The Perioperative management of skeletal metastases.
Article Type: Report
Subject: Radiotherapy (Health aspects)
Radiopharmaceuticals (Health aspects)
Radiopharmaceuticals (Research)
Bone cancer (Diagnosis)
Bone cancer (Care and treatment)
Bone cancer (Research)
Authors: Bhamra, Jagmeet S.
Malik, Atif A.
Aresti, Nick A.
Khan, Wasim S.
Pollock, Rob
Pub Date: 01/01/2012
Publication: Name: Journal of Perioperative Practice Publisher: Association for Perioperative Practice Audience: Academic Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2012 Association for Perioperative Practice ISSN: 1750-4589
Issue: Date: Jan, 2012 Source Volume: 22 Source Issue: 1
Topic: Event Code: 310 Science & research
Product: Product Code: 2834143 Radiopharmaceuticals NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: United Kingdom Geographic Code: 4EUUK United Kingdom
Accession Number: 280303366
Full Text: Bone metastasis is a common problem affecting a significant proportion of patients with metastatic cancer. Bone metastasis can present in a number of ways and the patients may need surgical stabilisation of their lesions. There are many important considerations in the care of these patients that need to be borne in mind including their increased anesthetic risks and potential risk of complications. There are continuous developments in the prevention, diagnosis and treatment with advances in imaging, orthopaedic technique and medication, particularly radiopharmaceuticals and cytotoxic, endocrine treatments with newer treatments based around the tumour cell-osteoclast interaction. Having a better understanding of these considerations and developments is important in allowing the optimisation of the care of the patient with bone metastasis.

Introduction

Cancer of the bone may be either primary, arising from the bone itself, or secondary, metastasising from a different source. It is widely accepted that secondary cancers are more common than their primary counterparts; however the true incidence is the subject of much debate. Calculating the incidence of metastatic bone disease is dependent on the source's methods: i.e. pathological presentation, incidental imaging findings, autopsy, etc (Table 1). The probability of disease can however be estimated by determining the prevalence of the primary cancer and its predilection for bone (Coleman et al 2001).

Pathology

Skeletal metastases to bone may occur through one of three mechanisms:

1) Seeding of embolic tumour cells via the systemic circulation

2) Direct extension

3) Retrograde venous flow.

The bone matrix provides a favourable microenvironment for the adherence and extravasation of tumour cells. Once there, they stimulate osteoclasts to reabsorb bone, which in turn triggers the release of growth factors, stimulating tumour cell growth. The surrounding bone is characterised by a deranged metabolism and re-models around the destruction of the tumour cells, with either osteoclastic or osteoblastic cells predominating (Salmon et al 2000, Coleman 2001, Mundy 2002, Clines & Guise 2008).

The degree of bone reabsorption and turnover is highly dependant on the bone affected and the origin of the metastatic tumour cell. The relationship between the predominating cell type and remodelling process determines whether a sclerotic, lytic or mixed lesion is seen on radiographs. Disruption of the bone remodelling process results in significant bone loss and therefore a reduced skeletal integrity, which underlies skeletal complications of metastatic cancers (Coleman 1997).

Effects of metastatic bone disease

Different primary cancers cause different rates of events in skeletal metastases (Table 2). Breast cancers tend to cause the most skeletal events (68% over 24 months) (Figure 1), closely followed by myelomas (51% over 21 months) and prostatic cancers (49% over 24 months) (Coleman et al 2004).

Pain

Bone pain in patients with a known primary cancer is highly suspicious of metastatic disease and should be investigated thoroughly. Pain may be caused by direct invasion of the bone causing micro-fractures, increased pressure of the endosteum or distortion of the periosteum. Vertebral collapse can lead to nerve root compression and muscles in the affected area have a tendency to spasm (Moos et al 2008). Pain can be treated by adhering to the WHO analgesic pyramid, initially with non steroidal anti-inflammatories and then with opioids. In severe cases radiotherapy or radionuclide therapy can be used and, although surgery is generally used to treat or prevent fractures, it is also successful in treating pain (Dalton & Youngblood 2000).

[FIGURE 1 OMITTED]

Hypercalcaemia

Hypercalcaemia of malignancy results from the up-regulation of osteoclastic activity, resulting in increased bone re-absorption and reduced renal clearance of calcium and phosphate. The hypercalcaemic state can cause a variety of symptoms including thirst, drowsiness, vomiting and ultimately death. Furthermore, it has been demonstrated that hypercalcaemia can precipitate or exacerbate pain threshold (Fleisch 1991). Patients with breast cancer are most susceptible to hypercalcaemia (13% over 24 months). The mainstay of treatment for hypercalcaemia of malignancy is bisphosphonates, both prophylactically and therapeutically (Coleman 2004).

Bone marrow depletion and anaemia

Metastases to bone generally affect areas that contain red marrow. The marrow which cancerous cells adhere to contains haematopoietic stem cells, stromal cells and immune cells that release inflammatory mediators such as cytokines and growth factors. This provides a fertile microenvironment for tumour cells to grow, which disrupts the normal physiology of bone marrow (Lipton 2004). This leads to a leukoerythroblastic anaemia which is most commonly seen in association with metastasis of cancers from the breast, lung, stomach and prostate (Rubins 1983).

Spinal cord compression

Spinal column metastases occur in 3-5% of cancer patients (Figure 2). The most commonly affecting cancers are breast, prostate and lung cancers, in which the incidence may be as high as 19%. Spinal metastases cause pain, vertebral collapse and metastatic spinal cord compression (MSCC). The pathology is caused by compression of the dural sac and its contents (the spinal cord and cauda equina) by an extradural mass.

[FIGURE 2 OMITTED]

In an ageing population, patients are more frequently presenting with oncological emergencies. MSCC is one of the most common, currently affecting 5-10% of patients (Loblaw et al 2003, Levack et al 2001). Once the spinal cord or cauda euqina are compressed, irreversible neurological damage ensues, with resulting paraplegia.

The gold standard for diagnosis is MRI of the whole spine (Levack et al 2001, Cook et al 1998) and once a diagnosis is made, the treatment goals are the restoration of neurology and prevention of further neurological decline, stabilisation of the spine and analgesia (Husband 1998, Held & Peahota 1993).

Pathological fractures

A pathological fracture occurs when an area of bone which has already been weakened by a pre-existing abnormality, i.e. a cancer, is fractured following a low velocity injury (Figure 3). Tumour extension and growth cause a local destructive effect in the bone cortex and matrix and this initially leads to micro-fractures causing pain and pathological fractures. Large, predominantly lytic lesions which affect the cortex of the bone are most likely to cause fractures, particularly in weight baring bones. The fracture of long bones or the spine cause the biggest disability and detriment to patients' health and so efforts are made to predict and prevent such fractures.

[FIGURE 3 OMITTED]

Pathological fractures are not a sign of terminal disease and so prophylactic fixation with internal stabilisation and radiotherapy to prevent progression are viable options (Haberman & Lopez 1989) (Figure 4).

[FIGURE 4 OMITTED]

Assessment of the patient

It is imperative to take a thorough history and examination of the patient as bone metastases are often multiple at time of presentation. 'Red flag' signs, such as pain (particularly at night) weight loss, loss of appetite, malaise and lethargy, fevers and temperatures, fractures and neurological signs (e.g. malignant cord compression) should be sought in the history taking. It is also important to include a systems review highlighting any areas of concern which may need investigating, such as shortness of breath suggesting a lung primary, or history of a breast lump which may be indicative of breast carcinoma. A complete laboratory blood work-up is completed: full blood count, urea & electrolytes, clotting, ESR, CRP, liver function tests and, if relevant, tumour markers are requested (Weber 2010).

In the majority of cases, patients' initial complaints are dealt with by their family doctor. An urgent cancer referral (within two weeks) is then made to specialist tertiary referral centres for definitive management. These specialist units consist of a large multidisciplinary team constituting: surgeons, radiologists, specialist cancer nurses, pathologists, dieticians, physiotherapists and occupational therapists. All referred cases are discussed at meetings and specialist opinions are sought and management plans established.

Patients are then investigated with relevant radiological imaging, biopsy of the lesion and further clinical assessment in an outpatient setting with histological results and relevant imaging available.

All patients with metastatic bone disease undergo a Technetium-99 ([.sup.99m] Tc) radionuclide scintiscanning bone scan. This modality is the most cost-effective and sensitive whole body imaging for assessing skeletal metastases, but is non-specific. Other screening radiology includes whole body MRI and flourodeoxyglucose (FDG) positive emission tomography. Both are more expensive, but more accurate than nuclear bone scanning (Aoki et al 2001, Cook & Fogelman 2000). Conventional imaging is reserved for investigating lesions identified on the bone scan (plain radiographic films, MR and Ultrasound imaging (Peh 2000, Merrick et al 1992, Traill et al 1999). Patients are further assessed for surgery using a staging CT (chest, abdomen and pelvis) which helps in deciding management options. Histological diagnosis is usually obtained by needle biopsy (under radiological guidance, CT) and, in difficult (e.g. anatomical) or painful cases, open biopsy is an option which is performed under general anaesthesia. Confirmed histological diagnosis, together with the extent of disease spread is then considered and finally, depending on patient prognosis a treatment plan is made after rediscussion at the multi-disciplinary meeting.

Treatment options

Depending on the outcome of the investigations above, fitness for surgery is assessed. If surgery is not an option (such as extensive spread of disease, frailty of patient, presence of multiple co-morbidities) then referral to the palliative team is made.

Symptomatic treatment is the mainstay is such cases. Patients fit for surgery may undergo radiotherapy prior to surgery and in palliative patients radiotherapy may be an option in treating 'bony pain'.

The changes to the metabolic and bone remodelling processes underlies the manifestation of skeletal complications. Better understanding of these processes has meant that there are better treatment options for skeletal metastases, preventing the aforementioned complications. Orthopaedic surgery is used to repair pathological fractures and stabilise impending fractures. Radiotherapy is used to treat bone pain and to stabilise bony lesions.

Bisphosphonates

Bisphosphonates are currently the standard of care for preventing skeletal complications of metastatic disease and are used to treat bone pain. They preferentially bind to bone surfaces which are undergoing remodelling and are released by the bone matrix during reabsorbion, inhibiting osteoclastic activity. This mechanism may reduce osteoclast-mediated bone reabsorbtion (Fleisch 2002). Various clinical trials have compared the various bisphosphonates to each other and to placebos using 'end points' or 'skeletal related events' (SRE) which generally include pathological fractures, cord compression, hypercalcaemia, radiation to bone or surgery.

Zoledronic acid, a bisphosphonate, is the current standard treatment for patients with osteolytic or mixed bone metastases or lesions. Studies have shown this drug to be more potent than bisphosphonates (e.g. pamidronate) and it is administered by intravenous infusion. Furthermore, it has been shown to significantly reduce rates of SREs in patients with breast or prostate cancer as well as other solid tumours and multiple myelomas (Rosen et al 2003, Kohno et al 2004, Small et al 2003, Major & Cook 2004).

It is widely accepted that the release of growth factors and cytokines during the normal bone reabsorbtion process attracts malignant cells to the bone surface and facilitates its growth and proliferation (Yomeda & Michigami 1999, van der Pluijim et al 2000).

Several animal models have demonstrated a reduction in metastatic bone disease, but these results have not been easily transferred to human trials, although some evidence does suggest that clodronate may be of benefit. For example, Diel et al (2008), looked at 302 patients with breast cancer who had cancer cells in the bone marrow identified by immunocytochemistry. There was a reduction in bone metastases at 36 months by using clodronate (11 versus 25).

It is therefore clear to conclude that bisphosphonates have an established role in preventing SREs in patients with metastatic bone cancer; more work is however required to identify the role of bisphosphonates in the prevention of skeletal metastases (Fleisch 2002).

Orthopaedic surgery

The roles of the orthopaedic surgery in the management of skeletal metastases are (BASO 1999):

1) Prophylactic fixation of bone where there is a significant risk of fracture.

2) Fixation and stabilisation following a fracture (Figure 5).

[FIGURE 5 OMITTED]

3) Decompression of spinal nerve roots and stabilisation of the affected vertebrae.

Mirels (1989) suggested a scoring system (Table 3) to evaluate the risk of a pathological fracture, and this is widely used in the USA. A high score would mean a high risk of fracture and so prophylactic fixation could be considered. This study found that scores of 7 or less carry a less then 5% risk of fracture and so conservative management and primary radiotherapy is indicated. Scores of 9 or more carry a high risk of fracture and so prophylactic surgery is indicated, whereas scores of 8 carry an intermediate ([approximately equal to] 15%) risk and therefore a decision should be made based on the clinical picture.

Where extensive bone destruction has occurred (commonly at the metaphyses of major long bones); reconstruction may only be achieved using custom or modular endoprostheses. Although, principally used in the management of primary bone tumours, these prostheses are now increasingly being used in the management of bone metastases for lesions in the proximal/distal femur or humerus and the proximal tibia. Procedures are performed in regional bone tumour centres and are effective in maintaining function whilst having a relatively low re-operation rate (BOA 2011).

An anaesthetic review is performed in all patients prior to surgery and specialist opinions sought with relevant investigations completed (RCoA 2004). Anaesthetic risk is assessed based on The American Society of Anaesthesiologists classification system, consisting of four grades (ASA I-IV). A patient with a higher ASA class has a higher risk of postoperative complications (RCS 2003).

Systemic disease presents with a multitude of symptoms. Symptomatic control is paramount in managing patients with skeletal metastases. At least 60% of surgical patients suffer from coexisting medical issues (Nierman & Zakrzewski 1999) Haematological, electrolyte and metabolic disturbance, respiratory support, analgesia, bowel and urinary management in particular, need to be addressed urgently prior to surgical treatment. Patients with a life expectancy of less than six weeks rarely gain benefit from major reconstructive surgery (BOA 2001). The burden of malignancy also increases the risk of thromboembolic events (deep vein thrombosis and pulmonary embolus) and therefore advice from haematologists should be sought or local guidelines strictly adhered to. A vena cava filter may also be required in patients with coexisting DVTs before to surgery.

Meticulous preoperative planning and a multidisciplinary approach are vital prior to proceeding with surgery. An alternative strategy must be made by the surgeon if the primary surgical plan fails. All surgical equipment must be sterilised, checked and be available prior to surgery (endoprostheses, cement, internal fixation instruments). In certain cases, the availability of general and vascular surgeon teams should be checked.

It is mandatory for the operating room to be well prepared (monitoring equipment, sterility) before surgery. Extra care must be given to patient positioning to prevent decubiti and nerve palsies. The use of extra padding is often helpful. Patient warming prevents risk of hypothermia in lengthy cases. Sequential compression devices, arterial and central venous lines, urethral catheters are all placed for monitoring and continuous blood sampling. End tidal Co2 is monitored during cementation as this can evoke a cardiopulmonary event. Spinal monitoring may also be required. Broad spectrum antibiotics are administered on induction of anaesthesia, followed by two postoperative doses in routine cases. Finally, the World Health Organisation (WHO) checklist should be performed in the operating room before surgery commences to minimise errors (Haynes et al 2009).

Postoperatively, patients are managed on the surgical unit. Unstable patients are transferred to the high dependency or intensive care unit, where closer monitoring and higher nurse to patient ratio is provided. Cardiopulmonary and haemodynamic monitoring provides a good indication of fluid balance, electrolyte and oxygenation. Drains which are placed intraoperatively also need requiring strict monitoring (ongoing blood loss) and play a role in the fluid replacement regime (Bibbo et al 2000).

Radiotherapy

Radiotherapy has for a number of years been used to successfully treat bone pain. It also induces remineralisation of bones which helps stability and can further be used to treat neurological symptoms due to nerve or spinal damage (Kardamakis et al 2009).

This is generally achieved through a short regime of one to five fractions, although several randomised controlled trials have shown that a singly fraction of 8Gy is sufficient to alleviate bone pain (Janjan et al 1997).

Summary

Bone metastasis is a common problem affecting a significant proportion of patients with metastatic cancer. There are continuous developments in the prevention, diagnosis and treatment with advances in imaging, orthopaedic technique and medication, particularly radiopharmaceuticals and cytotoxic, endocrine treatments with newer treatments based around the tumour cell-osteoclast interaction.

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by Jagmeet S Bhamra, Atif A Malik, Nick A Aresti, Wasim S Khan and Rob Pollock

Correspondence address: Atif A. Malik, Speciality Registrar, North East Thames (RNOH-Stanmore Rotation), Department of Spinal Deformity, Royal National Orthopaedic Hospital, Stanmore, HA7 4LP.

About the authors

Jagmeet S Bhamra

BM, BSc (Hons), MRCS (Eng)

Core Surgical Trainee, Bone Tumour Unit, Royal National Orthopaedic Hospital, Stanmore

Atif A Malik

MB ChB, MRCS Ed, MSc (Ortho Eng)

Speciality Registrar, North East Thames (RNOH-Stanmore Rotation), Department of Spinal Deformity, Royal National Orthopaedic Hospital, Stanmore

Nick A Aresti

BSc (Hons), MBBS, MRCS, FHEA

Core Surgical Trainee, London Deanery, Hillingdon Hospital

Wasim S Khan

MBChB. MSc, MRCS, PhD

Clinical Lecturer, University College London Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore

Rob Pollock

BSc, MBBS, FRCS (Tr & Orth)

Consultant Orthopaedic Oncologist, Royal National Orthopaedic Hospital NHS Trust

No competing interests declared
Type of    New cases of cancer diagnosed    Incidence of bone
cancer         in the UK, 2006-2008 *      metastases in cancer **

Multiple                           4,339                 70%-95%
myeloma
Breast                            46,840                 65%-75%
Prostate                          37,221                 65%-75%
Renal                              7,332                 20%-25%
Lung                              40,704                 30%-40%
Malignant                         11,095                 14%-45%
melanoma
of skin

Table 1 Incidence of new cancers diagnosed and sources of metastatic
disease
Source: Office for National Statistics 2011 Cancer incidence and
mortality in the UK, 2006-2008
Available online http://www.statistics.gov.uk [Accessed November 2011]


Primary tumour  Rate of spread

Breast          68% (24 months)
Prostate        49% (24 months)
Myeloma         51% (21 months)

Table 2 Rates of skeletal metastases from primary cancers
Source: Coleman 2004


Variable                      Score 1   Score 2       Score 3

Site                         Upper      Lower     Peri-trochanter
                             limb       limb
Pain                         Mild       Moderate  Functional
Lesion                       Blastic    Mixed     Lytic
Size

* Refers to the proportion (on radiograph) of a single cortical layer
destroyed

Table 3 Mirels' scoring system for evaluation of risk of pathological
Fracture
Source: Mirels 1989
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