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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