Articles:Bone metastases

Metastases within bone can cause extreme and debilitating pain. Bone metastases are far more common than primary bone cancer, and many different cancer types can spread to the bone. The most common types of cancer which spread to bone are:

• Breast
• Prostate
• Lung
• Kidney
• Thyroid

Cancer can theoretically metastasize to any bone in the body, but in reality there is a predilection for certain sites. The most common sites are the vertebrae, ribs, pelvis, sternum, and the skull.

Classification

A bone is a rigid organ, but it is far from physiologically static. To maintain bone strength, there is continuous breakdown and simultaneous reformation of bone, two processes which must finely balance for good bone health.

Osteoblastic (or sclerotic) metastases are characterised by the deposition of new bone. These are present most commonly in prostate cancer, but also occur in carcinoid, small cell lung cancer, medulloblastoma, and Hodgkin lymphoma. The molecular crosstalk between tumour and bone cells involves osteoblast-generating proteins such as Transforming Growth Factor, Bone Morphogenic Proteins (BMPs), and Endothelin-1.

Osteolytic (or lytic) metastases are characterised by the destruction and breakdown of normal bone. These often occur when breast cancer spreads to bone, which is primarily mediated by osteoclasts (bone cells that breaks down bone tissue) and is not a direct effect of metastasized tumour cells. Other tumour types with osteolytic metastases include multiple myeloma, non-small cell lung cancer, thyroid cancer, non-Hodgkin lymphoma, and Langerhans' cell histiocytosis. Osteolytic metastases are more common than osteoblastic metastases.

Mixed metastases are characterised by the presence of both osteolytic and osteoblastic lesions together in the same area of bone. These metastases are usually present in metastatic gastrointestinal and squamous cancers, as well as in secondary breast cancer. Although breast cancer gives rise to predominantly lytic lesions, around 15–20% of women have sclerotic or both types of lesions.

Diagnosis

Signs and symptoms

Bone metastases cause major morbidity, and high clinical suspicion should be kept for any patient with cancer that presents with:

• Severe pain (poorly localised, worse at night)
• Impaired mobility
• Bone fracture
• Bone marrow aplasia
• Symptoms of (metastatic) spinal cord compression (MSCC)
• Symptoms in keeping with hypercalcaemia:
  • Constipation
  • Fatigue
  • Polyuria/polydipsia
  • Acute kidney injury (AKI)
  • Cardiac arrhythmia

Bloods

When a patient with cancer presents with any of the signs or symptoms above, basic screening in the form of simple blood testing must be undertaken and complemented with appropriate imaging tests:

• Full evaluation of bone turnover and potential hypercalcaemia:
  • Serum calcium
  • Serum phosphate
  • 25-Hydroxyvitamin D
  • Thyroid-stimulating hormone (TSH)
  • Parathyroid hormone (PTH)
  • Serum creatinine
  • Alkaline phosphatase (ALP)
• Full blood count (myelosuppression, anaemia)
• Serum protein electrophoresis (SPEP; myeloma screen)
• Tumour markers (such as PSA in prostate cancer)

Imaging

Radiological tests are an essential component of diagnosing bony metastases. One or more imaging modalities may be required to confirm suspected cancerous spread to bone.

Plain radiographs (X-ray scans) are quick, cost-effective, and widely-available, and should be the initial diagnostic test of choice when investigating bone pain. They are highly specific but lack sensitivity (44-50%) because early-stage metastatic lesions, particularly those up to 1 cm, may be more difficult to visualise. More than 50% of the trabecular bone must be involved before the lesion will be apparent on film and, due to the poor contrast of trabecular bone, lesions within the medulla are often less evident than those within cortical bone. As outlined above, sclerotic metastases will appear more radiopaque than the surrounding bone, whereas lytic metastases will appear more radiolucent.

Bone scintigraphy (bone scans) on the other hand is highly sensitive but with low specificity. Data from Technetium-99m (^99mTc) scintigraphy have shown false-negative rates as low as 11 to 38% (good sensitivity), with false-positive rates as high as 40% (poor specificity). It thus provides a non-specific osteoblastic indication of bone status, be it inflammatory, traumatic, or neoplastic in origin. Scintigraphy is still more specific and sensitive than either plain radiography or computed tomography, whilst magnetic resonance imaging is more efficacious in assessing vertebral metastases.

Computed tomography (CT scans) has a high sensitivity, ranging from 71 to 100%, for the detection of metastatic bone lesions. Because of the excellent soft tissue resolution of the images produced by CT, it is a particularly helpful modality to distinguish lytic and sclerotic metastases and to visualise their precise location(s) for biopsy.

Magnetic resonance imaging (MRI scans) is useful in assessing bone marrow infiltration by tumour deposits, and is required (whole spine) for the proper diagnosis of MSCC. It has similarly high specificity (73 to 100%) and sensitivity (82 to 100%) in screening for bone metastases.

Positron emission tomography (PET scans) detects tumour indirectly by measuring metabolic activity in the form of fluorodeoxyglucose (¹⁸F) tissue uptake. As such, its use is not limited to visualising only bony metastases, as ¹⁸F PET will reveal non-bony metastatic spread also. The accuracy of PET is highly dependent on the primary tumour site from which imaged metastases originate. As a modality it is superior to scintigraphy in the screening of bony metastases from breast (specificity 94%, sensitivity 95%) and lung (specificity 99%, sensitivity 92%) malignancies, but has lower sensitivity in detecting the comparatively slower-growing bone metastases of prostate and renal cancers.

Biopsy

Sometimes it is necessary to diagnose metastases histologically, by removing cells or tissue from the bone lesion(s) directly. Usually this is in the form of a needle or surgical biopsy, and may be indicated if a primary cancer is not known. If the patient has a known primary cancer, then often imaging alone will suffice for the diagnosis of metastatic bone disease.

Treatment

There are a variety of therapeutic interventions available to patients presenting with bone metastases, but consideration must be given to several patient-specific and tumour-dependent parameters, which include (but are not limited to):

• Lesion site(s) (localised or widespread)
• Presence of extraskeletal metastasis
• Tumour type and features (like receptors)
• Prior treatment history (and response)
• Clinical symptoms
• Performance status

Radiotherapy

Radiation therapy can provide excellent pain relief and is the treatment of choice for localised metastatic bone pain. However, the analgesic mechanisms of therapeutic skeletal irradiation are poorly understood. Onset of pain relief is usually quick, with a majority of patients experiencing benefit within one to two weeks. Patients who have little reduction in pain by six weeks are unlikely to demonstrate significant overall benefit. Other than localised bone pain, additional indications for radiotherapy include MSCC and bones at high risk for pathological fracture. Two of the three main divisions of radiation therapy—the third being (sealed source) brachytherapy—can be used to treat bone metastases: both local- and wide-field external beam radiotherapy (EBRT), and systemic (unsealed source) radionuclide therapy.

Local-field EBRT is the standard choice of radiation therapy for treating bone metastases, as it focally targets the bone lesion and can achieve rates of substantial pain relief of up to 80 to 90%. Randomised controlled trials (RCTs) from the 1990s have shown that a single fraction of 8 gray (Gy) is as effective as fractionated doses of 20 Gy, 24 Gy, and 30 Gy.

Wide-field (or hemibody) EBRT is useful for widespread metastatic skeletal disease, though was more commonly used for multifocal pain when other effective therapies (chemo- and radionuclide) were not available. There are no RCTs comparing analgesic effect with and without wide-field radiotherapy. However, in terms of quasi-randomised and low-quality RCTs, there is data to suggest that use of fractionation is no more effective than single fraction treatment, that increasing doses beyond 8 Gy does not improve overall pain responses, and adding wide-field to local-field radiotherapy, whilst significantly halting disease progression (lesion size: P = 0.03; lesion number: P = 0.01), increases grade 3 to 4 haematological toxicity. [Gy doses from pubmed] + [structures to avoid].

Radionuclide therapy (or radioisotope therapy) is

Bisphosphonates

Poorly localised bone pain/previously irradiated bone lesions

Denosumab

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Analgesia

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Chemotherapy

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Hormonal therapies

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Surgery

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Bone cement

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Living with bone metastases

Pain, mobility and safety, survival