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Introduction

Bone Metastasis
The bone is the most common, and often the only site for metastases. Bone metastasis occurs in approximately 80% of men with advanced prostate cancer and can cause pain, spinal cord compression and fractures.

Bone homeostasis
Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoblasts not only play a central role in bone formation by synthesising multiple bone matrix proteins, but they regulate osteoclast maturation by soluble factors and interaction, resulting in bone resorption. Osteoclast maturation requires stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL), expressed on osteoblasts. RANKL is a type II membrane protein and a member of the tumour necrosis factor superfamily. RANKL has been identified to control the immune system and control bone regeneration and modeling.

Often, cancer cells secrete factors that switch on the osteoclasts. This leads to bone being broken down without new bone being laid down. This weakens the bones. The holes that develop when parts of bones dissolve are called osteolytic or lytic lesions.

Sometimes, the cancer cells release factors that stimulate osteoblasts. This leads to new bone being laid down without old bone broken down first. This makes areas of the bones harder, a condition called sclerosis. The areas in bones where this occurs are called osteoblastic or blastic lesions. Although these blastic areas are harder, the structure of the bone is abnormal and these areas actually break more easily than normal bone.

Both lytic and blastic types of bone metastases can cause pain.

Androgen Deprivation and Bone Fractures
Androgen deprivation therapy can reduce bone mineral density and weaken the bone further. This will increase the risk of fractures in this group of patients.

The treatment of advanced, hormone-resistant prostate cancer primarily involves relief of symptoms and improvement in quality of life. NICE recommend that bisphosphonates may be used to reduce pain experienced when other therapies have failed. There is little evidence to support the use of bisphosphonates to prevent or reduce complications of bone metastases in men with hormone refractory prostate cancer and reduce the risk of skeletal events in patients with bone metastases.

Temperature Check
Which one of these is not a bisphosphonate?

Zoledronate is the most potent bisphosphonate and is used in prostate cancer
Pamidronate is an IV bisphosphonate and is administered in prostate cancer
Alendronate is an oral bisphosphonate and there is little evidence supporting its use in prostate cancer
Denosumab is not a bisphosphonate – investigate the use at your trust within this indication

Bisphosphonates promote osteoclast apoptosis, which leads to a decrease in the number of osteoclasts and suppression of resorption. In addition to direct effects on osteoclasts, bisphosphonates may inhibit bone resorption by reducing RANKL expression and increasing Osteoprotegerin (OPG) secretion in osteoblast-like cells. OPG is a secreted protein that reduces osteoclast formation.

Bicalutamide and flutamide are anti androgens. They can be combined with an LHRH agonist to prevent flare as they will “mop” up any additional testosterone that is produced as a result in the rise in leutenising hormone.

Bicalutamide has a relatively long half life compared with flutamide. This is the reason it is administered once a day rather than 3 times a day. If an LHRH agonist needs to be administered within days then flutamide would be the drug of choice as it would rapidly reach steady state. In most situations bicalutamide is initiated 2-3 weeks prior to the LHRH and continued for 4 weeks then withdrawn.

Malignant Spinal Cord Compression (MSCC) – The Symptoms
These are four categories of symptoms of MSCC:

Back Pain: pain is often worse when lying down
Motor dysfunction: gait disturbance, lower limb weakness
Neurological symptoms: Sensory Symptoms, Ascending numbness and parasthesia
Bladder and Bowel dysfunction: urinary retention, constipation

Malignant Spinal Cord Compression
Malignant Spinal Cord Compression (MSCC) is an oncological emergency. It is a cause of severe pain and may result in an irreversible loss of neurological function.
Tumour metastasis from any primary site can cause MSCC. Prostate cancer is one of the most common primary malignancies that results in spinal cord compression.

Background Pathophysiology

The Spinal Column is composed of a stack of protective bones (the vertebrae) which enclose the spinal cord.
Surrounding the spinal cord is the thecal sac and the dura is the outermost layer.
Between the bone and the dura lies the epidural space.
At each spinal level nerve roots exit to the side of the spinal cord and behind the vertebral body.

Mechanism of Compression

The tumour invades the epidural space and compresses the thecal sac.
The tumour grows and takes the path of least resistance and encircles the cord /thecal sac.
Bones fragments indent the cord as a result of fracture.

Management
The Goals of Management are to:

Control Pain
Avoidance of complications
Preservation or improvement of neurological function.

Standard practice is usually to commence dexamethasone at a maximum daily dose of 16mg immediately. Definitive treatment will depend on presentation at diagnosis and could include surgery or radiotherapy. Chemotherapy is not usually indicated in prostate cancer patients however can be used for patients with a chemosensitive malignancy.

In Prostate Cancer patients hormonal therapy may be considered for patients with cord compression but no neurological symptoms. The main method of improving outcomes is through early detection. Look at your local AOS pathway on metastatic Spinal Cord Compression.

Tumour Flare

What is Flare?
When an LHRH agonist is commenced it paradoxically causes a rise in LH. This LH rise stimulates the testicles to make more testosterone during the first 5-12 days after initiation of the LHRH agonist. The rise stimulates prostate cancer cells to grow and is called “flare”.

Why Prevent Flare?
Flare can precipitate severe life threatening symptoms of disease progression in patients with prostate cancer having sub-clinical metastatic disease in critical locations. E.g. If the disease is growing close to the nerve roots, flare can result in pain in the distribution of that nerve. If the cancer is close to the spinal cord, the flare can result in spinal cord compression or paralysis.

Clinical Flare is?
When the tumour flare causes clinical symptoms such as bone pain, compression of the nerve root or spinal cord, or blockage of ureters.

Biochemical Flare is?
If the PSA rises but there is no evidence of clinical progression.

A Case Example of Flare
Patient 1 is an 81 year old man that has been following a watchful waiting approach until his PSA rose to 31. He was given a Zoladex injection and 5 days later he suffered from back pain. Radiological studies showed hydronephrosis and a cystoscopy revealed a tumour obstructing the bladder. The kidney needed to be decompressed and a uretral stent was placed and this involved a 5 hour operation.

The administration of an antiandrogen prior to beginning an LHRH agonist will help prevent clinical flare. By the inhibition of the androgen receptor, tumour production will be reduced. The different antiandrogens are varying in half life. Bicalutamide has a half life of 6 days whilst flutamide is less than 8 hours. The half life should be considered as the drugs need to have reached a steady state prior to the LHRH- agonist administration. When the agents are stopped a patient’s PSA should be monitored for anti-androgen withdrawal symptoms.

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