Local external beam radiotherapy

Local external beam radiotherapy is a reliable and effective modality for treating bone metastases. It is an outpatient treatment and is generally well tolerated. The definition of response to radiotherapy varies, however there are consistent reports of partial response rates (improvement in pain) of approximately 70–80% and complete responses in 30–40%. This can significantly improve a patient’s quality of life.

Many different radiotherapy fractionation schedules have been reported. In the UK, a single 8 Gy fraction is recommended. There is significant evidence that demonstrates that shorter fractionation schedules are as effective as longer schedules in controlling pain. Single fraction treatment is far easier on a frail patient. The need for retreatment is slightly higher in the shorter schedules and the greater the dose per fraction, the higher the risk of significant late toxicity, but the relevance of this depends on individual prognosis. If a single fraction is prescribed, the standard dose is 8 Gy, however there is evidence of efficacy for single doses as low as 4 Gy. Longer schedules may be considered for example if there is soft tissue associated with a bone lesion or significant fracture risk – 20 Gy in five fractions is commonly used in this scenario.

Radiotherapy to bone metastases is well tolerated especially in long bones where there is little normal tissue to be damaged. If large volumes of the pelvis or thoraco-lumbar spine are treated, acute toxicity from the small bowel may cause nausea and diarrhoea, and one needs to look out for myelosuppression due the large amount of bone marrow in the treatment field. ‘Pain flare’ – a temporary increase in pain shortly after radiotherapy – is reported from 2% to 44% and this is observed both with single and multi-fraction regimes.

Large metastatic lesions involving the cortex, particularly in weight-bearing bones should be considered for prophylactic fixation if the patient has a reasonable prognosis, as they pose a significant risk for pathological fracture ( Figure 1 ). Mirels’ score can be used as a guide in this situation. Postoperative radiotherapy is then recommended.

Lateral view of femur showing bone metastasis at risk of fracture.

Patients may present with a pathological fracture as their first manifestation of malignancy and it is always important to send a biopsy rather than bone reamings for histological diagnosis. Even when a patient is known to have a malignancy, biopsy is good practice at the time of surgery as additional information may be gleaned on the tumour to help guide further treatment options.

Bone metastases are frequently multiple and patients may complain of pain that is not easily localized. Hemi-body irradiation has been used to treat multiple sites in one radiotherapy field with good improvement in pain control however acute toxicity can be a problem with large volumes of irradiated tissues. The role of hemi-body irradiation has diminished significantly over recent years particularly as radiopharmaceuticals are now available which tend to have fewer gastrointestinal and bone marrow toxicities.

Stereotactic radiotherapy

Stereotactic radiotherapy (SBRT) involves the delivery of high doses of radiotherapy to precise targets whilst minimizing dose to adjacent normal structures. It is delivered in one or a small number of fractions. It can be useful for treating spinal metastases due to the sensitivity of normal surrounding tissues to radiation and the concern regarding late toxicity as a result of this. Those tumours that are traditionally radioresistant such as melanoma or renal carcinomas may also benefit from this technique and those patients who require re-irradiation. SBRT is now widely available and it can be of great use in oligometastic disease with local control rates of 80% and improvement in overall survival. ^,

Radioisotopes

Radium 223 ( ²²³ Ra) is an α particle-emitting agent that selectively binds to areas of high bone turnover and emits short-range α particles of high energy. These cause breaks in DNA with the drug preferentially targeting areas of osteoblastic activity. The ALSYMPCA trial randomized over 900 patients with symptomatic bone metastases from prostate cancer to receive either ²²³ Ra or placebo alongside best supportive care. Those patients who received ²²³ Ra had an improved overall survival, longer time to first skeletal event and were less likely to need external beam radiotherapy for bone pain or spinal cord compression. It is associated with low rates of myelosuppression and few adverse events. ^, It is recommended for hormone refractory prostate cancer with symptomatic bone (only) metastases. Radiopharmaceuticals need to be prescribed by radiation oncologists who are experienced with their use and the associated radioprotection issues.

Bisphosphonates in specific tumours

Breast cancer: approximately 70% of patients with advanced breast cancer will develop bone metastases. They are predominantly osteolytic but osteoblastic metastases may also be present. Untreated, 50% of these patients will have an SRE, 40% will sustain a pathological fracture and an even greater percentage will have problems with severe pain.

A Cochrane review reported a 17% reduced risk of SRE and a delay in median time to first SRE in patients taking bisphosphonates as secondary prophylaxis in bone metastases. There was no benefit seen in overall survival in patients taking bisphosphonates. Intravenous pamidronate, zoledronic acid and ibandronate and oral ibandronate have all been shown to reduce SRE.

Myeloma is a malignancy of plasma cells which is characterized by osteolytic bone destruction throughout the skeleton resulting in pain, pathological fractures and hypercalcaemia. Interleukins 1 and 6, tumour necrosis factor and receptor for activation of nuclear factor kappa B ligand are all cytokines produced by the myeloma cells and the stroma of the bone marrow. These cytokines help stimulate osteoclastic resorption of bone without accompanying bone formation leading to purely osteolytic metastases.

Time to first SRE and percentage of patients sustaining a SRE can be significantly reduced in patients receiving a bisphosphonate (41% placebo vs 24% treated with pamidronate). Bone pain can be significantly reduced with pamidronate but it does not alter overall survival.

The incidence of osteonecrosis of the jaw is higher in myeloma patients compared to patients with other malignancies receiving bisphosphonates. Zoledronic acid is perceived to have a higher risk of osteonecrosis of the jaw than other bisphosphonates and choice of bisphosphonate should be individualized.

Prostate cancer: skeletal metastases from prostate cancer are usually osteoblastic. It was initially thought that purely osteoblastic (sclerotic) bone metastases would not respond to bisphosphonates. It is now known that there is an element of increased bone resorption also, in metastatic prostate cancer. There is conflicting evidence as to the usefulness of bisphosphonates in metastatic prostate cancer but they can be considered if radiotherapy has been ineffective or is contraindicated. Zoledronic acid has demonstrated clinical benefit in reducing SRE in this patient group. Compared to placebo, intravenous doses of zoledronic acid every 3 weeks reduced the risk of SRE by 11% and significantly prolonged the time to first SRE by 5.5 months.

Osteosarcoma

There are two peaks in the age-related incidence of osteosarcoma. The first and largest is in adolescents and young adults and a second smaller peak in older adults. Teenagers and young adults should be offered treatment in an oncology centre where there is a specialized teenage and young adult oncology service to provide physical, psychological and social support. For some patients this may mean travelling a significant distance.

Histologically, 90% will be conventional osteosarcoma, predominantly osteoblastic. Until the 1970s surgical resection, which usually meant amputation, was the sole radical treatment for osteosarcoma. Despite good local control, 80–90% of patients subsequently died of metastatic disease. This was due to subclinical micro-metastases at the time of presentation and therefore a systematic approach to treatment is required, i.e. patients need chemotherapy as well as surgery to improve survival.

Neo-adjuvant chemotherapy is advantageous to treat micro-metastatic disease, and it potentially may shrink the tumour making surgery easier, and chemotherapy may sterilize the surgical bed making contamination less of a concern at the time of surgery. It also allows time for a customized endoprosthesis to be made. A possible risk of neoadjuvant chemotherapy however is that it delays definitive treatment and if the cancer does not respond to chemotherapy a potentially curable cancer may become inoperable or a potentially salvageable limb becomes unsalvageable.

Neoadjuvant chemotherapy also allows an in-vivo drug trial to determine the chemosensitivity of the tumour. A good response, currently defined as 90% or greater tumour cell necrosis, indicates a 5-year survival between 70% and 80%. In patients with less tumour necrosis the 5-year survival rate is significantly lower at 45–60%.

Currently the standard treatment for patients with localized high-grade osteosarcoma is two to three cycles of cisplatin, doxorubicin and high-dose methotrexate (MAP regime) followed by limb-preserving surgery, followed by a further three or four cycles of the same chemotherapy. The benefit of adding in high-dose methotrexate seems to be greater in younger patients. This combination chemotherapy is a highly toxic regimen which needs to be given as an inpatient via a central line.

The EURAMOS trial was a multinational phase 3 RCT which tried to address two points: whether changing chemotherapy drugs in those with less than 90% tumour necrosis after neo-adjuvant cisplatin and doxorubicin improves survival and can maintenance Interferon improve survival. Outcome data suggest that neither alteration in treatment improved event-free survival. ^,

Postoperatively the immune stimulant muramyl-tripeptide (mifamurtide) has shown an improvement in overall survival but strangely not disease-free survival. It is NICE approved in the adjuvant setting alongside standard multi-agent chemotherapy for patients aged 2–30.

Osteosarcoma is a relatively radioresistant malignancy and as a result radiotherapy has a very small role in the treatment of this cancer. The only indication for adjuvant radiotherapy is after an incomplete surgical resection when further surgery is not possible. Also palliative radiotherapy may be given for pain control.

The most common sites of metastases in osteosarcoma are lung and bone. The presence of bone metastases confers a poor prognosis. The only potential for long-term survival for patients with lung metastases is metastasectomy and chemotherapy, and this should at least be considered in all patients with disease confined to the thorax. The number of metastases resected depends on the distribution of the lesions and the underlying lung function. Five-year survival of 30% can be obtained with this multimodality approach. Radiofrequency ablation (RFA) is an alternative method for treating lung metastases and has been used in sarcoma patients with good results. It is a minimally invasive technique using thermal energy, which is used when surgical resection is not an option.

Overall, patients who relapse early (<2 years, at any site) after initial therapy do worse than those with a longer disease-free interval (>5 years), with those relapsing within 6 months having the poorest prognosis.

In patients with unresectable disease at presentation, treatment is with palliative intent and options include chemotherapy with various drug combinations, palliative radiotherapy for bone or lung metastases, or consideration of early phase trials. Phase 1 trials are trials designed to assess new drugs and establish their maximum tolerated dose in humans. They may or may not be specific for sarcoma patients. Phase 2 studies are more likely to be specific for a certain malignancy and are to establish early efficacy data for the drug. Patients need to be in good performance status for these trials and they often require multiple hospital visits and investigations.

Ewing’s sarcoma

Ewing’s sarcoma is the second commonest primary bone malignancy in childhood and adolescence. Treatment in a specialist paediatric or teenage and young adult department is important as in osteosarcoma. Ewing’s sarcoma is a tumour that has arisen from the neural crest and belongs to the small round blue cell family of tumours. The diagnosis can be confirmed by cytogenetic testing. Non-random chromosomal translocations involving the EWS gene on chromosome 22 cause fusion genes encoding transcription factors and thus promote cell replication and tumourogenesis. In 85% of cases it is a (11:22) translocation resulting in the gene fusion of EWS and FLI1.

Ewing’s sarcoma is a systemic disease. Without systemic treatment more than 90% of patients die from metastatic disease. Aggressive chemotherapy has increased survival rates to 55–65% for local disease and up to 35% in primary metastatic disease. The actual treatment a patient receives depends on the site of the primary and the presence and distribution of any metastatic disease. Most patients’ treatment will begin with a course of induction chemotherapy. The EE2012 trial established the alternating 2 weekly VDC/IE (vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide) regime as first-line chemotherapy.

If patients have localized operable disease, then they will have surgery and or radiotherapy followed by further chemotherapy, e.g. nine cycles VDC/IE preoperatively and five cycles postoperatively. Ewing’s sarcoma is a far more radiosensitive tumour than osteosarcoma and most soft tissues sarcomas. Postoperative radiotherapy is given if there are positive surgical margins but consideration needs to be given to the site of disease and the long-term effects of radiation on growing bones and the risk of second malignancies. Preoperative radiotherapy may also be considered. If the position of the primary tumour makes surgery impossible then radiotherapy alone without surgery can be used as radical treatment to the primary.

Given the often young age of patients, and possible critical sites of disease, proton therapy should be considered to help deliver effective dose to the tumour or tumour bed, whilst limiting dose to normal tissues which reduces late toxicity.

Patients with metastatic disease at presentation have a worse prognosis with 5-year survival of 20–30%. The prognosis depends on the site of metastases with lung only metastases doing better than those patients who have bone, bone marrow or other metastatic sites. Patients with lung metastases who respond well to chemotherapy should have their primary tumour treated radically and then receive low-dose irradiation to their whole lungs.

Chondrosarcoma

Chondrosarcomas are a heterogeneous group of malignant bone tumours that produce a cartilaginous matrix and commonly affect the long bones and pelvis. They account for 25–30% of primary bone malignancies and are seen most in adults over age 40. Approximately 90% are low or intermediate grade and are treated by surgical management alone. The conventional high grade and rarer mesenchymal chondrosarcomas have a high metastatic potential and less than 30% 10-year survival. The latter can also present as an extraskeletal tumour. For all grades of non-metastatic chondrosarcomas surgery offers the only potential cure. Adjuvant radiotherapy is recommended for these if surgical excision is incomplete, however a dose above 60 Gy is required. Dedifferentiated chondrosarcomas are highly aggressive and have an additional component of high grade non cartilaginous sarcoma. The prognosis is very poor and patients may be offered neoadjuvant and adjuvant chemotherapy with drugs such as cisplatin and doxorubicin.

Solitary plasmacytoma of the bone

Solitary plasmacytoma is a proliferation of monoclonal plasma cells which usually presents with a bony mass lesion, neurological compression or pain. They are most common in the axial skeleton and vertebrae where they can cause spinal cord compression. Before the diagnosis of solitary plasmacytoma can be made, multiple myeloma needs to be excluded including bone marrow assessment. An MRI of the spine and positron emission tomography-CT should also be done to ensure that the lesion is truly solitary.

These tumours are radiosensitive and should be treated with radical radiotherapy, usual doses are 45–50 Gy ( Figure 2 ). Local control rates are above 90%. Median survival is 10 years, however over half of these patients will go on to develop multiple myeloma usually within 2–5 years, but this can occur 20 years later. There is varying evidence at present regarding the benefit of adjuvant chemotherapy but may be considered for patients with large (>5 cm) plasmacytomas and lack of complete response to radiotherapy.

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