Introduction

Bone metastases (BM), the secondary spread of malignant cells from primary tumors to the skeletal system, are major challenge in the advanced stages of various cancers. BM often causes debilitating symptoms such as severe pain, pathological fractures, spinal cord compression, and hypercalcaemia [1]. Radiotherapy (RT), as a cornerstone treatment modality, plays a critical role in managing BM by alleviating symptoms, improving local tumour control, and improving overall patient outcomes.
RT has undergone significant scientific development and technological refinement over time. It involves the precise delivery of ionising radiation to the affected bone regions with the aim of maximising tumour eradication while minimising damage to surrounding normal tissues. External beam RT (EBRT) remains the primary approach, using specialised equipment such as linear accelerators to deliver high-energy radiation beams from outside the body [2]. Advanced modalities, including intensity modulated RT (IMRT) and stereotactic body RT (SBRT), have revolutionised treatment precision, allowing escalated doses of radiation to be delivered to the tumour while minimising radiation exposure to adjacent normal tissues. This increased precision has contributed to superior treatment outcomes and reduced treatment-related toxicities.
The efficacy of RT in BM is multifaceted. As a palliative intervention, it effectively relieves the pain associated with cancer-related bone lesions, significantly improving patient comfort and quality of life [3,4]. In addition, RT exerts local control by targeting neoplastic cells within the bone microenvironment, potentially delaying disease progression and preventing skeletal-related events such as fractures and spinal cord compression.
Oncology has advanced rapidly in recent years, driven by genomics, targeted therapies, immunotherapy and precision medicine. Genetic profiling allows personalised treatment based on specific mutations. Targeted therapies inhibit cancer cell growth with fewer side effects. Immunotherapy stimulates the immune system to fight cancer. Precision medicine tailors treatments to individual characteristics. Multidisciplinary approaches and advances in diagnostics have also played a key role. These developments have significantly improved patient outcomes and prolonged patient lives. New achievements in oncology enable long-term disease control, which in the case of BM, often requires a more intensive approach. Effective local therapy can significantly improve the patient’s chance of continuing effective systemic treatment or open new therapeutic options. It could also improve patients’ quality of life, especially those with a life expectancy of more than 3 months.
A multidisciplinary approach involving collaboration between radiation oncologists, medical oncologists and other healthcare professionals is essential to develop comprehensive treatment plans for patients with BM. Factors such as the extent and location of metastases, the histology of the primary cancer, the patient’s overall health and individual patient preferences are carefully considered to determine the optimal approach to RT. In selected cases, RT may be combined with systemic therapies or surgery to optimise outcomes.

Aim of the review

This narrative review aims to present the current state-of-the-art on the role of RT in the multidisciplinary management of patients with BM.

State of knowledge

Spinal metastases
The increasing availability of modern and effective systemic treatments, the associated increase in life expectancy and the dissemination of accurate diagnostic methods have led to an increase in the diagnosis of spinal metastases. These pose a serious problem in everyday clinical practice because of the associated neurological disorders, pain and fractures, which subsequently lead to a deterioration in the patient’s quality of life with a systematic decline in overall functional status [3,4]. Historically, spinal metastases have been treated with palliative EBRT using simple planning techniques [3,4]. Palliative EBRT reduces pain in approximately 60-70% of patients with a sustained effect for several weeks but does not provide adequate local efficacy [2,5]. The most common and recommended regimen is a single fraction of 8 Gy, which can be repeated after several weeks [2].
Due to the proximity of the spinal cord, it is impossible to deliver a radical dose of radiation using simple EBRT techniques. The use of SBRT in this group of patients offers significant advantages due to the high local efficacy and tolerability of such treatment at the expense of more complicated preparation, planning and delivery of the radiation. Qualification for SBRT of spinal metastases should take place in a multidisciplinary meeting involving at least a radiation oncologist, a clinical oncologist, a spinal surgeon and a radiologist. SBRT of spinal metastases is the treatment of choice if there is a history of previous radiation to the same or nearby volume [6]. It may also be considered instead of EBRT as an adjuvant treatment after surgical resection of a spinal metastasis. There is a consensus in the literature that discusses this issue in more detail [7].
The decision is based on performance status as assessed by the Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status (KPS) scale, current cancer progression and control, and the potential for effective systemic treatment. For patients with poor performance status (ECOG 3-4 or KPS <40) or an expected survival of less than 2 months, SBRT has no significant benefit. These patients should receive the best supportive care or single-fraction EBRT using simple planning techniques [3,4]. For patients with better performance status, the current stage of the cancer (number and extent of other organ involvement, symptoms) and the possibility of treatment should be assessed. If the disease is progressing rapidly and effective systemic treatment cannot be applied quickly, the validity of SBRT may be questionable. For all other patients with spinal metastases, SBRT should be considered. Notably, such treatment can be delivered on most modern linear accelerators without the need for dedicated SBRT or radiosurgery equipment [8].
Treatment algorithms are available in the literature to facilitate an appropriate decision regarding the optimal treatment regimen for spinal metastases, of which SBRT may be a component [9]. The two most commonly used algorithms are those covering neurologic, oncologic, mechanical assessment and systemic treatment options NOMS (neurologic, oncologic, mechanical, and systemic decision framework) and those considering metastasis location, mechanical instability, neurology, oncology, fitness, prognosis and response to prior therapy LMNOP (location of disease in the spine, mechanical instability, neurology, oncology, and patient fitness, prognosis and response to prior therapy framework). A detailed description of the above algorithms is beyond the scope of this paper, but it is worth reading [10,11]. In selected patients with spinal cord compression, an intensive approach that combines separation surgery, spinal stabilisation and postoperative RT could provide a substantial benefit [12]. An example of dose distribution in postoperative spinal SBRT is shown in Figure 1.
Eligibility criteria for SBRT of the spine include 3 or fewer vertebrae to be irradiated; mechanical stability of the spine as assessed by the Spine Instability Neoplastic Score (SINS); mild or absent meningeal compression (according to the Bilsky scale); controlled extra-spinal disease; available systemic treatment options or oligometastatic stage; life expectancy greater than 3 months; KPS >40-50. Patients should not be considered for SBRT if they have: mechanical spinal instability requiring surgical intervention; previous SBRT in the planned volume; EBRT in the planned volume within the last 90 days; increasing neurological symptoms; inability to maintain therapeutic position; spinal canal compression greater than 25% of its volume; contraindications to MR; life expectancy less than 3 months. Attention should be paid to the possible increase in side effects with concomitant use of some cytostatics (e.g., anthracyclines, 5-fluorouracil, busulfan) – a break in their use is required.
Determining target volumes in spinal SBRT is a complex process and, in some cases, requires the collaboration of a radiation oncologist, radiologist and spinal surgeon. Detailed recommendations have been developed by the International Spine Radiosurgery Consortium [13]. Magnetic resonance (MR) imaging with contrast is recommended for treatment planning in the therapeutic position. If this is not possible, a fusion of an available diagnostic MR scan (no more than 2 weeks old) with a computed tomography (CT) scan for treatment planning should be performed, with particular attention to the accuracy of the image fusion. The gross tumour volume (GTV) is determined based on all available imaging studies. The GTV should include the total tumour volume, including the extraperiosteal component and the part compressing the meningeal sac (in the spinal canal), as seen on CT and MR. The determination of the clinical target volume (CTV) is complex and based on dividing the vertebral surface into six sectors. Depending on the location of the metastasis, the CTV includes the entire GTV and the relevant parts of the vertebral body (bone margin), most commonly the segment affected by the tumour and adjacent segments. If the metastasis involves only bony parts, the elective extraperiosteal margin is not included in the CTV. If an extra-periosteal component and an intra-canal part are present, they should be included in the CTV, but there is no consensus on a possible elective margin. Inclusion of the entire periphery of the vertebral canal in the CTV should be avoided, except in situations where the tumour involves all bony parts of the vertebra or where circular infiltration of the epidural space is suspected. The planned target volume (PTV) is obtained by adding a margin to the designated GTV and/or CTV volumes, usually not exceeding 2-3 mm due to the assumed low intra-fraction mobility and imaging control at each fraction.
The PTV should be reduced by the spinal cord volume with a margin of error (planning organ at risk volume, PRV). The PRV is calculated by adding a margin of 1-2 mm to the planned volume of the spinal cord or, if the metastasis is in the lower lumbar spine or sacrum, the cauda equina. In addition to the elements of the nervous system, the volume of any critical organs typical of the site, e.g. lung, kidney or bowel volumes, should be determined. The dose may be prescribed to the mean PTV, isodose or reference point, depending on centre experience and institutional protocols. Planning using dynamic techniques (dose-intensity modulation) is recommended. Arc techniques have the added advantage of a shorter exposure time, which reduces the risk of inadvertent movement during fractionation and improves patient comfort. It is recommended that the time from imaging, treatment planning and delivery of the first fraction should not exceed 2 weeks. The use of image-guided RT (IGRT) techniques in the form of daily verification of the correct positioning of the patient on the treatment table is essential for proper treatment delivery. It is preferable to use cone beam computed tomography or, if this is not available, orthogonal two-dimensional radiography. Several fractions for the treatment of spinal metastases have been described in the literature, ranging from regimens with a single administration of the entire prescribed dose to multifraction regimens with total treatment times of up to two weeks. A regimen that combines the elective dose used in EBRT with simultaneous dose escalation to levels typical of SBRT is an interesting option. This approach is currently being investigated in a randomised phase II clinical trial (NCT02800551) [14].

Non-spinal bone metastases
The significant improvement in cancer survival associated with systemic treatment and the identification of new stages of cancer with the prefix oligo-, has prompted the search for local treatment modalities that offer higher local efficacy (“local cure”) than palliative-dose EBRT and are less invasive than classical surgery. SBRT of extra-spinal bone metastases allows very high local efficacy (around 90%) with minimal toxicity. Data from randomised phase II clinical trials suggest a benefit in terms of better pain control after SBRT compared with patients treated with conventional EBRT [15]. However, there are currently no results from well-designed phase III clinical trials that show a clear advantage of SBRT over EBRT or other local treatments for bone metastases [16]. The data available to date do not allow us to clearly identify the group of patients who would benefit most from SBRT. It should be considered primarily in patients with a limited number of metastases and with minimal progression of individual bone foci during previously successful systemic treatment. In 2019, an expert consensus was published for the first time on the characterisation and classification of the oligometastatic stage in a range of possible clinical scenarios, including in patients receiving systemic treatment [17]. It can be a very useful tool in the current assessment of the cancer stage, to define it correctly and to help select the group of patients who will benefit most from SBRT. In contrast to SBRT of the spine, there are no strict and absolute contraindications to this method for non-spinal BM. Preparation for treatment consists of selecting appropriate immobilisation and performing CT for treatment planning. In the case of lesions in the ribs, it is essential to consider the choice of mobility control method. It is helpful, but not mandatory, to perform other imaging studies (MR, PET/CT) to better assess the possible soft tissue component and bone marrow infiltration in long bones. GTV represents the tumour as visualised by the available imaging studies (taking into account the bone window), the area of the tumour lesion in the bone and the possible soft tissue component and bone marrow infiltration. CTV is controversial. Due to the structure and physiology of bone, there are no methods to optimally determine the risk of microscopic disease. On the other hand, CTV of the entire bone volume would exceed the applicability of SBRT in most cases. The decision should be made on a patient-by-patient basis. For SBRT of non-spinal BM, no clear advantage of any fractionation regimen has been demonstrated [18]. Dose constraints and potential toxicity depend on the location of the treated BM.

Pathological fractures
Pathological fractures affect both spinal and non-spinal bones and can significantly impact a patient’s performance status and quality of life [19]. Preceding fracture, a vulnerable lesion may cause pain or discomfort, potentially indicating an impending fracture. Once a pathological fracture occurs, the patient typically experiences increased pain and a noticeable deformity of the fractured bone or kyphosis of the spine [20]. In extremity fractures, this may include shortening or deformity. Fractures of weight-bearing bones may leave the patient unable to walk. Pathological fractures in long bones are frequently found in the femur, tibia, and humerus.
It is crucial to identify metastatic lesions at a high risk of fracture to ensure timely preventive fixation. Mechanical stability of the spine can be assessed using the SINS scale described above [21,22]. The Mirels scoring system is a useful tool for assessing fracture risk in long bones [23]. This system incorporates four criteria (clinical and radiographic), with each criterion assigned a weight of one to three points. The total score corresponds to the fracture risk and provides recommendations for preventive surgical treatment. A score of 9 or higher indicates an impending pathologic fracture, warranting prophylactic stabilisation. A simpler and more clinically practical predictor of fractures involves assessing the presence of 30 mm of axial cortical involvement on plain radiography in femoral BM, along with an increase in pain.
Treating a patient with a threatened fracture depends on several factors, including fracture location, tumour histology, patient’s general health and expected survival. In general, a multidisciplinary approach with surgical stabilisation followed by postoperative RT is recommended as the primary treatment option, especially for fractures in weight-bearing bones [24,25]. The choice of surgical fixation method should take into account the patient’s estimated survival, as the chosen treatment should be durable for the remainder of the patient’s life [26,27]. The recovery time after surgery should also be considered in relation to the patient’s estimated survival time. Tumour progression can occur after surgery without any additional treatment. Postoperative RT plays a role in eliminating residual tumours, preventing disease progression, and addressing further osteolysis. Two retrospective studies have shown that postoperative RT combined with surgery, leads to significantly better recovery of normal functional status compared to RT alone [28,29].
For patients with chemosensitive tumours who are about to undergo chemotherapy (e.g., myeloma and lymphoma), or those with poor performance status and limited prognosis, non-surgical treatment options such as RT, chemotherapy or a combination thereof should be considered, even for fractures in weight-bearing bones [30].

Summary and conclusions

Multidisciplinary management plays a crucial role in the treatment of BM. Several important conclusions can be drawn regarding the multidisciplinary management of bone metastases:
1. Individualised treatment plans: The choice of treatment should be tailored to each patient, taking into account factors such as the site of metastasis, tumour histology, general health and estimated survival. A personalised treatment plan can help optimise outcomes and minimise unnecessary interventions.
2. Surgical stabilisation: Surgical stabilisation followed by postoperative RT is often recommended for spinal and weight-bearing BM. The choice of surgical fixation method should consider the patient’s estimated survival and recovery time to ensure that the chosen treatment provides long-term durability.
3. Role of postoperative RT: Postoperative RT plays a vital role in eliminating residual tumours, preventing disease progression and relieving pain. It also helps to reverse inflammation resulting from bone metastases and promote the recalcification of lytic lesions.
4. SBRT: modern high-dose and precise RT enables excellent local control with acceptable toxicity. It should be offered to patients who require more intensive systemic treatment.
5. Risk assessment: Several risk factors and scoring systems exist to assess fracture risk in BM. However, caution should be exercised as no universally accepted gold standard has been defined. Risk estimates should be interpreted in conjunction with clinical judgement and individual patient factors.
6. Need for further research: There is a need for further research to improve our understanding of bone metastases and treatment approaches. Areas of interest include validation and refinement of scoring systems, exploration of novel therapeutic options, and assessment of long-term outcomes and quality of life in patients undergoing multidisciplinary management.

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