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: systemic (unsealed source) radionuclide therapy and external beam radiotherapy (EBRT).

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. It is possible to classify wide-field treatments into three body regions, each with recommended single-fraction dose limits. Upper treatments (from skull or C1 to L2–L3) should be limited to 6 Gy, whereas mid-body (from L1 to upper third of femur) and lower (from L3–L4 to above knee) treatments should be limited to 8 Gy. Any treatments must be delivered with fields shaped to minimise irradiation of organs at risk, such as lung, liver, kidney and bowel.

Stereotactic EBRT is a promising treatment option which delivers higher doses of radiation to tumours in shorter periods in time. When used for extracranial cancers it is interchangeably termed Stereotactic Body Radiation Therapy (SBRT) or Stereotactic Ablative Radiotherapy (SABR), the latter of which is appealingly onomatopoeic. When this technique is used for treating malignancy within the brain or some other part of the head, it is termed Stereotactic RadioSurgery (SRS). SBRT/SABR can be used both for primary cancers (lung, liver, prostate, renal) and secondary metastases (bone/spine, lung, liver). There are a number of advantages of stereotactic radiotherapy, the most obvious of which is the potential completion of treatment within a single day, rather than over a number of weeks. The other major benefit is that it obviates the need to irradiate large portions of bone, which lowers the risk of further functional marrow depletion in a patient cohort already at risk of poor marrow reserve. Preserving skeletal marrow function can permit continuous chemotherapy in these patients. The primary limitations of SBRT/SABR are that it is more expensive to deliver than conventional EBRT and that there is a paucity of RCT data comparing its use to standard EBRT management. However, a recent single-centre phase II trial appeared to show that SBRT/SABR provides superior pain relief to conventional multifraction radiotherapy, with no observed difference in adverse events or other aspects of quality of life.

Radionuclide therapy (or radioisotope therapy) is the systemic administration of radionuclides (also known as radioisotopes) as unsealed radioactive sources that selectively deliver radiation to tumours or target organs. They are taken up predominantly at sites of bone formation, and are therefore most likely best effective for the palliation of osteoblastic (sclerotic) metastases. Common radionuclides approved for the treatment of painful bone metastases include phosphorus-32 (³²P; β-decay), strontium-89 (⁸⁹Sr; β-decay), samarium-153 (¹⁵³Sm; β- and γ-decay), and rhenium-186 (¹⁸⁶Re; β- and γ-decay). The added advantage of gamma ray emission during decay is that it permits nuclear imaging monitoring of radionuclide biodistribution during therapy. These radionuclides target bone through various mechanisms. ³²P passes through inorganic phosphate pathways, whereas ⁸⁹Sr is a calcium mimetic and is taken up as a direct analogue of this earth metal. The final two agents are targeted to bone via chelation to phosphonate compounds: ¹⁵³Sm is paired to ethylenediaminetetramethylenephosphonate (EDTMP) and ¹⁸⁶Re to 1,1-hydroxyethylidene diphosphonate (HEDP). Common toxicities from treatment include myelosuppression and a transient pain flare, the latter of which usually heralds a favourable response. A more recently developed radionuclide, radium-223 (²²³Ra; α-, β-, and γ-decay) is a calcium mimetic which emits over 95% of decay energy in the form of alpha radiation. Owing to their comparatively large size the emitted alpha particles have a more limited depth of penetration into surrounding tissues (around 2–10 cells), thereby producing a more potently localised cytotoxic effect. Despite their symptomatic benefits in refractory, widespread bone metastases, neither ⁸⁹Sr nor ¹⁵³Sm have been shown to improve overall survival in interventional trials; however, ²²³Ra use in metastatic castration-resistant prostate cancer patients in the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial was shown to significantly prolong overall survival.

Bisphosphonates

Analogues of the natural bone demineralisation inhibitor pyrophosphate, bisphosphonates are useful in the treatment of poorly localised bone pain and in previously irradiated bone lesions. They bind with high affinity to exposed bone mineral where they are internalised by osteoclasts, within which they disrupt the processes of bone resorption and can induce apoptosis. Data have shown that bisphosphonates may have direct pro-apoptotic effects on nearby metastatic cancer cells also. In halting the mobilisation of calcium and phosphate from bone, bisphosphonate use (together with rehydration) is now standard of care for malignancy-induced hypercalcaemia. The analgesic effect of these agents is independent of underlying tumour characteristics, with osteolytic and osteoblastic lesions responding similarly. Many patients tolerate bisphosphonates without major concern, but common side-effects include flu-like myalgic symptoms, diarrhoea, nausea and reflux. It is exceedingly rare but one must be aware of the risk of developing osteonecrosis of the jaw. These medications undergo renal excretion and as such should be avoided in tumour-induced hypercalcaemia or metastatic bone disease if serum creatinine is greater than 400 μmol/L or 265 μmol/L, respectively. Bisphosphonates are divided into three generations of drug: first-generation (tiludronate, clodronate, etidronate), second-generation (ibandronate, alendronate, paimdronate), and third-generation (zoledronate, risedronate). One of the newest agents, zoledronate is 100-times more effective than second-generation pamidronate. Whilst receiving bisphosphonate therapy, patients should take protective vitamin D and calcium supplements.

Denosumab

Denosumab is a monoclonal antibody which binds to and inhibits the action of the RANK receptor ligand (RANKL). RANK is located on the surface of osteoclast progenitor cells and its activation stimulates their development into mature osteoclasts. Therefore denosumab, administered as a subcutaneous injection of 120 mg every four weeks, can help prevent bone destruction and fracture in patients with bone metastases. The antibody is cleared from the body by the reticuloendothelial system and can therefore be used in patients with poor renal function, in whom bisphosphonate use would be contraindicated. Additionally, data have shown that denosumab use causes greater suppression of osteolytic markers than bisphosphonate use in metastatic patients with breast or prostate cancer. However its effectiveness in comparison to bisphosphonates for patients with lung cancer or multiple myeloma is similar for the prevention of skeletal-related events (SRE), and indeed patients with multiple myeloma showed worse overall survival when treated with denosumab instead of zoledronate.

Systemic anticancer therapies

Systemic anticancer therapy (SACT) refers to all drugs administered systemically with direct anticancer activity. This includes all conventional cytotoxic chemotherapies, all small molecule or antibody treatments, and all types of immunotherapy. Hormonal agents are not included within this categorisation. SACT may be considered for bone metastases if a primary tumour is known or subsequently confirmed. The specific therapy used will be the same therapy as typically used for the culprit primary cancer, though the precise dose and schedule will vary. SACT is sometimes used concurrently with other treatments such as bisphosphonates or radiotherapy. Side-effects will be treatment-specific.

Hormone therapies

Hormone therapy is an indirect antitumour treatment which blocks the action of endogenous hormones or reduces their production within the body. Certain hormone-sensitive malignancies, particularly those of the prostate and breast, will often grow in response to specific hormones (androgens and oestrogens, respectively). Secondary metastases stemming from these primary tumours will, by extension, respond to hormone levels too. Androgen-responsive prostate cancer may be treated with drugs which lower androgen levels, such as gonadotrophin-releasing hormone (GnRH) receptor antagonists (peptides: '-relix'; small-molecules: '-golix'), GnRH receptor agonists ('-relin'), and CYP17A1 inhibitors (such as abiraterone). Alternatively, androgen receptor blockers, such as bicalutamide or flutamide, can be effective. Oestrogen-responsive breast cancer may be treated with drugs which lower oestrogen levels, such as type I (exemestane) and type II (anastrozole, letrozole) aromatase inhibitors. Alternatively, selective oestrogen receptor modulators (SERMs), such as tamoxifen, can be effective. These modulators have mixed oestrogenic and antioestrogenic activity, which differs according to receptive tissue. Usefully in breast cancer, it is antioestrogenic in the breast; however, in the uterus and liver it is oestrogenic.

Interventional radiology

The role of the interventional radiologist is ever-expanding. In the treatment of metastatic cancer there are procedures which are shared with or done solely by these interventionists. Two important treatments offered by the specialty for bone metastases are ablation and cementoplasty.

Ablation is a medical term for when a procedural probe is introduced to an area of tissue (in this case tumour) and, using physical energy (heat or cold) or chemicals, cellular necrosis with subsequent scarring is achieved. It is useful for bony lesions if only there are one or two lesions to be targeted. The most common types of ablation are radiofrequency ablation (RFA), where an electric current passes through and heats a needle within the lesion, and cryoablation, where a cold probe within the lesion freezes and destroys cancer cells. Both are effective analgesic therapies; however, unlike in RFA, the ablation edge in cryoablation can be readily visualised with CT monitoring (as low-attenuation) and does not produce increased pain in the periprocedural period. Complications rates for each procedure are low, but localised infection and enduring neuropathic pain have been reported.

Cementoplasty is a generic term for a group of medical procedures whereby acrylic bone cement, commonly polymethylmethacrylate (PMMA), is injected percutaneously into bone lesions for analgesic effect and/or stabilisation. It is commonly performed under sedation with local anaesthesia, and the cement is mixed with a radiopaque agent to allow visualisation with multi-plane fluoroscopy during injection. Depending on where cementoplasty is used, it may be termed differently:

• Osteoplasty (generic term, injection into non-axial bone lesions)
• Vertebroplasty (injection into a vertebral lesion)
• Kyphoplasty (mostly for vertebral fractures, this is vertebroplasty with use of intravertebral balloon inflation beforehand to restore vertebral height)
• Sacroplasty (injection into a sacral lesion)

Surgery

Surgery is not considered to be amongst the conventional treatments for bony metastases. It is indicated for fractures of the hip and of long bones, and if there is need for vertebral surgery in MSCC. Sometimes if bone involvement leads to fracture causing peripheral nerve impingement or compression, surgery may also be necessary.

Living with bone metastases

It is important to grasp that, in many instances, patients live with their bone metastases as a chronic (non-curable) condition. Adjustments will often need to be made to permit a continued good quality of life.

Pain is very common with metastatic bony disease, and many treatments can be given to alleviate this pain. If pain is difficult to manage then input from pain and palliative care specialists (doctors and nurses) can be enormously helpful. Some patients find complementary therapies, such as massage and acupuncture, to be of benefit to their symptoms.

Mobility can be severely impacted by skeletal metastasis. Depending on the location, burden, and extent of the bone disease, the risk of fracture can be high. Input from occupational therapists and physiotherapists can enhance the safety of patients and their environments, and minimise the risks of falling and fracture.

Survival is an understandably common topic of discussion, particularly in the context of advanced metastatic cancer. The factors affecting survival with bone metastases are multifarious and as such any attempt at predicting exact survival is impracticable. However, there is some scope for estimation. The survival of patients who develop bone metastases from prostate or breast cancer is often measured in years, whereas the survival of patients with bone metastases from lung cancer is often measured in months.