GIANT CELL TUMOR OF BONE (GCTB)M. Abdulla M.D.Prof. of Clinical OncologyKasr Al-Aini School of MedicineCairo University – Egypt.

SUN Annual MeetingAmgen SymposiumLe Meridien Cairo AirportFriday 21/10/2016

Member of Advisory Board, Consultant, and Speaker for:• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen

Cilag, Merck Serono, Novartis, Mundipharma, MSD, Eli Lilly, Bayer.

Speaker Disclosures:

GCTB: Basic Facts & Figures:• 3 – 5% of all primary bone tumors.• 15 – 20% of benign bone tumors.• Mostly benign with aggressive behavior.• Pulmonary metastases in 3 – 5% indolent behavior “Benign

Pulmonary Implants”. • Peak Incidence in 3rd & 4th decades of life.• Slight female predominance. • Origin: epiphysis & adjacent metaphysis of long bone, yet flat

bones can be affected.• Presentation: Pain & Swelling (Long Bones), Deformity &

Limitation of Mobility (Spine & pelvic).• Surgical Resection & Curettage The corner stone in

management

Normal Bone Physiology:

O.Blast O.BlastO.Blast

Bone Formation

O.Clast Precursor Cells

RANKL

DifferentiatedO.Clast

Mature Multinucleated

O.Clast

Bone Resorption

H+ Enz

OPG

Rana et al. Hematol Oncol Clin N Am 27 (2013) 1261–1283 Ca++, Cytokines, NTX

Vit DPTH

PGE2IL1

E2

• Estrogen + Osteoblast = Osteoprotegerin.• Osteoprotegerin + RANKL = RANK. • RANK Arrest of Osteoclast Differentiation Apoptosis NO BONE LOSS.

Normal Bone Physiology:

• Females:• Premenopausal Preservation of skeletal integrity.• Postmenopausal & Endocrine Therapy (Breast Cancer) Osteoporosis.

• Males:• Androgens –Aromatase Estrogen Bone Preservation.• Orchiectomy & ADT Androgens Estrogen Bone Loss.

Boyle WJ, et al. Nature 2003; 423:337-42..

GCTB: Histopathology:

Round to Oval Mononuclear Cells

Large Osteoclast Giant Cells:• Multinucleated, up to 50.• From monocytes.• > 50% of cellular content.

Osteoblast Precursor Malignant Stromal Cells ++ RANKL Expression Recruitment of Osteoclasts.Salerno M, Avnet S, Alberghini M, et al. Histogenetic characterization of giant cell tumor of bone. Clin Orthop Relat Res 2008;466(9):2081–91.

Treatment of GCTB:1. Surgical Resection with Wide Margins:

• Lowest Recurrence Rates.• Might be Associated with DEFORMITIES.

2. Surgical Curettage with Burring :• Most Effective in Long Bones.• Skull, Spinal & Pelvic Locations Mutilating & Incomplete.

3. Intra-Lesional Curettage:• Functional Preservation.• Higher RECURRENCE Rates.

4. Adjuvant Filling:• Phenol, Zinc Chloride, H2O2 …….• Variable recurrence rates.

5. Intensity Modulated Radiation Therapy:• Improves Local Control by 80%.• Risk of Subsequent Development of Sarcoma > 45 Gy.

Vult vS et al. J Bone Joint Surg Br 2006;88(4):531–5.Zhen et al. J Bone Joint Surg Br 2004 Mar;86(2):212–6. Roeder et al. Radiat Oncol 2010;5(1).

RANK-L Inhibitor:Denosumab

The Concept of Molecular – Based Targeted Therapy

Fully Human IgG2 Antibody

High Affinity to RANKL

No Interaction with RANK

Disrupt Cycle of Bone Destruction

Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncology 2010;11(3):275–80.

EMERGING ROLE OF DENOSUMAB IN THE MANAGEMENT OF GIANT CELL TUMOR OF BONE (GCTB)M. Abdulla M.D.(1) & W. Ebeid M.D.(2)

(1) Department of Clinical Oncology(2) Department of OrthopedicsKasr Al-Aini School of MedicineCairo University – Egypt.

EMSOS 28TH – Friday, 1 May 2015Athens, Greece.

The Study:• Pilot.• Experience of a Single Private Center with MDT Approach.• Salvage Therapy.

Patients’ Profile: • 17 patients with tissue & radiologic diagnosis of advanced

and/or metastatic GCTB not amenable for curative local procedures were included in the study, (2010 till now)

• Female Sex = 14 patients (82.4%).• Median Age = 29.5 (St Dev = +/- 12.06) years.• All patients had active local disease (Residual Progressive

and not recurrent).• 7 patients had pulmonary metastases at presentation.• Prior Therapy:

• Failed Surgical Procedure (Incomplete): 13 patients.• Arterial Chemo-embolization: 8 Patients.• Radical Conformal Radiation Therapy: 2 Patients

Clinical Features:• 1ry Anatomical Location:

Anatomical Location Number of Patients

Dorso-lumber & Sacral Spine 10

Tibia 2

Pelvic Bones 2

Femur 1

Ulna 1

Temporal Bone 1

Clinical Features:• Symptoms at Presentation:

Symptom Number

Pain 17

Neurological Deficits (Motor & Sensory) 10

Shortness of Breath & Cough 4

Treatment Received:• All patients (Except One) were treated with Denosumab

120 mg by SC injection every 28 days, except one patient• 4 patients had received Zoladronic acid 4 mg infusion for a

maximum of 5 injections; (No access to Denosumab at scheduled dates). 2 patients had started treatment by Zoladronic acid, and 2 received Zoladronic acid during treatment course.

• 2 patients: Systemic Chemotherapy following documented progression in the lung deposits.

• 1 patient: No active treatment PS 4.

Treatment Outcome:• Number received Denosumab injections per patient: 5 – 18

injection.• Pain: alleviated in all treated patients following the 2nd (13

patients = 81.3%) and the 3rd injection (3 patients = 18.7%).• Neurological Deficits: All patients showed stable neurological

status except 1 patient with Temporal GCTB showed improvement of Trigeminal Neuralgia.

• Pulmonary Metastatic Disease: (7 Patients)• > 50% Regression in 3 patients, of them one underwent metastatectomy

and proved to be of GCTB origin. Maximum response after 7 - 9 courses then stable disease.

• Disease Progression in 2 patients following initial stability, encountered after 5 & 6 injections.

• Stable disease in 1 patient.• 1 patient did not receive active treatment (PS 4) with extensive bilateral lung

deposits.

Treatment Outcome:• Radiologic Response of Primary Tumor:

• 15 patients had stable radiologic findings all through the study period.

• 1 Patient had progressive disease in distal ulna and resected successfully and kept free locally thereafter although showed progression of her pulmonary disease.

• Adverse Events: No Denosumab related comorbidity was reported in treated patients.

2010

2012

2014

Conclusions:• Denosumab is safe and effective in salvage treatment of

advanced and/or metastatic GCTB.• Denosumab is highly effective in pain alleviation due to

associated bone destruction early in course of treatment.• Although pulmonary metastases is rare in GCTB; yet,

Denosumab had shown significant response rate in the form of stationary course to significant down-sizing up to resolution of some of pulmonary lesions particularly those of small size.

• Denosumab represents a successful application in the era of personalized medicine and targeted therapies.

Thank You