Seminar in Palliative Care

Seminar in Palliative CareSeptember 26 – October 02, 2010

Salzburg, Austria

in Collaboration with

Skeletal Skeletal ComplicationsComplications

Eugenie A.M.T. Obbens, MD PhD

Pain & Palliative Care ServiceMemorial Sloan-Kettering Cancer Service

Objectives

• Discuss the physiology of bone

metastasis

• Know skeletal related events and

complications

• Review the treatment options for

skeletal metastasis

Take Home Message:

Poorly managed skeletal metastasis

can lead to diminished quality of life

and increased suffering.

Pathophysiology Pathophysiology of Bone of Bone

MetastasisMetastasis

Mechanism of Bone Metastasis

1. Ca cells detach from primary

tumor

2. Travel via blood and attaches to

target tissue (bone)

3. Adhere to endosteal surface and

colonize bone

Mechanism of Bone Metastasis

• Bone Microenvironment

– Highly favorable for tumor invasion

– Hypoxic

– Acidic pH

– Extracellular Calcium

– Growth factors

Kingsley LA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609-2617.

Mechanism of Bone Metastasis

• Vicious Cycle

– Promoted by crosstalk between tumor

cells and microenvironment

– Results in tumor growth and bone

destruction

Kingsley LA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609-2617.

Types of Bone Metastasis

• Osteolytic

• Osetosclerotic

• Mixed type

Osteolytic

• Result of stimulation of bone resorbing

cells

• Radiolucent on X-ray

Skull, long bones

• Increased fracture risk

• Breast Ca, M. Myeloma

Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis 2007(24):599-608.

Osteosclerotic

• Stimulation of bone forming cells

• Appear as dense areas on X-ray

Axial skeleton, vertebral bodies, pelvis

• Poorly organized bone structure

• Increased fracture risk

• Prostate Ca

Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic implications. Clin Exp Metastasis 2007(24):599-608.

Cancers That Metastasize to Bone

1. Breast

2. Prostate

3. Lung

4. Colon

5. Stomach

6. Bladder

7. Uterus

8. Rectum

9. Thyroid

10. Kidney

Wilfred CG. http://www.emedicine.com/radio/byname/bone-metastases.htm

Diagnosis and Diagnosis and Risks of Bone Risks of Bone

MetastasisMetastasis

Case:Diane G.

Diane G.

47 yr old F with L leg pain, L arm pain

• 8/10 in Leg, 4/10 in Arm

• Dull, ache

• Worse with movement, ok at rest most of time

• Motrin of no help

• Xray: lytic lesions in L femur, L humerus

• Biopsy: metastatic Breast Cancer

Diagnosis

• Plain radiographs

• Radionuclide bone scan

• CT

• MRI

• Positron emission tomography (PET)

• Biopsy if no diagnosis yet

Guise TA. Molecular mechanisms and treatment of bone metastasis. Expert Reviews in Molecular Medicine. Vol 10; e7; March 2008.

Skeletal Related Events (SRE)

• Pain

• Fracture

• HypercalcemiaAddressed in PC Emergencies

• Spinal Cord CompressionAddressed in PC Emergencies

Pain

• Most frequent type of cancer pain

– Direct invasion with microfractures

– Increased pressure on endosteum

– Distortion of periosteum

– Nerve root compression

– Chemical mediators of pain

Mercadante S, Fulfaro F. Management of painful bone metastasis. Curr Opin Oncol 2007; 19:308-314.

Fracture

• Causes pain

• May require surgical repair

• Reduces quality of life

– Decreases mobility

– Increases care giving needs

Hypercalcemia of Malignancy

• Lung/Breast Ca accounts for > 50%

• Symptoms

– N/V, renal dysfunction, delirium, abd pain, coma,

cardiac arrhythmias

• Treatment

– Hydration, Bisphosphonates, Calcitonin

Ernst DS, Wolch G. Textbook of Palliative Medicine. Great Britain: Hodder Arnold, 2006.

Spinal Cord Compression

• Palliative Care Emergency– Paralysis

– Dysreflexia

– Incontinence of Bowel/Bladder

• Suspect with worsening back pain

• Paraplegia >24-48 hrs may be

irreversibleFerris FD, et al. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin N Am. 2001 Jan;10(1):185-201.

TreatmentOptions

Analgesics

• WHO Stepladder

• NSAIDS

– Prostaglandin inhibitor

• Pain mediator within bone

• Opioids

• Co-analgesics

Corticosteroids

• Decreases peritumoral edema

– Alleviates symptoms

• Response may indicate favorable

response to radiation

• Dexamethasone is preferred

– Minimal mineralocorticoid effect

Ferris FD, et al. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin N Am. 2001 Jan;10(1):185-201.

Bisphosphonates

• Hypercalcemia of malignancy

• Prevention of SRE’s

• Relieve pain

• Improve pt functioning and QOL

• Does not prolong life in advanced Ca

Body JJ. Bisphosphonates for malignancy-related bone disease: current status, future developments. Support Care Cancer. 2006(14):408-418.

Bisphosphonates

• Mechanism of action

– Pyrophosphate analogue

– Bind to active sites of remodeling

– Inhibit osteoclast mediated bone

resorption

– Causes osteoclast apoptosis

Body JJ. Bisphosphonates for malignancy-related bone disease: current status, future developments. Support Care Cancer. 2006(14):408-418.

Bisphosphonates

• Zoledronic Acid

– Proven efficacy across solid tumors

• Pamidronate

– Breast, Prostate, M. Myeloma

• Clodronate

– Breast, Prostate, M. Myeloma

• Ibandronate

– Breast

Coleman RE. Risks and benefits of bisphosphonates. British Journal of Cancer. 2008(98):1736-1740.

Bisphosphonates: Treatment Risks

• Transient fever, Muscle/Joint aches

– 15 - 30% with first dose

• Renal dysfunction

– IV agents at high dose or rapid

infusion

Bisphosphonates: Treatment Risks

• Osteonecrosis of the Jaw– Nonhealing area of exposed bone in

maxillofacial region after 8 weeks in pt who

was receiving Bisphosphonates and no XRT

– Conservative management

• Oral rinses and antibiotics

Coleman RE. Risks and benefits of bisphosphonates. British Journal of Cancer. 2008(98):1736-1740.

Bisphosphonates

• American Society of Clinical Oncology,

2007

– M. Myeloma, Met Breast Ca to bone

• Bisphosphonate from time of diagnosis

• Development of SRE does not mean

failure

– Can delay onset of subsequent SRE

Coleman RE. Risks and benefits of bisphosphonates. British Journal of Cancer. 2008(98):1736-1740.

Radiation Therapy

• Pathology

• Location

• Size of tumor

• Performance

status

• Goals of Care

• Potential benefit

• Risk if not

radiated

• Adverse events of

treatment

• Life expectancy

Considerations

Ferris FD, et al. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin N Am. 2001 Jan;10(1):185-201.

Radiation Therapy

• Radiosensitivity

– Cell type

– Degree of differentiation

– Volume of tumor

Ferris FD, et al. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin N Am. 2001 Jan;10(1):185-201.

Radiation Therapy• Indications for Palliative XRT of

Bone Metastasis– Relieve pain

– Prevent pathologic fracture

– Prevent neurologic dysfunction

– Prevent/delay progression of metastatic

disease at surgically repaired pathologic

fracture sites

Ferris FD, et al. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin N Am. 2001 Jan;10(1):185-201.

Radioisotopes

• Indicated for widespread bone metastasis

• Strontium-89– Emits high energy ß-particle

• Samarium-135

– Shorter t1/2 so can give larger doses over shorter time

– Lower energy particle therefore reduced marrow

toxicity

Guise TA. Molecular mechanisms and treatment of bone metastasis. Expert Reviews in Molecular Medicine. Vol 10; e7; March 2008.

Chemotherapy

• Effect depends on chemosensitivity

of the cancer

• Lymphoma, myeloma, testicular ca >

renal or hepatocellular

Mercadante S, Fulfaro F. Management of painful bone metastasis. Curr Opin Oncol 2007; 19:308-314.

Hormonal Therapy

• Hormone sensitive tumors

• Breast Ca– Selective Estrogen Receptor Modulators

– Aromatase Inhibitors

• Prostate Ca– Gonadotropin releasing hormone agonists

– Antiandrogens

Guise TA. Molecular mechanisms and treatment of bone metastasis. Expert Reviews in Molecular Medicine. Vol 10; e7; March 2008.

Surgery

• Fracture Prevention

– Plate Osteosynthesis

– Nailing

– Prosthetic Inserts

• Fracture Repair

– Vertebroplasty

– Kyphoplasty

Let’s not forget Diane G.

• Pain control

Morphine PCA

Dexamethasone

NSAID

Bisphosphonate

XRT

• Fractured L humerus (pathologic)

Surgical repair of L humerus, prophylactic

strengthening of L femur

Summary

• Skeletal metastasis can lead to

diminished quality of life

• Treat SREs aggressively to prevent

morbidity

• Select the most appropriate treatment for

each patient