Bone metastases

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Bone metastases are common problem in patients with palliative illnesses, often presenting with pain. In addition to pharmacotherapy, radiotherapy is often a good option for pain relief.

Epidemiology and Pathophysiology

Bone is the third most common site for metastatic disease, closely following liver and lung.

Bone metastases can occur in any malignancy however the following malignancies are especially associated with bone metastases:

  • Breast cancer (between 20 and 40% of patients will develop symptomatic bone metastases; 70% of patients are found to have metastases here at post-mortem)
  • Prostate cancer
  • Lung cancer
  • Renal cell cancer
  • Hodgkin's disease
  • Myeloma
  • Thyroid

Although the reason for bone metastasis is not well understood, it appears that cancers that express certain adhesive molecules such as CXCR4, bone sialoprotein (in small cell lung cancer) and annexin II (in prostate cancer) are more likely to metastasize to bone.

In general bony metastases are classified in one of three ways:

  • Osteolytic
  • Osteoblastic (or osteosclerotic)
  • Mixed

Pain Pathogenesis

Metastases in the bone frequently cause pain. Animal models used to replicate bone metastases have been perfomed to try to better understand that pathogenesis of the pain. Two main animal model techniques have been developed for this:

  • Injection of malignant cells in left ventricle (with spread to multiple sites including bone)
  • Injection of malignant cells directly into bone

Following injection of malignant cells in animal models, there is rapid proliferation of tumour cells with replacement of the bone marrow by tumour and inflammatory cells. There is proliferation of osteoclasts at the tumour-bone interface causing destruction of the bone. It appears that tumour cells stimulate osteoclasts via various factors including Macrophage Inflamatory Protein a – MIP1. In these animal models the amount of osteoclast activity appears to correlates with bone pain.

Osteoclasts are phagocytic cells that originally differentiate from monocytes. They resorb bone by creating an acid extracellular microenvironment with a pH of around 4 to 5. The low pH is probably partially related to the pain because numerous sensory nerves in the bone are excited by protons due to the expression of two acid-sensing ion channels (TRPV1 and ASIC-3). Additionally mechanical pressure on mechanosensitive nerves occurs due to the stress on bones that have become less stable and this probably also plays a role in the pain. Finally cytokines (such as prostaglandins, bradykinin, TNF-alpha, IL-1 and IL-6 and nerve growth factor) are produced by per-tumour inflammatory cells and these also activate some sensory neurons.

Clinical features

Bony metastases may be asymptomatic or may cause pain. The pain is often worse at night and commonly described as an ache. Incident pain is also relatively common with pain from vertebral and femoral metastases often worse on standing and walking.

Investigations

Local imaging

In patient's with a focal area of pain where a bony metastasis is a differential, local imaging is appropriate, initially with a plain film, and if necessary, CT or MR imaging.

Plain film

Imaging with a plain film is the usual first investigation of choice for a presumed single bony metastasis. The x-ray may reveal lytic changes or sclerotic changes. The absence of obvious bony metastases does not exclude them however.

X-ray - Proximal femoral shaft sclerotic metastasis.jpg

  • Image above - An x-ray from a man with metastatic prostate cancer causing severe pain on weight bearing. The x-ray shows a large sclerotic lesion in the femur.

CT or MRI

Both CT and MR imaging can be used to investigate bone metastases at a local site. If bony metastases are suspected in a patient with back pain, MRI is the preferred modality as it can also be used to evaluate for spinal cord compression.

Whole body imaging

Whole body bone scan

A whole body technetium bone scan is an excellent test to look for evidence of bony metastases. Most metastatic lesions are picked up (85% sensitivity) and there is a high degree of specificity (90% specific).

Whole body MRI (DWIBS)

An alternative to a radionuclide whole body bone scan is a whole body MRI or DWIBS scan (Diffusion-weighted Whole-body Imaging with Background body signal Suppression) with some evidence that it is more sensitive than a bone scan.[1]

DWIBS MRI - prostate cancer with bony mets including left lesser trochanter lesion.jpg

  • This slice of a whole body MRI in a patient with prostate cancer shows a large metastatic deposit in the left lesser trochanter.

FDG-PET Scan

PET scanning is another highly sensitive and specific alternative to a standard whole body technitium bone scan.

Management and Prognosis

Pharmacotherapy and Analgesia

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Fracture risk and surgical intervention

Mirel's and SINS scores

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Prophylactic surgery

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Palliative radiotherapy

Radiotherapy is one of the best treatment options for painful bony metastases that have not responded to simple analgesia. Up to one half of patients treated experience complete or near complete resolution of their pain within 2 to 4 weeks. A little under one-third of patients experience a small degree of relief of pain and the 20 to 30% of patients do not experience any pain relief at all.

Interventional radiology percutaneous ablation

An emerging alternative to radiotherapy for painful metastases is ablative therapy via the interventional radiologist. In these techniques a probe is inserted into the painful bony metastatic deposit and the surrounding tumour cells are ablated. Various techniques are possible including radio-frequency ablation, cryobablation and microwave ablation.[2] An early multi-centre trial of 62 patients showed evidence of efficacy with 95% of patients experiencing pain relief of greater than 2-points on a 10-point scale after ablative therapy.[3] Studies comparing the efficacy between different modalities to date haven't shown convincingly that one method superior to any other.

Radiofrequency ablation

In radiofrequency ablation, necrosis is induced through local heat of up to 100 degrees Celsius that is generted when electrical alternating current via an inserted electrode. The procedure itself takes a number of minutes (e.g. 10 minutes) and the radius of tissue death from the eletrode is related to the time the current is applied for. Thus the area of cell death can be well controlled. Contra-indications for radiofrequency ablation include tumours adjacent to metalic prosthesis and implants.

Cryoablation

In cryoablation, the tip of an probe is cooled with a liquified gas such as argon, resulting in ice-crystals to form in the nearby cells resulting in cellular rupture and death. The time taken for an ablation freeze-thaw cycle is a number of minutes (e.g. 20 minutes).

Microwave albation

In microwave ablation, microwaves of frequencies between approximately 1 GHz and 2 GHz are transmitted via an inserted probe resulting in heat-induced necrosis.

Radiopharmaceutical treatment including Strontium-89, Samarium-153 and Radium-223

In patients with multiple painful bony metastases, targeted therapies such as radiotherapy and interventional radiology ablation techniques are of limited value given the multiple locations of pain. In these cases, radioactive pharmaceutical treatments that selectively localize to the bone can potentially bring widespread analgesia when the pain continues despite usual oral analgesia. Radiopharmaceutical agents that localize to bone after intravenous infusion include Phoshorous-32, Strontium-89, Samarium-153, Yttrium-90, , Tin-117, Holmium-166, Thulium-170, Lutetium-177, Rhenium-186, Radium-223.

In centres where radiopharmaceuticals are used, the choice of agent varies depending on what is available in that centre. Strontium and samarium are the most commonly used agents for bony metastases. They both release beta particles which have a range of a few millimetres in tissue which commonly results in toxicity to the surrounding bone marrow. This can cause cytopaenias, which is usually mild, but occasionally is prolonged and profound.

Strontium-89

For strontium-89 good pain relief is achieved in up to 90% of patients, with analgesic effects on average lasting 3 to 6 months. Studies have shown that up to 20% of patients experience complete relief of their pain and a slightly higher number (approximately 25%) of patients are able to stop all oral analgesic agents. Treatment with strontium is only for symptomatic relief as it has not been shown to extend life expectancy. Platelet counts typically drop by about 50%[4] with the time of maximal thrombocytopaenia usually between 3-4 months post infusion. Leucopaenias are also common, often within the first 3 weeks post-administration.

Radium-223

Radium is a newer treatment that has shown benefits in recent studies with metastatic prostate cancer. It releases alpha particles which have a range of about 100 micrometres in tissue. This short distance of action has the theoretical advantage of causing less surrounding tissue damage than beta-particle emitting agents. This translates into less haematological toxicity / cytopaenias. Uptake in bone occurs within an hour of IV administration, with approximately 50% being taken into bone. Excretion is mostly via the gastrointestinal tract and so is not significantly altered by renal failure. A study of radium in metastatic prostate cancer showed that analgesia usually occurs within 2 weeks with approximately 70% of patients having a good response.[5] Analgesia typically lasts for a little under two months. Mild and temporary myelosuppression is often seen with the low point of cell counts occurring 2 to 4 weeks post administration, with complete recovery in cell counts by 8 weeks. Gastrointestinal self-limiting adverse effects are common including diarrhoea, nausea and vomitting. Fatigue is also common.

References

  1. S Gandage et al. A comparative study of whole body DWIBS MRI versus bone scan for evaluating skeletal metastases. Australas Med J. 2012;5(12):619-22.
  2. Patel IJ et al. Palliative Proceures for the Interventional Oncologist. Vascular and Interventional Radiology. 2013; 726-735.
  3. Callstrom MR et al. Image-guided ablation of painful metastatic bone tumours: a new and effective approach to a difficult problem. Skeletal Radiology. 2006; 35:1-15.
  4. Silberstein. Teletherapy and radiopharmaceutical therapy of painful bone metastases. Semin Nucl Med. 2005 Apr;35(2):152-8.
  5. Nilsson et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer. 2012 Mar;48(5):678-86.

Authors

Graham Llewellyn Grove