METASTATIC BONE

DISEASE:

AN OLD DOGMA

& NEW INSIGHT

MOHAMED ABDULLA M.D.

PROF. OF CLINICAL ONCOLOGY

CAIRO UNIVERSITY

Tanta University – 17/02/2015

Bone Metastases: The Old

Dogma:

Cancer Related Bone Disease:

Effect of Treatment.

Effect of Metastases.

Improved Survival more disease and

therapy related events.

Breast Cancer 50% Bone Metastases

Prostate Cancer 60% Bone Metastases.

Heavy Burden: Medical, Psychological, Social

and Economic.

Decision of Treatment:

Diagnosis.

Osseous +/- visceral crisis

Performance status.

Number and location

Outcome of every modality and when

combined.

Availability of newer therapeutic modalities.

Expected life span.

What do we need to achieve?

The FRAX Tool: Assessing

Fracture Risk

http://www.sheffield.ac.uk/FRAX

Cellular and molecular physiology of

bone

The most peculiar feature of bone physiology is

Bone Remodeling

Continuous interplay

between

Osteoblasts:

Laying down new bones

Osteoclasts:

Dissolving old bones

● Continuous maintenance program in order to provide a

mechanism for self-repair and renewal

● The old bone matrix is replaced by a new one

● The process takes about 4-6 months.

MMP H+CATH H+

Osteoclasts (Derived From

Haematopoietic System (GM-CFU))

Bone resorption ● H+ Dissolve bone mineral

Digestion of organic

matrix

Ca++ release

Cytokines & growth factors (TGFß, IGF)

Degradation products of type I bone

collagen (serve as biochemical marker

of bone resorption NTX in urine

Adapted from Roodman GD. J Clin Oncol 2001; 19: 3562–71.

Bone

resorption

products

Proteolytic enz (MMP, Cathepsins)

● Osteoclasts attach to bone surface and secrete acid and hydrolytic

enzymes

Formation and Activation of

Osteoclasts

Receptor activator of NF-kB

Receptor expressed on mature

Osteoclasts and precursors

Osteoprotegerin

Molecular insights

RANK/RANKL/Osteoprotegerin (members of TNF family)

RANK Ligand

RANK

● Cytokine expressed by osteoblasts, stromal cells,

some tumour cells leading to osteoclastic activation

● Natural antagonist of RANKL secreted by bone

lining cells (decoy/scavenger receptor)

1,25D3

PTH/

PTHrP

PGE2

IL-11

Stromal cell/

Osteoblast

OCL

Precursor

Activated

OCL

RANK

RANKL

PTH-rP, PTH, TNF, IL-1 Induce Osteoclastic Bone

Resorption via Transactivation of RANKL Gene on

Stromal/Osteoblastic Cells

Kitazawa S and Kitazawa R. J Pathol 2002 Oct;198(2):228-36.

Estrogen & Bone Health:

Estrogen

Receptors:

• BM Stromal

Cells

• Osteoblasts

• Osteoclasts

++

OPG

Estroge

n

RANK

L

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

Estrogen

Osteoblasts

Bone formation

Estrogen Limits RANKL Expression

and Stimulates OPG Production

Bone

resorptionOsteoclasts

Androgen

OPG, osteoprotegerin;

RANKL, receptor activator for nuclear factor κ B ligand.

AROMATASE

Apoptotic

osteoclasts

Fractures with Adjuvant Aromatase

Inhibitors

Trial Mean F/U Fx w/AI Fx w/Tam

ATAC1 68 mo. 11% 7.7%(p<0.0001)

BIG 1-982 51 mo. 8.6% 5.8%(p<0.001)

IES3 55.7 mo. 7.0 4.9(p=0.003)

1Forbes JF et al. Lancet Oncol. 2008;9(1):45-53; 2Crivellari D et al. J Clin Oncol. 2008;26(12):1972-9; 3Coombes RC et al. N Engl J Med. 2004;350(11):1081-92;

ADT-related fracture risk

Shahinian VB, et al. N Engl J Med 2005; 352:154-164.

Years After Diagnosis

Un

ad

jus

ted

fra

ctu

re-f

ree

su

rviv

al

(%)

2 3 4 5 6 7 8 9 101

0

100

90

80

70

60

50

40

30

20

10

Over a 4-year period

19.4% fractures on ADT

12.6% fractures not on ADT

No ADT (N=32,931)

GnRH Agonist, 1- 4 doses (N = 3763)

GnRH Agonist, 5 - 8 doses (N = 2171)

GnRH Agonist, 9 doses (N = 5061)

Orchiectomy (N = 3399)

GnRH, gonadotropin-releasing hormone;

ADT, androgen deprivation therapy.

Molecular basis of Bone

Metastases

Bone is mainly

composed of a hard

mineralized tissue

It is more resistant to

invasion and destruction

by cancer cells than other

organs

On their own: Cancer cells

can not destroy

mineralized bone

Hamdy A. Azim , Nermine S. Kamal , Hatem A. Azim Jr: Bone metastasis in breast cancer : The story

of RANK-Ligand JENCI 43 ,June 2012

The pivotal role of osteoclasts in

cancer induced bone destruction

Osteoclasts are the only cells capable of

resorbing mineralised bone

In order to grow in bones, cancer cells must

possess the capability to induce osteoclastic

bone destruction

Roodman GD. J Clin Oncol 2001; 19: 3562–71.

Tumour Cell / Bone Microenvironment

Interaction

Tumor cell – Bone microenvironment interactions:

Collagen fragments ,TGFb, and IGFs are

chemotactic for tumour cells

Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin Dunitz Ltd; 1999;23-25.

Ca++, TGF

Stimulate tumour

cells to produce PTH-rP

TGF, IGFStimulate tumour

cell growth

Bone

resorption

products

Bone microenvironment is a kind of fertile soil which can attract and support the growth of circulating tumour cells (seeds)

Bone-derived

growth factors

IGF, TGF

Tumour cell –Bone microenvironment Interactions:

The Vicious Circle in Breast Cancer

Cancer cells

Osteoclasts

Osteoblasts

Osteolytic factors

PTHrP, IL-11

RANKL

Most of osteolytic

factors act via

osteoblast

production of

RANKL

Mineralised bone matrix

The Soil and Seed Theory

Tumour cell –Bone microenvironment Interactions:

the Vicious Circle in Prostate Cancer

Osteoblastic

factors

Adrenomedullin

ET-1,Bone-derived

growth factors

IGF, TGF

New bone

Cancer cells

Osteoclasts Mineralised bone matrix

Osteoblasts

Osteolytic factors

PTHrP,RANKL, IL-11

RANKL

The Soil and Seed Theory

Osteoblasts

RANKL

Bone matrix

RANKL and Chemotactic Migration of Circulating Cancer Cells

to Bone

Tumour Cell / Bone Microenvironment Interactions

Circulating Cancer cells

expressing RANKRANKL may act as a

chemotactic factor which

attracts circulating cancer

cells expressing RANK to

migrate into the bone

Adapted by Hamdy Azim from Armstrong AP, et al. Prostate 2008; 68:92-104.

Treatment of bone metastases:

cellular and molecular based

therapy Target osteoclasts : Bisphosphonates

Target PTHrP: monoclonal antibodies

Target RANKL:

– Recombinant osteoprotogerin:(AMGN-0007)

– Anti-RANKL monoclonal antibodies (AMG 162)

Target TGF:

Inhibitors of TGF signaling in tumour cells (MAP kinase pathway) ???

x

xDesonumab

Histologic Response to

Denosumab

Pre-treatment Week 13 post-treatment

Giant cells No giant cells

Irregular bone trabeculae (ovals)

Osteoid (arrows)

Biopsy of the sacrum

Thomas D, et al. J Clin Oncol. 2008;26:553S. Abstract 10500 and oral presentation.

Denosumab or Zoladronic Acid?

Parameter Denosumab Zoladronic Acid

Mechanism RANKL Inhibitor Mechanical Inhibition of Osteoclasts

Administration SC IV Infusion

Elimination RES Renal

Immunogenic

Reaction

No Yes

ONJ +++ +

Anti-Tumor Effect Prostate Breast & Prostate

Denosumab vs Zoledronic Acid: Double-

Blind, Placebo-Controlled Phase III Trial

Patients with CRPC and bone

metastases, and no

current or past IV

bisphosphonate treatment

(N = 1901)

*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.

Denosumab 120 mg SC +Placebo IV* q4w

(n = 950)

Zoledronic acid 4 mg IV* +Placebo SC q4w

(n = 951)

Calcium and vitamin D supplemented in both treatment groups

Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to bone, spinal cord compression)

Fizazi K, et al. Lancet. 2011;377:813-822.

Zoledronic acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Patients at Risk, nStudy Mo

0

1.00

Pro

po

rtio

n o

f S

ub

jec

ts W

ith

ou

t S

RE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Mos

Denosumab

Zoledronic acid

20.7

17.1

HR: 0.82 (95% CI: 0.71-0.95;P = .0002, noninferiority;P = .008, superiority)

18%Risk

reduction

Time to First On-Study SRE

Fizazi K, et al. Lancet. 2011;377:813-822.

Radium-223 Targets Bone

Metastases

Radium-223

functions as a

calcium mimic

Targets sites of

new bone growth

within and

around bone

metastases

Excreted by the

small intestine

Ra

Ca

Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

Parker C, et al. ASCO GU 2012. Abstract 8.

Patients with symptomatic CRPC and ≥ 2 bone metastases with no

known visceral metastases, either

post-docetaxel or unfit for docetaxel

(N = 921)

Primary endpoint: OS

Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, ALP normalization, time to PSA progression, safety, QoL

Radium-223 50 kBq/kg +

BSC

Placebo (saline) +

BSC

Stratified by total ALP, previous docetaxel, and

bisphosphonate use; randomized 2:1

Up to 6 treatments at 4-wk intervals

ALSYMPCA: Phase III Trial of

Radium-223 in Symptomatic

Prostate Cancer

ALSYMPCA: Overall Survival

Radium-223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

Parker C, et al. 2012 ASCO GU Cancers Symposium. Abstract 8.

OS

(%

)

Radium-223 (n = 541)

Median OS: 14.0 mos

Placebo (n = 268)

Median OS: 11.2 mos

HR: 0.695 (95% CI: 0.552-0.875;

P = .00185)

3 6 9 12 15 18 21 24 27

MosPts at Risk, n

0

10

20

30

40

50

60

70

80

90

100

0

ALSYMPCA: Time to First SRE

Radium-223 541 379 214 111 51 22 6 0

Placebo 268 159 74 30 15 7 2 0

0

10

20

30

40

50

60

70

80

90

100

Pa

ts W

ith

out S

RE

(%

)

HR: 0.610 (95% CI: 0.461-0.807;

P = .00046)

Radium-223 (n = 541)

Median: 13.5 mos

Placebo (n = 268)

Median: 8.4 mos

0 3 6 9 12 15 18 21

Pts at Risk, n Mos

Sartor O, et al. ASCO GU 2012. Abstract 9.

EBRT: ASTRO Task-Force

Guidelines:

EBRT: ASTRO Task-Force

Guidelines:

Continues to be, the mainstay for the

treatment of painful, uncomplicated bone

metastases.

Many schedules and fractionation.

SBRT special situation clinically.

Combination with other bone directed

therapies.

Take Home Message:

Metastatic bone disease is a highly

challenging and treatable disease.

Effective pain relief with radiation therapy.

Surgical correction is an option.

Radiopharmaceuticals.

Systemic Therapies

Thank you