MANAGEMAENT OF BONE SECONDARIES

BY :SUMMARMOHAMEDELMORSHIDY

SUPERVISED BY :DR: MARWA ISMAIEL KHALAF

Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells.

This leads to disruption of normal bone metabolism, with the increased osteoclastactivity seen in most, if not all, tumor types providing a rational target for treatment.

The clinical course of metastatic bone disease in multiple myeloma,

breast and prostate cancers is relatively long, with patients experiencing

sequential skeletal complications over a period of several years. And

therefore optimizing treatment is crucial

Cancer cells target bones with an extensive blood supply: arms, legs,

ribs, spine, pelvis. Tend not to travel to hands and feet.

SITES OF METASTASIS

ribsspin

e

pelvis

Pelvi

s

femurs

Most common

sites for bone

metastases

Thoracic

70%

Lumbar 20%

Cervical 10%

Epidemiology – incidence at

autopsy

Primary Site % metastasis to Bone

Breast 50-85

Lung 30-50Prostate 50-70Hodgkin’s 50-70

Kidney 30-50

Thyroid 40

Melanoma 30-40

Bladder 12-25

Osteolytic metastases

Tumor cells produce growth factors that stimulate bone destruction

•i.e. RANK ligand

Osteoclasts are activated and break down bone

Osteoblasts cannot build bone back fast enough

Decreased bone density and strength; high risk for fracture

Lytic = black

hole in the

bone

Osteoblastic Metastasis

Osteoblasts are stimulated by tumors to lay down new bone

Bone becomes abnormally dense and stiff

Paradoxically bones are also at risk of breaking

Blastic =

abnormal white

area

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?

Treatment Options

Goals:

Attack the cancer

Strengthen the bone

Reduce symptoms

Includes:

Systemic therapy

Local therapy

Local therapy ( 1.surgical

management) The role of surgery

Indicated if: previous Radio Rx/ no response

Radioresistant tumor life expectancy > three months

single site unstable spine no tissue diagnosis

1.Prophylactic Fixation of metastatic deposits where there is a risk of fracture.

2.Stabilization/Reconstruction following pathological fracture.

3.Decompression of spinal cord & nerve roots and stabilization for spinal instability.

The goals of surgical intervention for spinal surgery in patients with

metastatic bone disease includes decreasing or eliminating pain,

decompressing neural elements to protect cord function, and

mechanically stabilizing the spine.

Anterior or posterolateral decompression, combined with

anteroposterior reconstruction, may be used in the following:

Diagnostic spinal surgery

Cervical spinal surgery

Thoracic and lumbar spinal surgery

Vertebroplasty, in which polymethylmethacrylate is percutaneously

introduced, may be a minimally invasive treatment alternative for

patients with 1- or 2-level vertebral body compression fractures.

For the management of long bone metastatic disease accompanied by an impending or completed fracture, open internal fixation is usually the preferred method of treatment.

Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred.

2.Radiation therapy in bone

metastasis

Indications 1. Radiosensitive tumor not previously

irradiated

2. Widespread spinal metastases with multilevel neural compression

3. Total neurological deficits below the level of compression > 48 hours

4. Patient’s condition (or prognosis) precludes surgery: high surgical risk or short life expectancy

How does RT reduce pain ?

Cell kill – reduced tumor size and pressure effects

Endothelial damage of micro-vasculature – reduced

blood flow. Reduces edema

Reduces pain related neuro-transmitter concentrations

Bone – promotes re-mineralisation leading to structural

stability.

Radiotherapy Modalities

Conventional External Beam

Radiotherapy (EBRT)

Intensity-modulated radiation therapy

(IMRT)

Stereotactic radiotherapy

Stereotactic radiosurgery

Radioisotopes

Radiation Results

• Overall 85% response rate

• Complete relief in 54%

• 50% respond by 2 weeks, 80% by 1 month

• Median duration of pain relief 12-15 weeks

• The Xrays or scans may take months to show improvement (Recalcification by 2-3 months)

Fractionation regimens

8 Gy in 1 fraction

20 Gy in 5 fractions

30 Gy in 10 fractions

Endpoints using pain relief, narcotic relief and quality of life measures show consistent similarity in the regimens

Adjuvant Radiotherapy

Done after operative decompression

Wait 3 weeks for wound healing before

starting radiation

3.Interventional Radiology

What is it?

Minimally invasive procedures performed by specialized radiologists to treat symptoms from bone metastases

Indications:

To treat bone pain refractory to other conservative pain control measures

Specialized technique for metastatic cancer to spine bones

Vertebroplasty:

Injection of bone cement to support

weakened bones

Provides immediate and

substantial pain relief

Kyphoplasty:

Balloon inflation of compressed spine bone

is performed before cement injection

Used for compression fractures

Other Local Techniques

Radiofrequency Ablation (RFA) and cryoablation

Minimally invasive procedures to “burn” or “freeze” a tumor

Desensitizes by killing nerve endings near the metastasis

Most commonly used for cancer in the spine

Techniques can achieve excellent pain control

Systemic

therapy

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 .

Tumor cell – Bone microenvironment interactions:

Bone

resorption

products

Collagen fragments ,TGFb, and IGFs are

chemotactic for tumour cells

Ca++, TGF

Stimulate tumour

cells to produce PTH-rP

TGF, IGFStimulate tumour

cell growth

Most of osteolytic factors act via

osteoblast production of RANKL

Some Circulating Cancer cells

expressingRANK

RANKL may act as a chemotactic factor

which attracts circulating cancer cells

expressing RANK to migrate into the bone

.

RANKL is the primary mediator of

osteoclast formation, function, and

survival and plays a vital role in

physiologic and cancer-induced bone

resorption

Metastatic tumor cells stimulate RANKL

activity, leading to a self-reinforcing cycle

of bone resorption (“vicious cycle”

hypothesis)

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)

DENSOMAB

Target TGF:

Inhibitors of TGF signaling in tumourcells (MAP kinase pathway) ???

x

x

Histologic Response to

Denosumab Pre-treatment Biopsy of the sacrum

Week 13 post-treatment

Giant cells No giant cells

Irregular bone trabeculae (ovals)

Osteoid (arrows)

Denosumab or Zoladronic

Acid?DENSUMAB

ZOLEDRONIC ACID MechanismParameter

RANKL Inhibito

Mechanical Inhibition of Osteoclasts Administration

SC IV Infusion Elimination

RESRenal

Immunogenic ReactionNo

Yes

ONJ

+++ +

In phase II trials, denosumab significantly

lowered bone turnover markers and

reduced SREs, including in patients with

elevated uNTx levels, despite IV

bisphosphonate therapy

Denosumab vs Zoledronic Acid

Pivotal Phase III SRE Prevention

Trials In total, > 5700 patients with bone

metastasesR

A

N

D

O

M

I

Z

A

T

I

O

N

Denosumab 120 mg SC q4w

+

Placebo IV q4w†

Zoledronic Acid 4 mg IV q4w†

+

Placebo SC q4w

Study 136[1]

Breast cancer

(N = 2049)

Study 103[2]

Prostate cancer

(N = 1904)

Study 244[3]

Other solid tumors/MM

(N = 1779)

Integrated Analysis: Denosumab

Delayed Time to First On-

StudySREvsZATime to progression is 27.6 months in case of

densomab

And 19.4 months in case of ZA.

17% risk reduction with densomab .

Question: What is the Maximum

Time You Provide Bone-

Modifying Therapy

A. 1 year

B. 2 years

C. Indefinite, same schedule i.e.

monthly

D. Indefinite, reduced frequency

E. Until first SRE

F. Until disease progression

Guidelines and Duration of Bone-

Targeted Therapy ESMO

[1]

“The timing and optimal duration of bisphosphonate treatment are unknown; benefit of duration beyond 2 yrs has not been demonstrated . . . Long-term treatment seems wise due to ongoing risk of skeletal events” NCCN

[2]

“Optimal schedule and duration are unknown . . . Limited long-term safety data indicating bisphosphonate treatment can continue beyond 2 yrs”

ASCO[3]

“Until evidence of substantial decline (clinical judgment) in general performance status”

Choices in Bone-Modifying

Agents

Conclusions

Bisphosphonates and denosumab are both effective at

Preventing SREs and HCM

Palliating pain from bone metastases

Preventing the development of pain

2 distinct choices

Different toxicity profiles

Zoledronic acid: flulike symptoms, fevers, bone pains, renal toxicity

Denosumab: hypocalcemia

Subcutaneous vs intravenous administration