Recent advances in metastatic bone disease

Abstract

Metastatic bone disease (MBD) is a common sequela of malignancy and can lead to significant morbidity on patients. Systemic medical therapies and oncology surgery have greatly enhanced cancer survival rates over recent decades. Orthopaedic surgeons occupy a key position within the multidisciplinary team and coordinate surgical care for bone metastases where appropriate. This review describes the investigations for, and management of, patients with metastases to the appendicular skeleton. National British Orthopaedic Association Standard (BOASt) guidelines exist to help orthopaedic clinicians and departments optimize patient care. We outline and illustrate the freely available OPTIModel app, which is an innovative, straightforward and useful tool for prognostic evaluation and suggestion of loco-regional treatment options for patients with symptomatic long bone metastases.

Introduction

Approximately 367,000 new diagnoses of malignancy are made each year in the UK, which is 5% higher than the incidence a decade ago. From 1971/72 to 2010/11, cancer outcomes have dramatically improved in England and Wales, with 5-year survival rates increasing from 30% to 54%, and 10-year survival rates rising from 24% to 50%. Neoplastic disease commonly metastasises to the skeleton, with variable lengths of survival after identification of metastatic bone disease (MBD) ( Table 1 ). The presence of MBD at the time of a cancer diagnosis can be as high as 30% and the incidence of bony metastases is rising due to an ageing population, rapid developments in diagnostic methods and advances in non-surgical anti-cancer treatments. Chemotherapy, immunotherapy, hormonal treatment and bone-targeting agents have contributed greatly to the prognostic improvements. Cancers not frequently or traditionally linked with skeletal spread are now demonstrating secondary bony deposits because of the elongated survival of patients. Estimates show that around 330,000 people were living with bone metastases in the USA in 2012.

Table 1

Incidence of bone metastases and median survival following metastatic bone disease (MBD) diagnosis, by cancer type ^,

Cancer	Incidence of MBD (%)	Median survival after diagnosis of MBD (months)
Multiple myeloma	70–95	–
Prostate	65–90	12–53
Breast	65–75	19–25
Thyroid	65	48
Lung	17–64	6–7
Melanoma	14–45	6
Bladder	40	6–9
Renal cell	20–25	12
Colorectal	10	–

MBD is most commonly found in the axial skeleton, with highest rates in the spine and ribs ( Table 2 ). Skeletal metastases are a significant source of morbidity with pain, pathological fracture and spinal cord compression. Generally, the aim of MBD treatment is not curative, but instead concentrates on improving quality of life and length of survival. Decreasing pain and gaining function are key to this. With debulking procedures reducing tumour burden, there is potential to contribute to improved survival, especially in the context of a solitary bone metastasis or oligometastatic disease.

Table 2

Frequency of bony metastases, by anatomical location, identified on bone scan in patients with breast, prostate, gastrointestinal and lung malignancies

Anatomical location	Frequency of bone metastases (%)
Spine	18.8
Ribs	14.4
Pelvis	9.4
Sternum	7.5
Femur	5.0
Scapula	3.8
Skull	3.8
Humerus	1.9
Clavicle	1.3
Tibia and fibula	0.6

Data from reference .

The increasing prevalence of MBD is coupled with an increasingly complex patient cohort with respect to co-morbidities, higher functional demands and expectations.

Presentations of MBD can occur in a variety of manners from asymptomatic findings on bone scans, to acute hospital admissions for pathological fractures or spinal cord compression; and from attendance at outpatient clinics with bone pain, to direct oncology referrals. Moreover, patients may present to a variety of orthopaedic services with varying experience in the management of MBD.

In 2013, Harvie et al. noted significant idiosyncratic variations in practice in the management of patients of MBD in the UK. This coincided with the publishing of new and updated national guidelines by the British Orthopaedic Oncology Society (BOOS) and British Orthopaedic Association (BOA) in 2015. The consensus guidelines, stated that management of skeletal metastases should involve a multidisciplinary team (MDT), including an orthopaedic surgeon for advice and input. Therapies should be carefully planned and organized by clinicians to optimize the treatment combination and the schedule of delivery. Surgery can play a crucial and complementary role alongside medical oncological treatment. Even with a relatively short prognosis, operative intervention can offer an important reduction in pain, improvement in mobility and improvement in quality of life. Doctors in primary care, oncology and orthopaedic services should be aware of what surgical management can accomplish, and which patients might be suitable candidates for it. The guidelines were developed further in 2022 forming an updated BOA Standard (BOASt) of practice for suspected MBD of the appendicular skeleton, pelvis and scapula.

This review focuses on the role of orthopaedic surgeons and orthopaedic surgery in MBD of the appendicular skeleton.

Role of the orthopaedic surgeon

The four integral roles an orthopaedic surgeon may play within the MDT are:

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diagnosing skeletal metastases
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prophylactically managing MBD
•

fixing or reconstructing the skeleton after pathological fracture
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decompressing the spinal cord and/or stabilizing the spine.

National guidelines for MBD recommend that every orthopaedic service has a nominated, lead orthopaedic surgeon for competently diagnosing, investigating and coordinating care. This may necessitate additional training for the post and dedicated sessions for MBD work to be integrated into the job plan; it will demand continuous professional development in the area. The lead surgeon will require a web of specialist, regional contacts for advice on, and management of, complex patients. Referral to a supra-regional orthopaedic oncology unit can be very important to ensure optimal management, especially for patients with longer prognoses.

The 2015 BOOS/BOA recommendations highlight the four minimum standards of surgical care:

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Every patient with MBD should be able to receive an expert orthopaedic opinion as part of the MDT
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Options for surgical management should be reviewed with the oncology team and considered with a holistic approach to the patient and the primary cancer
•

Postoperative follow-up should examine fracture union, local progression of the malignancy and stability of the fixation or prosthesis
•

Detailed data collection should be undertaken where possible to continue advancing evidence-based orthopaedic care for MBD.

MBD service delivery and structure

With the prevalence of MBD expected to continue to rise, developing robust treatment pathways is essential in ensuring patients receive timely and expert care.

The 2022 BOASts highlighted two standards for service delivery structure:

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Each unit should have an agreed policy for the multidisciplinary discussion and management of MBD including clear pathways for onward referral.
•

All specialist centres should have agreed pathways to enable prompt opinion, advice, and transfers within their network.

Developing MBD networks follow a hub-and-spoke model structure where local orthopaedic services are able refer on and seek advice from recognized tertiary centres, defined by the BOA as ‘a unit managing complex MBD with appropriate multidisciplinary capabilities’. The development of regional tertiary centres aims to provide some relief to the few national primary bone sarcoma units, which are otherwise at risk of being overwhelmed by local referrals, and drive management of MBD regionally.

An example of the proposed service structure is outlined in Figure 1 .

Diagnosis

A thorough work-up of a patient with suspected or confirmed MBD facilitates the diagnosis, staging and prognosis of the disease, and can subsequently establish if surgical intervention is appropriate and inform on which operation may be most suitable. Pathological fractures are generally sustained through low-energy mechanisms, with little soft tissue trauma and low risk of significant haematoma. Initial treatment is with traction if appropriate, immobilization, venous thromboembolism prophylaxis, and adequate analgesia. There is no urgency to operate on a patient with a pathological fracture. Emphasis must be on comprehensive investigation, referrals and diagnosis pre-operatively in order to avoid inappropriate management.

A detailed history and examination need to be followed by a range of investigations. Blood tests including full blood count, urea and electrolytes, liver function tests, calcium and bone profile, prostate-specific antigen in men, myeloma screen should be performed. Imaging should include plain film radiographs of symptomatic bones ( Figure 2 ), with two views and including the joints above and below. Metastatic lesions may need to occupy a significant proportion of the bone (50–70%) before being identifiable on plain film. Radioisotope bone scanning should be utilized if radiographs are negative but clinical suspicion is present. A CT scan can provide a detailed picture of cortical destruction for lesions noted on bone scans but not visible on plain radiographs. MRI scanning is a highly sensitive technique for detecting MBD and can be used to determine precise radiological characteristics of a metastasis and any invasion of soft tissues or neurovascular structures. Staging CT of the thorax, abdomen and pelvis (CT-TAP) can evaluate for a primary malignancy and visceral metastases, as well as for other skeletal secondary deposits and should be performed within 24 hours of orthopaedic assessment.

Importantly, clinicians must not assume a solitary bone lesion to be a metastasis, even in the context of a previously treated cancer (especially if after many years). This frequently requires a biopsy to establish a skeletal diagnosis prior to surgery, as a primary bone sarcoma needs to be ruled out first. As such, the 2022 BOASt standards advise that all patients presenting with solitary bone metastasis should be referred to a recognized tertiary centre. Unsuitable intervention can disseminate a primary skeletal malignancy and have devastating consequences, potentially compromising a patient’s life and limb by removing reconstructive and curative options, and by accelerating disease progression. Prompt, rigorous diagnosis pre-operatively is therefore critical.

A patient with radiographic features of a primary bone tumour, including bone destruction, new bone formation, periosteal reaction, or soft-tissue swelling should be referred to directly to a bone sarcoma centre within 72 hours of first suspicion or diagnostic imaging. Additionally, patient with no evidence of malignancy on a staging CT-TAP may be indicative of a primary bone tumour and should be referred to a bone sarcoma centre within 72 hours. Patients already with known disseminated cancer do not ordinarily need a biopsy before surgery. However, this may be required if there is clinical suspicion of an alternative pathology or of an altered phenotype in the metastasis compared to the primary tumour (with implications for the optimal regime of systemic oncological therapies).

Biopsy

Tissue sampling to rule out a primary bone or soft tissue malignancy should be carried out at a dedicated sarcoma centre. Core needle biopsies are frequently performed percutaneously for bone lesions. Careful discussion with the surgical and radiology team prior to biopsy ensures that improper tracts are not generated. Open biopsy can also be used with a longitudinal incision (placed in line with a potential future surgical incision), avoidance of neurovascular structures, involvement of only the affected compartment, meticulous haemostasis and drain placement (if required) out through the incision.

Intramedullary canal reamings, taken during a long bone nailing procedure and sent for histopathology, are not an acceptable substitute for a formal biopsy of the bony abnormality. Reaming biopsy samples have a reported sensitivity of 40–61% for detecting a metastatic tumour on histological analysis. If a tissue sample is deemed necessary for histopathological assessment, then this must be obtained with a formal biopsy.

Decision for operative management

Surgical management of MBD should be consultant led and can be undertaken to lengthen survival, prevent fracture, reduce pain, improve function and increase quality of life. It may also be performed to simply maintain the current level of function and prevent further deterioration in mobility. Patients with longer prognoses, for example in some breast, renal or thyroid carcinomas, have a higher chance of improved survival with surgery, and this is particularly true for those with an isolated metastasis or with oligometastases. Bony resection and endoprosthetic implants can be more suitable for this cohort of patients.

The indications for surgery are:

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pathological fracture
•

high risk of pathological fracture (impending)
•

compromised stability of weight-bearing joints
•

persistent and significant bone pain, despite analgesia and non-surgical management
•

significant impact on mobility and/or quality of life.

Patients should be involved in the decision-making process regarding surgical interventions and, where appropriate, their relatives and/or the individuals closest to them should also be included. Discussion should cover the details of the operation and the anticipated risks and benefits. Consideration must be given to the patient’s expected survival and baseline medical health and function. The responsible surgeon must also liaise with the MDT about patient suitability for surgery and the integration of a surgical intervention into the proposed plan and schedule of non-operative treatments. This communication is imperative, but distinctly so for patients with poor prognoses and functional statuses. Surgery may still be indicated on a weight-bearing bone for those with life expectancies as short as 1 month, and 3 months for non-weight-bearing bones.

Evaluating risk of pathological fracture

Pathological fracture is an acute, painful condition which is more technically difficult to treat than its impending counterpart. Planned, prophylactic internal fixation, before a fracture occurs, is preferred and is indicated for patients at high risk. Patients with pathological fractures suffer greater morbidity through the escalation in pain, greater risk of surgical complications, longer operating time and longer stays in hospital, as well as poorer postoperative outcomes for length of survival and quality of life. This highlights the importance of recognizing red flag symptoms and signs of MBD early, and of prompt investigation and referral.

Assessing risk of future fracture is key to identifying those patients who would likely benefit from prophylactic surgery. This led to the development of medical criteria and scoring methods to guide management. Harrington’s criteria for predicting high-risk long bone metastases were not validated, and preceded the now well-established Mirels’ score.

Harrington’s criteria are:

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greater than 50% cortical destruction
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femoral lesion greater than 2.5 cm in size
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associated avulsion fracture of the lesser trochanter
•

persistent pain on weight-bearing despite radiotherapy.

Mirels took a novel approach by combining gradings for multiple lesion characteristics to generate his weighted scoring system ( Table 3 ). Retrospective analysis of data from 38 patients, with 78 long bones containing metastases, calculated risk of pathological fracture within six months after irradiation. This informed Mirels’ corresponding suggestion for management ( Table 4 ).

Table 3

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