Royal Prince Alfred Hospital Missenden Road, CAMPERDOWN ... · •Giant Cell Tumour of Bone Primary...

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

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 %

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

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

Malignant Sarcomas

Presentation

• Mass 80%

• Discomfort/pain 40%

• Fracture 2%

• Metastases 4%

– Lung symptoms 2%

– Bone pain 2%

• Systemic symptoms 40%

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

Staging Investigations

LOCAL SYSTEMIC BIOPSY

Plain X-ray

CT Scan

MRI

CXR

CT Lungs

PET Scan

Core

Open

Excisional

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% **

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

Limb Salvage

• 90 – 95% of cases

Surgical Margins

• Intralesional

• Marginal

• Wide (en block)

– tumour not seen at time of resection

• Radical

M 35 yr

GCT

M 35 yr

GCT

F 13 yr

Osteosarcoma

F 13 yr

Osteosarcoma

42 yr M Chondrosarcoma

42 yr M Chondrosarcoma

54 F

MFH

51 F Chondrosarcoma

51 F Chondrosarcoma

51 F Chondrosarcoma

37 yr M GCT

37 yr M

GCT

1 yr post-op

8 yrs post-op

13 yr F Ewing’s

13 yr F

Ewings

5 yrs post-op

The Ultimate Goal

BIOLOGICAL RECONSTRUCTION

26 yr M Osteosarcoma

26 yr M

Osteosarcoma

26 yr M Osteosarcoma

26 yr M

Osteosarcoma

2 yrs post-op

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”

Technique

Multi-layer wrapping

- inner layer moist

- maximum air exclusion

Irradiation to 50Gy

- large specimens linear accelerator

- small specimens blood product irradiator

EXTRACORPOREAL IRRADIATION

- 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

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.

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

D.B

Male 7 years

Ewing’s Sarcoma

Pre-chemotherapy

D.B

Male 7 years

Ewing’s Sarcoma

Pre-chemotherapy

D.B

Male 7 years

Ewing’s Sarcoma

Post-chemotherapy

D.B

Male 7 years

Ewing’s Sarcoma

Post-chemotherapy

D.B

6 months post-op

D.B

5 years post-op

D.B

5 years post-op

D.B.

14 years post op

Now aged 21

N.K.

Female 14 years

Ewing’s

S+I1

N.K.

23 months

Post-op

N.K.

Female 14 years

Ewing’s

S+I1

N.K.

29 months

Post Ewing’s

N.K.

8 years

Post Ewing’s

F.G.

Male 39 years

Gd 2 Chondrosarcoma

F.G.

Male 39 years

Gd 2 Chondrosarcoma

F.G.

Immediate post-op

F.G.

12 months post-op

F.G.

10 years post-op

Femoral Reconstruction

• Intercalary resection performed where

possible, with irradiated graft fixed with nail

and/or plate

• 2/3rds had vascularised fibula graft

augmentation

R.S.

Female 13 years

Ewing’s Sarcoma

R.S.

6 months post-op

R.S.

3 years post-op

R.S.

14 years post-op

R.S.

14 years post-op

A.K.

Female 12 years

Osteosarcoma

A.K.

6 month post-op

A.K.

12 month post-op

A.K.

4 years post-op

A.K.

8 years post-op

Female 12 years

Osteosarcoma

7 years follow-up

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

A.K.

Male 14 years

Osteosarcoma

B.S.

6 months post-op

B.S.

6 months post-op

AVN head

4 years

Composite

Hemiarthroplasty

plus plate

Tibial Reconstruction

Male 65 years

MFH

Immediate post-op

8 years post-op

A.T.

Male 12 years

Osteosarcoma

6 year follow up

6 months post op 12 months post op

J.W.

Osteosarcoma

J.W.

Corrective osteotomy

3 years post op

Age 11 years

5 cm short

Skeletal maturity

Age 16 years

ECI Discussion

• ECI reconstruction demonstrates very good long term

functional outcomes

• Functional scores better in younger age groups and in

femoral tumour sites

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

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

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

Female 5 yrs - osteosarcoma

Female 5 yrs - osteosarcoma

Pre-lengthening Post-lengthening

Male 11 yrs - osteosarcoma

Current Management of Giant Cell Tumour of Bone

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.

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

• 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

Microscopically

– Uniform distribution

– Large, osteoclast like

– 50-100 central nuclei

– Abundant, dense cytoplasm

– +/- vacuolation

Giant cells Stromal cells

round

spindled

Giant cells:

Microscopically

Giant cells Stromal cells

round

spindled

– Short plump cells

– Elongated fibroblast like

– Small / Intermediate size

– Mitoses common

Stromal cells:

Behaviour

Locally aggressive:

– Cortical destruction

– Expansion

– Soft tissue involvement

“Metastasis” 1-2%

Malignant transformation v. rare

PLAIN FILM / CT

Giant Cell Tumour of Bone

Eccentric / lytic lesion

Giant Cell Tumour of Bone

Eccentric / lytic lesion

Well defined borders

PLAIN FILM / CT

Giant Cell Tumour of Bone

Eccentric / lytic lesion

Well defined borders

Expansile / remodelling 40%

PLAIN FILM / CT

Giant Cell Tumour of Bone

Eccentric / lytic lesion

Well defined borders

Expansile / remodelling 40%

PLAIN FILM / CT

Giant Cell Tumour of Bone

Eccentric / lytic lesion

Well defined borders

Expansile / remodelling 40%

Trabeculae / soap bubble

PLAIN FILM / CT

Eccentric / lytic lesion

Well defined borders

Expansile / remodelling 40%

Periostitis 10 – 30%

Trabeculae / soap bubble

Septations

Giant Cell Tumour of Bone

PLAIN FILM / CT

MRI

T1WI

Low / Intermediate SI

Giant Cell Tumour of Bone

T2WI

Giant Cell Tumour of Bone

MRI

Intermediate/High SI

Giant Cell Tumour of Bone

MRI

T2WI

Intermediate/High SI

(Soft tissue mass)

Intermediate/High SI

Fluid / Fluid levels

Assoc ABC component

(Soft tissue mass)

Giant Cell Tumour of Bone

MRI

T2WI

• Xray

• Ct scan

• MRI scan

• PTH assay

• Biopsy

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

Enbloc Resection without

Reconstruction

Current Surgical Management of

Giant Cell Tumours

37 yr M

GCT

37 yr M

GCT

1 yr post-op

8 yrs post-op

32 Male

Biopsy proven

GCT

Vascularised Fibular

Graft

8 months post-op : both osteotomies united

20 yr F

GCT

Initial presentation

6 months post

curette/graft

20 yr F

GCT

9 years post-op

38 yr M

GCT

38 yr M

5 yrs post-op

• 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

Figure 1. RANKL is a Central Mediator of the

Vicious Cycle of Bone Destruction in GCTB

Figure 2. Denosumab May Interrupt the Vicious

Cycle of GCTB-induced Bone Destruction

Management of Giant Cell

Tumours with Denosumab

• Patient outcomes

– Cervical Spine

– Sacrum

– Ankle

– Femur

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

Initial imaging – November 2010

Dec 2010: CT - Destructive lesion C4

Initial imaging - December 2010

Post-operative x-ray (1st) - April

2011 Apr: C4 vertebrectomy Dec: Recurrence – Debulking + laminectomy C2-C6 + stabilisation

Post operative imaging – May 2011

Follow up imaging – June 2011

Follow up imaging Decemeber 2011 –

Recurrence

2012 Feb: Residual tumour left vertebral artery Mar: PET positive 23cm mass

Post operative (2nd) x-ray – December 2011

Pre-trial imaging March 2012 – Extensive recurrence

Follow up PET 6 months post trial enrolment – September

2012

Without Denosumab With Denosumab

Risk of Quadraplegia Normal functioning /life

Severe c-spine instability and pain Avoidance of contact sports

Risk of death

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

Pre trial MRI - March 2010 Pre trial CT – March 2010

Follow up MRI 20 months post trial enrolment - Aug

2012

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

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

Initial imaging – April 2010

Increasing lower back/buttock pain

Pre trial imaging - September 2010

Follow up imaging 5 month post trial enrolment – March 2011

Follow up imaging 21 Months post trial enrolment - May 2012

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

DM, M 77 – GCT Pelvis/Sacrum

• 2010

– Oct: Increasing pain ? Arthritic

– Imaging dates

– Oct: Biopsy – GCT

• Dec 2010

– Commenced denosumab

• 2012

– Oct: Continuing denosumab

Initial imaging - October 2010

Follow up imaging – Sept 2011

Follow up imaging March 2012

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

KB, F 30 – Distal Femur

• 2011/12

– Nov – Feb: 4 month history right knee pain

• 2012

– Biopsy

• March 2012 – Commenced Denosumab

Initial x-ray – January 2012

Pre-trial imaging – February 2012

Follow up imaging 6 months post trial enrolment –

September 2012

Without Denosumab With Denosumab

Endoprosthetic Replacement or Pain free function

Cementation

Lengthy Hospitalisation Unrestricted activities of daily

living

DI, F 30 – Left Ankle

• 2011

– July: Biopsy

– Aug: Curettage + cement injection

• Dec 2011

– Biopsy confirmed local recurrence

• January 2012 – Commenced Denosumab

Initial imaging – July 2011

Post operative x-ray – November 2011

Pre-trial imaging – December 2011

Follow up imaging 4 months post trial enrolment – May

2012

Follow up imaging 8 months post trial enrolment–

September 2012

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

Denosumab - Benefits

• Management of local recurrence

• Avoidance of surgery

– Particularly spinal and axial regions

• Management of inoperable tumours

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.