% sarcomatous degeneration - especially spinal/sacral lesions
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Enbloc Resection without
Reconstruction
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Current Surgical Management of
Giant Cell Tumours
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37 yr M
GCT
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37 yr M
GCT
1 yr post-op
8 yrs post-op
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32 Male
Biopsy proven
GCT
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Vascularised Fibular
Graft
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8 months post-op : both osteotomies united
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20 yr F
GCT
Initial presentation
6 months post
curette/graft
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20 yr F
GCT
9 years post-op
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38 yr M
GCT
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38 yr M
5 yrs post-op
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• Denosumab is a fully human antibody that binds RANKL, inhibiting osteoclast activity and osteoclast-mediated bone destruction.
• GCTB contains osteoclast-like giant cells and precursors that express RANK and mononuclear cells that express RANKL, which mediates osteoclast activation. Excessive secretion of RANKL causes an imbalance in bone remodeling in favor of bone breakdown
• Our study of patients with GCTB, responded to denosumab, as demonstrated by:
– Elimination of giant cells
– Reduction of RANKL-expressing-stromal cells
– Formation of cartilage, and bone
• All patients experienced clinical benefit (reduced pain or improvement in functional status)
Targeted Agents -Denosumab
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Figure 1. RANKL is a Central Mediator of the
Vicious Cycle of Bone Destruction in GCTB
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Figure 2. Denosumab May Interrupt the Vicious
Cycle of GCTB-induced Bone Destruction
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Management of Giant Cell
Tumours with Denosumab
• Patient outcomes
– Cervical Spine
– Sacrum
– Ankle
– Femur
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JT, M 33– GCT Cervical Spine
• 2010 – Dec: CT - Destructive lesion C4
• 2011 – Apr: C4 vertebrectomy
– Dec: Recurrence – Debulking + laminectomy C2-C6 + stabilisation
• 2012 – Feb: Residual tumour left vertebral artery
– Mar: PET positive 23cm mass
• March 2012 – Commenced Denosumab
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Initial imaging – November 2010
Dec 2010: CT - Destructive lesion C4
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Initial imaging - December 2010
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Post-operative x-ray (1st) - April
2011 Apr: C4 vertebrectomy Dec: Recurrence – Debulking + laminectomy C2-C6 + stabilisation
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Post operative imaging – May 2011
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Follow up imaging – June 2011
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Follow up imaging Decemeber 2011 –
Recurrence
2012 Feb: Residual tumour left vertebral artery Mar: PET positive 23cm mass
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Post operative (2nd) x-ray – December 2011
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Pre-trial imaging March 2012 – Extensive recurrence
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Follow up PET 6 months post trial enrolment – September
2012
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Without Denosumab With Denosumab
Risk of Quadraplegia Normal functioning /life
Severe c-spine instability and pain Avoidance of contact sports
Risk of death
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JP, M 44 – GCT Sacrum
• 2007 – Fall – L5/S1 discectomy
• No evidence of sacral tumour • Intermittent back pain post injury
• 2010 – Jan: Increasing sacral/sciatic pain – Feb: CT - Large sacral tumour
• 6.4x4.4cm • Posterior extension & S1 nerve root displacement
– Feb: Biopsy – Mar: MRI – Soft tissue mass occupying right sacrum with S1
encasement • April 2010
– Commenced Denosumab • 2012
– Continuing on Denosumab
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Pre trial MRI - March 2010 Pre trial CT – March 2010
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Follow up MRI 20 months post trial enrolment - Aug
2012
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Without Denosumab With Denosumab
Facing potentially morbid surgery Avoidance of surgery
Loss of bowel,bladder and sexual function
Lengthy hospital stay No pain requirements
Chronic pain issues Normal day to day life
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HM, F 22 – GCT Sacrum
• 2009/10
– Nov – Apr: Increasing lower back/buttock pain
• 2010
– Apr: MRI/PET
– May: Biopsy
• Oct 2010
– Commenced Denosumab
• 2012
– Continuing on Denosumab
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Initial imaging – April 2010
Increasing lower back/buttock pain
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Pre trial imaging - September 2010
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Follow up imaging 5 month post trial enrolment – March 2011
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Follow up imaging 21 Months post trial enrolment - May 2012
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Without Denosumab With Denosumab
Total sacrectomy/resection Avoidance of major high risk
risking loss of bowel, bladder and destructive surgery
Sexual function
Risk of being left wheelchair Opportunity to move to Lyon,
Dependent France – where pt continues
on Denosumab
Normal life
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DM, M 77 – GCT Pelvis/Sacrum
• 2010
– Oct: Increasing pain ? Arthritic
– Imaging dates
– Oct: Biopsy – GCT
• Dec 2010
– Commenced denosumab
• 2012
– Oct: Continuing denosumab
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Initial imaging - October 2010
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Follow up imaging – Sept 2011
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Follow up imaging March 2012
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Without Denosumab With Denosumab
Unlikely to survive surgery Avoids major surgery
Confined to crutches/wheelchair
Housebound Normal bladder and bowel
Pain function, no pain
Pt comes down for treatment
from central coast NSW, unaided
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KB, F 30 – Distal Femur
• 2011/12
– Nov – Feb: 4 month history right knee pain
• 2012
– Biopsy
• March 2012 – Commenced Denosumab
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Initial x-ray – January 2012
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Pre-trial imaging – February 2012
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Follow up imaging 6 months post trial enrolment –
September 2012
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Without Denosumab With Denosumab
Endoprosthetic Replacement or Pain free function
Cementation
Lengthy Hospitalisation Unrestricted activities of daily
living
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DI, F 30 – Left Ankle
• 2011
– July: Biopsy
– Aug: Curettage + cement injection
• Dec 2011
– Biopsy confirmed local recurrence
• January 2012 – Commenced Denosumab
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Initial imaging – July 2011
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Post operative x-ray – November 2011
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Pre-trial imaging – December 2011
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Follow up imaging 4 months post trial enrolment – May
2012
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Follow up imaging 8 months post trial enrolment–
September 2012
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Without Denosumab With Denosumab
Ankle Arthrodesis Preservation of native ankle
Rigid flat foot gait Excellent pain free range of mvt
Difficulty bending down or walking on Unrestricted daily activities
uneven ground Avoidance of high impact sports
Risk of arthritis in surrounding joints
Lengthy rehabilitation
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Denosumab - Benefits
• Management of local recurrence
• Avoidance of surgery
– Particularly spinal and axial regions
• Management of inoperable tumours
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Summary
• This cohort analysis describes adult and adolescent patients with GCTB who received treatment with denosumab.
• Many of these patients had recurrent or unresectable disease and had received previous treatment with surgery, chemotherapy, radiotherapy, and IV bisphosphonates.
• In this cohort , denosumab had an acceptable safety profile, with no side effects.
• Patients had no disease progression based on subjective assessment.