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(iii) Musculoskeletal malignancy – non-surgical management
MINI-SYMPOSIUM: MUSCULO-SKELETAL MALIGNANCY
(iv) The non-surgical management of musculoskeletal malignancy
impacting on the patient’s quality of life and survival. ‘Skeletal Related Events’ (SRE) help to objectively measure the impact of bone metastases and are often chosen as end points in clinical studies. These include pain, pathological fracture, hypercalcaemia, spinal cord compression, necessitating palliative radiotherapy or surgical intervention. Prognosis in patients with bone metastases from breast and prostate cancer can be several years however survival for lung cancer patients is generally measured in months. The aim of palliative treatment for bone metastases should be pain relief, preservation of function and skeletal integrity. There are two main approaches to treatment: 1) Treating the underlying malignancy 2) Palliating the symptoms of SRE Chemotherapy, hormone treatment and biological agents are systemic modalities that can reduce the burden of cancer cells and in some cancers can help improve survival as well as improve symptoms and quality of life by controlling the underlying disease. Simple analgesia, bisphosphonates, radiotherapy, radiological interventions and surgery are treatment modalities to help improve symptoms and quality of life but do not generally reduce the burden of malignancy or improve survival. Treatment is different for each cancer subtype and varies for each individual patient.
Lesley Speed Claire Esler
Abstract Primary musculoskeletal cancers are relatively rare and should be managed by specialist centres which can deliver multimodal, multiprofessional treatment. Patients with localized primary bone or soft tissue sarcomas may be cured but prognosis has to be guarded due to high rates of local recurrence and many are not curable. To reduce patient suffering and maintain quality of life requires a multidisciplinary approach.
Keywords bisphosphonates; bone metastases; chemotherapy; Ewing’s sarcoma; osteosarcoma; radiotherapy; soft tissue sarcoma
Introduction Palliative radiotherapy for bone metastases Radiotherapy can be used in three ways to treat bone metastases: local external beam radiotherapy, hemi-body radiotherapy and radio-pharmaceuticals.
Musculoskeletal malignancies fall into two main categories: 1) Primary malignancy which includes primary bone tumours and primary soft tissue sarcomas. 2) Secondary malignancy i.e. bone metastases. The incidence of metastatic bone disease is far higher than that of both primary bone malignancy and soft tissue sarcomas (STS).1 The treatment of the two groups is vastly different but all patients require a multi-disciplinary approach to diagnosis, treatment and subsequent management. A patient with a musculo-skeletal malignancy, primary or secondary, may require the input of specialist nurses, oncologists, orthopaedic, spinal and plastic surgeons, radiologists, pathologists, palliative care teams, occupational and physiotherapists etc. This review is an introduction to the basic non-surgical, oncological management of bone metastases, primary bone tumours and extremity soft tissue sarcomas.
Local external beam radiotherapy: local external beam radiotherapy is a reliable and effective method of 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 70e80% and complete responses in 30e40%. Many different radiotherapy fractionation schedules have been reported. In the UK a single 8 Gy fraction or 20 Gy in five fractions are the most commonly used schedules. Single fraction treatment is easier on the patient where quality of life is paramount and there is abundant level 1a evidence, including three meta-analyses,3e5 that shorter fractionation schedules are as effective as longer in controlling pain. The need for retreatment however is higher in the shorter schedules and the greater the dose per fraction, the higher the risk of significant late toxicity. If a single fraction is prescribed, the usual standard dose is 8 Gy but there is evidence of the efficacy of single doses as low as 4 Gy. Low doses may be considered when a patient needs retreatment of an area several times which can arise in myeloma.6 There is a tendency for oncologists to prescribe longer fractionation schedules for those patients in whom the prognosis is of survival for several years, as this reduces the need for retreatment and limits late toxicity. As an example of this would be a patient with breast cancer and bone metastases as the only site of metastases. However, there is little evidence to support this practice and for the majority patients, a single 8 Gy fraction is entirely appropriate. It usually takes at least one week before any relief in pain and response may subsequently increase until a plateau is reached at 4e6 weeks. Pain flare, a temporary worsening of pain in an irradiated bone immediately after radiotherapy, may occur.
Metastatic bone disease Bone is the third most common site of metastatic disease after liver and lung. The incidence of bone metastases varies depending upon the primary cancer, occurring in approximately 70% of patients with prostate and breast cancer and 30e40% of patients with lung, kidney and thyroid cancer.2 Bony metastases may be present at diagnosis or become apparent during the disease course. They can cause significant morbidity, adversely
Dr Lesley Speed MBChB MRCP MSc FRCR Consultant Clinical Oncologist, Department of Oncology, Leicester Royal Infirmary, Leicester, UK. Conflict of interest: none declared. Dr Claire Esler BMedSci BMBS MRCP MMedSci FRCR Consultant Clinical Oncologist, Department of Oncology, Nottingham City Hospital, Nottingham, UK. Conflict of interest: none declared.
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antiemetic e.g. ondansetron, and monitoring of a full blood count are usually necessary. The response to HBI is similar to that seen in localized radiotherapy with a 60e70% improvement in pain. In 25% of patients a rapid response to pain is seen within 24 hours.
Reported rates range from 2 to 44% and is seen both with single and multi-fraction regimes.7 Large metastatic lesions involving the cortex of weight bearing bones should be considered for prophylactic fixation as they pose a significant risk for pathological fracture. This should be followed by radiotherapy. 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 arising from concomitant exposure of the small bowel may cause nausea and diarrhoea, and myelo-suppression due the large amount of bone marrow in the treatment field may occur. There are varying opinions about what volume should be irradiated after a long bone has had surgical fixation. One argument is to irradiate the entire long bone on the basis that the marrow cavity may have been contaminated with tumour cells at the time of surgery. The alternatives are to only irradiate the metastasis or the prosthesis plus a margin as this is the area most at risk of residual tumour and hence recurrence. A single 8 Gy fraction is usually appropriate post-operatively. In patients with a very poor life expectancy and deteriorating condition surgery may be inappropriate and palliative radiotherapy alone may help to reduce pain and aid healing even once fracture has occurred. Patients may present with a pathological fracture as their first manifestation of malignancy and it is always important to send bone reamings for histological diagnosis. Even when a patient is known to have a malignancy occasionally a second malignancy is identified and this may alter future treatment decisions.
Radio-pharmaceuticals: strontium 89 (89St) is a bone targeting radioisotope which, when administered intravenously, localizes to areas of osteoblastic bone activity.10 It is a beta-emitting radioisotope with a half-life of 50.5 days. Prostate cancer patients with widespread, predominantly osteoblastic metastases have historically been those to receive this therapy. It is used to treat pain not controlled by other treatments. The onset of pain relief occurs seven to 20 days after injection. Doses can be repeated after three months. 89St can cause significant bone marrow toxicity and should not be given to bone marrow suppressed patients. Its myelo-suppressive nature and cost have limited its use in the UK. It has not shown any improvement in survival. Radium 223 (223Ra) is an alpha particle emitting agent which appears to have more clinical benefit than 89St. It selectively binds to areas of high bone turnover and emits high energy short range alpha particles. These cause breaks in DNA with the drug preferentially targeting areas of osteoblastic activity.11 The ALSYMPCA trial randomized over 900 patients with symptomatic bone metastases from prostate cancer to receive either 223Ra or placebo alongside best supportive care. Those patients who received 223Ra had an improved overall survival of three and a half months to 14.9 months. They also had 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 myelo-suppression and few adverse events.11
Stereotactic body radiotherapy: stereotactic body radiotherapy (SBRT) is a special method of external beam radiotherapy using high doses to precise targets whilst minimizing the dose to adjacent normal structures. It is delivered in one or a small number of fractions. It is particularly useful in the treatment of spinal metastases causing spinal cord compression due to the sensitivity of normal surrounding tissues to radiation and consequent concern with regard to late toxicity. Tumours that are traditionally radioresistant such as melanoma or renal carcinomas may also benefit from this technique and patients who require re-irradiation.8 SBRT is not yet in routine use nor is it funded in the UK for treatment of metastatic disease as it is still under investigation.
Bisphosphonates Bisphosphonates are a group of compounds that are stable analogues of naturally occurring inorganic pyrophosphate. They are potent inhibitors of osteoclast-mediated bone resorption by affecting differentiation and maturation of osteoclasts and also they also have a direct apoptotic effect on osteoclasts. Bisphosphonates also have a direct effect on cancer cells by inhibiting tumour cell invasion and adhesion to bone matrix. In animal models bisphosphonates can inhibit the development of bone metastases. There are ongoing trials in humans looking at their role in preventing bone metastases. There are three generations of bisphosphonates available, from first generation clodronate to second generation pamidronate and more recently third generation zoledronic acid and ibandronate. With succeeding generations of bisphosphonates the in-vitro potency significantly increases. Many studies have confirmed the effectiveness of bisphosphonates in treating hyper-calcaemia of malignancy and in preventing skeletal related events in patients known to have bone metastases (secondary prophylaxis). Most supportive evidence is for patients with breast cancer, multiple myeloma and prostate cancer. (Table 1). A systematic review by Ross et al.12 included 21 randomized controlled trials (RCTs) of patients with bone metastases from myeloma and solid malignancies, predominantly breast and prostate cancer. Primary end-points were time to first SRE and
Hemi-body irradiation (HBI): bone metastases are frequently multiple and patients may complain of poorly localized pain that flits around. Attempts to ‘chase’ the cause of pain may lead to multiple localized radiotherapy treatments with unsatisfactory results. HBI can be an alternative option for such patients. HBI was traditionally considered as upper or lower hemi-body radiotherapy with the ‘cut off’ at the umbilicus. Today it is planned as a large field of external beam radiotherapy covering the areas of painful bone metastases either in the upper or lower body. A typical linear accelerator will be able to produce a radiation field size of 40 40 cm. Treatment to the upper hemibody is 6 Gy in a single fraction and to the lower hemi-body is typically 8 Gy in a single fraction. HBI has also been shown to delay the appearance of new painful bone metastases in the treatment field.9 When treating large volumes with radiotherapy, acute toxicity can be a major problem especially gastrointestinal toxicity and bone marrow toxicity. Prophylactic 5HT3 antagonist
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MINI-SYMPOSIUM: MUSCULO-SKELETAL MALIGNANCY
Bisphosphonates are considered the normal standard of care for breast cancer patient with bone metastases who have a reasonable prognosis. Grade 1 evidence from five RCTs and three systematic reviews conclude that bisphosphonates reduce the risk of predefined SRE. 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.13 However, there was no improvement in overall survival. Intravenous pamidronate, zoledronic acid and ibandronate and oral ibandronate have all been shown to reduce SRE. Recent NICE guidelines for advanced breast cancer are that bisphosphonates should be considered for patients with newly diagnosed bone metastases to prevent SRE and reduce pain, but do not make recommendations on which bisphosphonate to use.
Drugs that reduce skeletal related events in metastatic bone disease Primary tumour Bisphosphonate
Breast
Prostate
Myeloma
Other solid tumours
Pamidronate Zoledronic acid Ibandronate Denosumab
þ þ þ þ
þ e þ but not approved
þ þ þ but not approved
þ þ
Table 1
reduction in skeletal morbidity. It did not assess pain relief. The risk of developing an SRE e.g. vertebral fracture or hypercalcaemia was significantly improved compared with patients receiving radiotherapy. There was no benefit seen with regards to spinal cord compression. Time to SRE was also reduced with bisphosphonates. The review concluded that patients needed to be on bisphosphonates for at least 24 months before there was a significant reduction in the need for orthopaedic surgery, twelve months before hyper-calcaemia and non-vertebral fractures were reduced, and six months before there was a reduction in the need for radiotherapy. Studies giving less than six months of bisphosphonates showed no significant benefit in any end-point. Treating patients with a prognosis of less than six months, is probably therefore not beneficial or cost-effective. Evidence for the use of bisphosphonates for pain control from bone metastases is inconsistent. Several trials support the effectiveness of these drugs in providing some pain relief for bone metastases but there is insufficient data to recommend them as first line treatment. There is insufficient data to conclude which bisphosphonate was most efficacious for pain or to say which primary tumour type benefits most. Bisphosphonates are generally well tolerated but do cause acute phase reactions including nausea and electrolyte imbalances. They can also cause osteonecrosis of the jaw and patients must be counselled accordingly and consideration made of any dental treatment that may be needed before or during treatment. One of the major difficulties in comparing the results of trials that look at different treatments for bone metastases is the varying primary end-points and inconsistent timings of these events. Biochemical surrogate markers have therefore been sought to try and make assessment more objective. Urinary and blood markers of bone remodeling can be useful in the assessment of bisphosphonates efficacy.
Bisphosphonates in myeloma Myeloma is a malignancy of plasma cells characterized by osteolytic bone destruction throughout the skeleton resulting in pain, pathological fractures and hyper-calcaemia. Cytokines such as interleukins and tumour necrosis factor produced by the myeloma cells and the stroma of the bone marrow stimulate osteoclastic resorption of bone without accompanying bone formation leading to purely osteolytic metastases. For patients with at least one lytic bone lesion, four-weekly Pamidronate in addition to chemotherapy is recommended. Berensen et al. reported that the time to first SRE and the number of patients sustaining an SRE were significantly reduced for those receiving a bisphosphonate (41% of patients in the placebo group versus 24% in the pamidronate group).14 Bone pain was significantly reduced with pamidronate but there was no difference in overall survival between the two groups. 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 recent guidelines from the USA have recommended against the use of zoledronic acid in myeloma patients. Bisphosphonates in prostate cancer It was initially thought that purely osteoblastic (sclerotic) bone metastases would not respond to bisphosphonates. Skeletal metastases from prostatic cancer are usually osteoblastic but it is now known that there is an element of increased bone resorption in metastatic prostate cancer. This probably explains the response seen to zoledronic acid which is the only bisphosphonate that has been demonstrated to confer clinical benefit in reducing SRE in this patient group.15 Compared to placebo, three weekly intravenous doses of zoledronic acid reduced the risk of SRE by 11% and significantly prolonged the time to first SRE by 5.5 months.
Bisphosphonates in breast cancer Approximately 70% of patients with advanced breast cancer will develop bone metastases. They are predominantly osteolytic but some may be osteoblastic. 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. Systemic treatment options for metastatic breast cancer patients with bone metastases include analgesia, hormone treatments, chemotherapy, biological agents e.g. trastuzumab, and bisphosphonates.
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Bisphosphonates in other solid malignancies There is less evidence about the efficacy of bisphosphonates in other types of malignancy. In the UK only patients with breast, prostate cancer and myeloma patients are routinely prescribed bisphosphonates. However, a large RCT comparing zoledronic acid with placebo in patients with metastases from lung, renal and a variety of other primary cancers concluded that zoledronic acid was beneficial.16 A significantly lower proportion of patients
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receiving zoledronic acid had an SRE and in those that did, there was a longer time to first SRE. Based on these data, zoledronic acid is the only bisphosphonate to have worldwide regulatory approval for patients with bone metastases from solid tumours other than breast cancer.
theoretical, benefits of neo-adjuvant chemotherapy are that micro-metastases can be treated earlier, the tumour may shrink making surgery easier, and chemotherapy may sterilize the surgical bed making contamination less of a concern at the time of surgery. The risks of neo-adjuvant chemotherapy are that it delays definitive treatment and if the cancer does not respond to chemotherapy a potentially curable cancer may become inoperable. Neo-adjuvant chemotherapy also allows an in vivo drug trial to determine the chemo-sensitivity of the tumour. A good response, defined as 90% or greater tumour cell necrosis, indicates a five year survival between 70 and 80%. In patients with less tumour necrosis the 5 year survival rate is significantly lower at 45e60%. The POG trial 8651 randomized patients with high grade osteosarcoma to surgery and adjuvant chemotherapy or 10 weeks of neo-adjuvant chemotherapy followed by surgery. There was no statistically significant difference between five year recurrence-free survival in the two arms: 65% for the adjuvant arm versus 61% in the neo-adjuvant arm.18 Currently the standard treatment for patients with localized high grade osteosarcoma is two/three cycles of cisplatin and doxorubicin and high dose methotrexate (the 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 is controversial although there seems to be more benefit in younger patients. This is a highly toxic regimen which needs to be administered as an inpatient via a central line (Table 2). The recent 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 (randomized to continue Cisplatin/Doxorubicin or switch to Ifosfamide/Etoposide), and whether maintenance Interferon improves survival (patients with good response randomized to two years of Interferon or observation.) The only data available so far is from an analysis of the 715 patients in the ‘good response’ arm which showed the addition of Interferon to MAP did not confer a statistically superior event free survival (77 vs 74%).19 The benefit of adding a fourth drug to the MAP combination pre-operatively has not yet been established. There may be some increased response rates but at the cost of increase toxicity and as yet no benefit in survival. Post-operatively the immune stimulant muramyl-tripeptide (Mifamurtide) has shown an improvement in overall survival but strangely not disease free survival.20 It has been granted a European license and is now NICE approved in the adjuvant setting alongside standard multi-agent chemotherapy. Osteosarcoma is relatively radio-resistant, thus radiotherapy has a very small role in its treatment. The only indication for adjuvant radiotherapy is after an incomplete surgical resection where further surgery is not possible when 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 is indicative of a poor prognosis. The only potential for long term survival for patients with lung metastases is metastatectomy and chemotherapy and this should be considered in all patients with
New agents to treat bone metastases Denosumab is a fully humanized monoclonal antibody that binds to and neutralises RANK (Receptor Activator of Nuclear Factor kB) ligand, resulting in inhibition of osteoclast function and bone resorption. It is given as a subcutaneous injection every four weeks. Combined analyses of three large randomized trials examining Denosumab in metastatic bone disease has shown superiority compared to zoledronic acid with increased time to first (on study) SRE by 8.2 months and reducing the risk of developing an SRE by 17%. It is well tolerated but does cause more hypocalcaemia than bisphosphonates.17 It has now been approved by NICE for use in metastatic bone disease where a bisphosphonate would otherwise be considered (other than prostatic).
Primary musculoskeletal tumours Malignant primary bone and connective tissue tumours are rare, accounting for about 1e2% of all new cancers diagnosed in the UK annually. In England all patients presenting with a suspected primary bone sarcoma should be referred to a specialist bone sarcoma centre for their surgical treatment. Less than 0.2% of all cancers are primary bone malignancies. The most common is osteosarcoma, then chondrosarcoma and Ewing’s disease. In 2011 there were 559 new cases in the UK of primary bone sarcoma and there were 3272 new diagnoses of soft tissue sarcomas. In comparison, there were over 50 000 new cases of breast cancer and 43 000 new lung tumours.1 The treatment of soft tissue sarcoma is very different from the treatment of primary bone tumours and the treatment of each subtype of sarcoma is different. For the purposes of this review the main principles for the more common tumours will be discussed. Osteosarcoma There are two peaks in the age-related incidence of osteosarcoma. The first is in adolescents and young adults and there is a second smaller peak in older adults. Teenagers and young adults (under 24) should be offered treatment in an oncology centre with a specialised teenage and young adult oncology department to provide physical, psychological and social support. For some patients this may mean travelling a significant distance. Until the 1970s surgical resection, which usually meant amputation, was the sole radical treatment for osteosarcoma. Despite good local control, 80e90% of patients subsequently died of metastatic disease, due to subclinical micro-metastases present at presentation. Thus a systemic approach to treatment is required with chemotherapy in addition to surgery to improve survival. Uncertainty remains as to whether pre-operative (neo-adjuvant) or post-operative (adjuvant) chemotherapy is superior. Neo-adjuvant chemotherapy became popular as limb salvage surgery was introduced to give patients treatment while allowing time for a customized endo-prosthesis to be made. Other,
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MINI-SYMPOSIUM: MUSCULO-SKELETAL MALIGNANCY
Toxicities associated with chemotherapy regimes used to treat sarcoma patients Doxorubicin
Doxorubicin and ifosfamide
Sarcoma type STS STS Common toxicities Nausea, vomiting, mucositis, As doxorubicin þ CNS toxicity alopecia, myelosuppression, diarrhoea, fatigue, skin necrosis, nail changes
Rare but serious toxicities
Cardiotoxicity, infertility, liver toxicity
Doxorubicin and cisplatin
Osteosarcoma Nausea, vomiting, mucositis, alopecia, myelosuppression, diarrhoea, renal impairment, hearing loss, peripheral neuropathy, nail changes, fatigue, skin necrosis þ bladder, renal and liver toxicity, Cardiotoxicity, infertility, infertility, second malignancy liver toxicity
VIDE Ewings Nausea, vomiting, mucositis, alopecia, myelosuppression, diarrhoea, constipation, fatigue, skin necrosis, nail changes, CNS toxicity Cardiotoxicity, infertility, bladder, renal and liver toxicity. Second malignancy
Table 2
depends on the site of the primary and the presence and distribution of any metastatic disease. Most patients’ treatment will consist of six cycles of in-patient vincristine, ifosfamide, doxorubicin and etoposide (VIDE). If there is localized operable disease, then the treatment is surgery and or radiotherapy followed by further chemotherapy. If there is more than 90% necrosis of the tumour after initial chemotherapy, the prognosis is improved which is similar in principle to osteosarcoma. Further chemotherapy decisions are dependent on the degree of tumour necrosis. Ewing’s sarcoma is a far more radiosensitive tumour than osteosarcoma and most soft tissues sarcomas. Lower doses of radiotherapy are needed, usually around 50e55 Gy. Postoperative radiotherapy is given if there are positive surgical margins or <90%necrosis, 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. If the position of the primary tumour makes surgery impossible then radiotherapy alone without surgery can be used as radical treatment to the primary. Patients with metastatic disease at presentation have a worse prognosis with five year survival of 20e30%. 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. Patients with other sites of metastatic disease who respond well to conventional chemotherapy regimens may be considered for high dose chemotherapy with stem cell rescue (i.e. transplant). The evidence to support this approach is small and is currently being reviewed in the ongoing analysis of the international ‘EuroEwings 99’ trial protocol.
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. Radiofrequency ablation (RFA) is a new method to treat lung metastases. It is a minimally invasive technique used when surgical resection is not an option. An electrode is placed into the area to be treated and causes tissue destruction with thermal energy. While good early results have been obtained, there is as yet no evidence from randomized controlled trials comparing RFA to surgery. 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 an unresectable tumour at presentation, treatment is aimed at palliation. Options include various combinations of chemotherapy and palliative radiotherapy for bone or obstructing lung metastases. Patients may be considered for 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 particular malignancy to establish early efficacy data for the drug. Ewing’s sarcoma Ewing’s sarcoma is the second most common primary bone malignancy of childhood and adolescence. Treatment in a specialist paediatric or teenage and young adult department is as important as for osteosarcoma. The tumour arises from the neural crest and is one of the small round blue cell family of tumours. The diagnosis can be confirmed by cytogenetic testing which shows 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 and without systemic treatment more than 90% of patients die from secondary metastases.21 Since the 1970s aggressive chemotherapy has increased survival rates to 55e65% for local disease and up to 35% in primary metastatic disease. Treatment a patient receives
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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 20e27% of primary bone malignancies. Approximately 90% are low or intermediate grade and are treated by surgery alone. High grade and the rarer mesenchymal chondrosarcomas have a high
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grade sarcomas the ten year local recurrence rates were 4% versus 33% in favour of radiotherapy. There was no benefit in overall survival for either low or high grade sarcomas with radiotherapy. Traditionally the standard of care has been adjuvant radiotherapy for patients with either high grade, >5 cm in size or deep tumours. Patients who have positive margins after surgery in whom further surgery is not possible should also receive postoperative radiotherapy. To plan radiotherapy treatment the oncologist needs to outline on a CT planning scan of the site of the original tumour, add a margin for possible subclinical spread, and a margin to allow for patient movement and daily radiotherapy set up error. They need to have the pre-operative imaging, histopathology report, and surgical operation notes. Ideally, the sarcoma surgeon will have placed clips around the tumour bed which can be seen on imaging. It also helps if the oncologist sees the patient preoperatively and can talk to the surgeon after surgery about what the intra-operative appearances of the tumour were to ascertain which margins the surgeon might be concerned about. Patients typically are treated daily, for 6e7 weeks with a dose of 60e66 Gy in 33 fractions. Historically, large volumes of tissue were irradiated with margins of 5e7 cm superiorly and inferiorly to the site of the original tumour. Irradiating such large volumes can cause significant morbidity and there is evidence that local recurrences occur much closer to the initial tumour. The Vortex study was a National Cancer Research Network trial to ascertain whether such large treatment margins are necessary. Results are awaited. There is now an increasing body of evidence to support the use of neo-adjuvant radiotherapy. There are potential benefits from both approaches. An RCT comparing pre- and postoperative radiotherapy was designed to assess differences in the incidence of wound complications.24 The trial was stopped prematurely because of increased acute wound complications in the pre-operative treatment arm. 35% of patients developed wound complications in the pre-operative arm versus 17% in the post-operative arm (p ¼ 0.01). Updated data from this trial however, with a median follow up of 6.9 years show over 90% local control in both arms but the post-operative radiotherapy arm had significantly more patients with late toxicity (86% versus 68%). In the UK now there is a changing emphasis on when to use radiotherapy with much more pre-operative treatment being given particularly for those tumours in the extremities that are radiosensitive such as myxoid liposarcomas. Patients have repeat imaging and then surgery within 6e8 weeks of completing radiotherapy. A post-operative boost of radiotherapy is recommended for those patients who have positive margins after resection. Radiation toxicity varies dependent on the site being treated, the volume being irradiated and a patient’s individual sensitivity to radiotherapy (Table 3). Acute wound complications can generally be managed whilst late toxicities such as loss of subcutaneous tissue and fibrosis are generally irreversible. Patient education and physiotherapy are important to aid recovery after surgery and radiotherapy in order for patients to recover to their maximum potential. With regard to adjuvant chemotherapy there have been many trials showing conflicting results with regards to improvements in Progression Free Survival (PFS) and overall survival. Several meta-analyses and a recent pooled analysis of two large European trials have shown no overall benefit for adjuvant
metastatic potential and less than 30% ten year survival. 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. De-differentiated chondrosarcomas are highly aggressive and have an additional component of high grade soft tissue sarcoma. The prognosis is very poor and patients are offered neo-adjuvant and adjuvant chemotherapy with cisplatin and doxorubicin.22 Solitary plasmacytoma of the bone A solitary plasmacytoma is a proliferation of monoclonal plasma cells which usually presents with a bony lesion, neurological compression or pain. They are most common in the axial skeleton and in the spine they can cause spinal cord compression. Before the diagnosis of solitary plasmacytoma can be made, multiple myeloma needs to be excluded, by bone marrow aspirate, skeletal survey, urine Bence-Jones protein, immunoglobulin levels, serum calcium, renal function and full blood count. MRI of the spine is necessary to confirm that the lesion is truly solitary. These tumours are radiosensitive and should be treated with radical radiotherapy with a dose 45e50 Gy. Local control rates are above 90% and median survival is 10 years. However, over half of these patients will go on to develop multiple myeloma usually within two to five years but even after 20 years. There is no strong evidence at present that adjuvant chemotherapy is of benefit. Primary lymphoma of bone Primary non Hodgkin lymphoma of bone accounts for about 3% of primary bone malignancies. The vast majority are diffuse large B cell lymphomas. Presentation is usually with pain and about half will have a palpable mass secondary to soft tissue around the bone. B symptoms (night sweats, fever and weight loss) may be present. NHL is both chemo- and radiosensitive. Treatment consists of ReCHOP chemotherapy i.e. rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone. Chemotherapy is often followed by radiotherapy to the primary bone site with a dose of 40e45 Gy but treatment is individualized based on extent and site of disease.
Soft tissue sarcoma Soft tissue sarcomas (STS) can occur in any part of the body where there is mesenchymal tissue and there are over 50 different histological types in the WHO sarcoma classification. The non-surgical treatment for the majority of these is similar. For some sub-types such as rhabdomyosarcoma, Gastro Intestinal Tumours (GISTs) and Kaposi’s sarcoma, the treatment is very different and beyond the scope of this article. The goal of treatment for localized extremity STS is a functioning limb without local recurrence. In the 1980s it became clear that wide local excision (limb conservation) and adjuvant radiotherapy could produce local control rates similar to amputation without prejudicing overall survival. Yang et al. randomized patients with STS to adjuvant radiotherapy or not, after wide excision.23 In high grade sarcomas the ten year local recurrence rate was 0% versus 22% in favour of radiotherapy. In the low
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approximately 30e40% but at the cost of considerably more toxicity, the need for inpatient treatment and no benefit in overall survival. In 2007 Trabectedin, a novel DNA binding compound derived from the marine creature Ecteinascidia turbinata, the mangrove tunicate, was licensed for treatment of STS. This was the first newly licensed drug for STS in over 20 years. Studies have shown Trabectedin can stop tumour growth or induce a partial response in 50% of patients with one year survival rates of 50%. It is now commonly used as second line treatment particularly for leiomyosarcomas and liposarcoma. Other drug options include chemotherapy with Gemcitabine based combinations or alone, and Pazopanib, a multi-targeted tyrosine kinase inhibitor that improves PFS compared to placebo by 3 months. Inevitably like most cases of metastatic cancer, patients will deteriorate and need active symptom control and palliative care. Palliative radiotherapy can be very effective in locally advanced STS to control symptoms of bleeding, pain or compression. Occasionally palliative surgery can be a useful treatment for intractable local symptoms.
Comparing neo-adjuvant and adjuvant radiotherapy in STS
For
Against
Pre-op radiotherapy
Post-op radiotherapy
Smaller volume treated Easier to delineate tumour in situ Lower dose of radiotherapy Acute wound complications Delay in definitive treatment
Known histology Already had definitive treatment
Late toxicity impacting on function
Table 3
chemotherapy.25 In the UK adjuvant chemotherapy is rarely used outside the setting of clinical trials. Occasionally neo-adjuvant chemotherapy is given in an attempt to make a surgical excision possible or to attempt to avoid amputation. There are however no data from randomized controlled trials to support this approach. Patients with localized but inoperable disease or co-morbidity can be treated radically with radiotherapy alone. Doses in excess of 66 Gy need to be used with reasonable local control rates. 50% of patients with STS will either present with, or develop locally advanced or metastatic disease. When they do, the median survival is around 12 months. As with bone sarcomas, the commonest site of metastatic disease is the lung and the possibility of metastatectomy should always be considered as this is the only way to achieve long term survival (Figure 1) For the majority of patients the aim of treatment is palliation intent. Chemotherapy with doxorubicin alone or in combination with ifosfamide is the standard option. Response rates for doxorubicin alone are approximately 20%. Ifosfamide and doxorubicin together have a higher response rate of
Conclusion Malignancy affects the musculo-skeletal system in many ways. The incidence of metastatic bone disease is much higher than that of primary musculo-skeletal malignancy. There are many treatment options for metastatic disease, but it is almost always for palliation. Primary bone or soft tissue malignancy is rare and can be challenging to treat. Bone sarcomas still have a disappointingly poor prognosis even for localized disease, particularly as patients are often young. Other primary bone tumours such as NHL and plasmacytoma have a much better prognosis. Patients should be offered the opportunity to take part in clinical trials at all parts of their disease course if appropriate. For all patients with these conditions there is a need for a truly multidisciplinary approach in order to ensure they are diagnosed and treated to the highest possible level. A REFERENCES 1 Cancer Research UK. www.cancerreasearchuk.org. (Accessed Feb 2015). 2 Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12(20 suppl). 3 Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy e a systematic review of randomized trials. Clin Oncol 2003; 15: 345e52. 4 Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007; 25: 1423e36. 5 Wu JSY, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2006; 55: 594e605. 6 Dennis K, Makhani L, Xang L, Lam H, Chow E. Single fraction conventional external beam radiation therapy for bone metastases; a systematic review of randomized controlled trails. Radiother Oncol 2013; 106: 5e14. 7 Hird A, Chow E, Zhang L, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three Canadian cancer centres. Int J Radiat Oncol Biol Phys 2009; 75: 193e7.
Figure 1 Chest radiograph of a patient with a metastatic soft tissue sarcoma who had a left pneumonectomy for metastatic disease and five years later has a metastasis in her right lung.
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8 Gerszten PC, Burton SA, Ozhasoglin C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases froma single institution. Spine 2007; 32: 193. 9 Poulter C, Cosmatos D, Rubin P, et al. A report of RTOG 82-06:a phase III study of whether the addition of a single dose hemibody irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys 1992; 23: 207e14. 10 Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium 89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994; 31: 33e40. 11 Sartor R, Coleman R, Nilsson S, et al. Effect of Radium223 dichloride on symptomatic skeletal events in patients with castrate resistant prostate cancer and bone metastatses. Results from a phase 3, double blind, randomized trial. Lancet Oncol 2014; 15: 738e46. 12 Ross JR, Saunders Y, Edmonds PM, et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327: 469e75. 13 Pavlakis N, Stockler M. Bisphosphonates for breast cancer. In: The Cochrane Library, Issue 1. Oxford: Update Software, 2002. 14 Berenson JR, Lichtenstein A, Porter L, et al. Myeloma Aredia Study Group. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996; 334: 488e93. 15 Saad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. Long term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879e82. 16 Rosen LS, Gordon D, Tchekmedyian NS, et al. Long term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non small lung cancer and other solid tumours:a randomised phase III double blind, placebo controlled trial. Cancer 2004; 100: 2613e21.
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17 Lipton A, Fizazi K, Stopeck AT, et al. Superiority of Denosumab to Zoledronic acid for prevention of skeletal-related events; a combined analysis of three pivitol, randomized, phase III trials. Eur J Cancer 2012; 48: 3082e92. 18 Goorin AM, Schwartzentruber DJ, Devidas M, et al. Pre-surgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for non metastatic osteosarcoma: pediatric Oncology Group Study POG-8651. J Clin Oncol 2003; 21: 1574e80. 19 Bielak SS, Smeland S, Whelan J, et al. MAP plus maintenance pagylated Interferon alpha-2b (MAPIfn) versus MAP alone in patients with resectable high grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 “good response” randomization (abstract). J Clin Oncol 2013; 31 (suppl; abst 10504). 20 Bielak SS, CArrle D, Casali PG. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(suppl 4): 137. 21 Patricio MB, Vilhena M, Neves M, et al. Ewings’ Sarcoma in children: twenty five years of experience at the Instituto Portuges do Oncologia de Francisico Gentil. J Surg Oncol 1991; 47: 37e40. 22 Mitchell AD, Ayoub K, Mangham DC, et al. Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Jt Surg 2000; 82B: 55e61. 23 Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1988; 16: 197e203. 24 O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359: 2235e41. 25 Le Cesne A, Ouali M, Leahy MG, et al. Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma; pooled analysis of two STBSGEORTC phase III clinical trials. Ann Oncol 2014; 25: 2425e32.
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(iv) The non-surgical management of musculoskeletal malignancy
impacting on the patient’s quality of life and survival. ‘Skeletal Related Events’ (SRE) help to objectively measure the impact of bone metastases and are often chosen as end points in clinical studies. These include pain, pathological fracture, hypercalcaemia, spinal cord compression, necessitating palliative radiotherapy or surgical intervention. Prognosis in patients with bone metastases from breast and prostate cancer can be several years however survival for lung cancer patients is generally measured in months. The aim of palliative treatment for bone metastases should be pain relief, preservation of function and skeletal integrity. There are two main approaches to treatment: 1) Treating the underlying malignancy 2) Palliating the symptoms of SRE Chemotherapy, hormone treatment and biological agents are systemic modalities that can reduce the burden of cancer cells and in some cancers can help improve survival as well as improve symptoms and quality of life by controlling the underlying disease. Simple analgesia, bisphosphonates, radiotherapy, radiological interventions and surgery are treatment modalities to help improve symptoms and quality of life but do not generally reduce the burden of malignancy or improve survival. Treatment is different for each cancer subtype and varies for each individual patient.
Lesley Speed Claire Esler
Abstract Primary musculoskeletal cancers are relatively rare and should be managed by specialist centres which can deliver multimodal, multiprofessional treatment. Patients with localized primary bone or soft tissue sarcomas may be cured but prognosis has to be guarded due to high rates of local recurrence and many are not curable. To reduce patient suffering and maintain quality of life requires a multidisciplinary approach.
Keywords bisphosphonates; bone metastases; chemotherapy; Ewing’s sarcoma; osteosarcoma; radiotherapy; soft tissue sarcoma
Introduction Palliative radiotherapy for bone metastases Radiotherapy can be used in three ways to treat bone metastases: local external beam radiotherapy, hemi-body radiotherapy and radio-pharmaceuticals.
Musculoskeletal malignancies fall into two main categories: 1) Primary malignancy which includes primary bone tumours and primary soft tissue sarcomas. 2) Secondary malignancy i.e. bone metastases. The incidence of metastatic bone disease is far higher than that of both primary bone malignancy and soft tissue sarcomas (STS).1 The treatment of the two groups is vastly different but all patients require a multi-disciplinary approach to diagnosis, treatment and subsequent management. A patient with a musculo-skeletal malignancy, primary or secondary, may require the input of specialist nurses, oncologists, orthopaedic, spinal and plastic surgeons, radiologists, pathologists, palliative care teams, occupational and physiotherapists etc. This review is an introduction to the basic non-surgical, oncological management of bone metastases, primary bone tumours and extremity soft tissue sarcomas.
Local external beam radiotherapy: local external beam radiotherapy is a reliable and effective method of 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 70e80% and complete responses in 30e40%. Many different radiotherapy fractionation schedules have been reported. In the UK a single 8 Gy fraction or 20 Gy in five fractions are the most commonly used schedules. Single fraction treatment is easier on the patient where quality of life is paramount and there is abundant level 1a evidence, including three meta-analyses,3e5 that shorter fractionation schedules are as effective as longer in controlling pain. The need for retreatment however is higher in the shorter schedules and the greater the dose per fraction, the higher the risk of significant late toxicity. If a single fraction is prescribed, the usual standard dose is 8 Gy but there is evidence of the efficacy of single doses as low as 4 Gy. Low doses may be considered when a patient needs retreatment of an area several times which can arise in myeloma.6 There is a tendency for oncologists to prescribe longer fractionation schedules for those patients in whom the prognosis is of survival for several years, as this reduces the need for retreatment and limits late toxicity. As an example of this would be a patient with breast cancer and bone metastases as the only site of metastases. However, there is little evidence to support this practice and for the majority patients, a single 8 Gy fraction is entirely appropriate. It usually takes at least one week before any relief in pain and response may subsequently increase until a plateau is reached at 4e6 weeks. Pain flare, a temporary worsening of pain in an irradiated bone immediately after radiotherapy, may occur.
Metastatic bone disease Bone is the third most common site of metastatic disease after liver and lung. The incidence of bone metastases varies depending upon the primary cancer, occurring in approximately 70% of patients with prostate and breast cancer and 30e40% of patients with lung, kidney and thyroid cancer.2 Bony metastases may be present at diagnosis or become apparent during the disease course. They can cause significant morbidity, adversely
Dr Lesley Speed MBChB MRCP MSc FRCR Consultant Clinical Oncologist, Department of Oncology, Leicester Royal Infirmary, Leicester, UK. Conflict of interest: none declared. Dr Claire Esler BMedSci BMBS MRCP MMedSci FRCR Consultant Clinical Oncologist, Department of Oncology, Nottingham City Hospital, Nottingham, UK. Conflict of interest: none declared.
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antiemetic e.g. ondansetron, and monitoring of a full blood count are usually necessary. The response to HBI is similar to that seen in localized radiotherapy with a 60e70% improvement in pain. In 25% of patients a rapid response to pain is seen within 24 hours.
Reported rates range from 2 to 44% and is seen both with single and multi-fraction regimes.7 Large metastatic lesions involving the cortex of weight bearing bones should be considered for prophylactic fixation as they pose a significant risk for pathological fracture. This should be followed by radiotherapy. 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 arising from concomitant exposure of the small bowel may cause nausea and diarrhoea, and myelo-suppression due the large amount of bone marrow in the treatment field may occur. There are varying opinions about what volume should be irradiated after a long bone has had surgical fixation. One argument is to irradiate the entire long bone on the basis that the marrow cavity may have been contaminated with tumour cells at the time of surgery. The alternatives are to only irradiate the metastasis or the prosthesis plus a margin as this is the area most at risk of residual tumour and hence recurrence. A single 8 Gy fraction is usually appropriate post-operatively. In patients with a very poor life expectancy and deteriorating condition surgery may be inappropriate and palliative radiotherapy alone may help to reduce pain and aid healing even once fracture has occurred. Patients may present with a pathological fracture as their first manifestation of malignancy and it is always important to send bone reamings for histological diagnosis. Even when a patient is known to have a malignancy occasionally a second malignancy is identified and this may alter future treatment decisions.
Radio-pharmaceuticals: strontium 89 (89St) is a bone targeting radioisotope which, when administered intravenously, localizes to areas of osteoblastic bone activity.10 It is a beta-emitting radioisotope with a half-life of 50.5 days. Prostate cancer patients with widespread, predominantly osteoblastic metastases have historically been those to receive this therapy. It is used to treat pain not controlled by other treatments. The onset of pain relief occurs seven to 20 days after injection. Doses can be repeated after three months. 89St can cause significant bone marrow toxicity and should not be given to bone marrow suppressed patients. Its myelo-suppressive nature and cost have limited its use in the UK. It has not shown any improvement in survival. Radium 223 (223Ra) is an alpha particle emitting agent which appears to have more clinical benefit than 89St. It selectively binds to areas of high bone turnover and emits high energy short range alpha particles. These cause breaks in DNA with the drug preferentially targeting areas of osteoblastic activity.11 The ALSYMPCA trial randomized over 900 patients with symptomatic bone metastases from prostate cancer to receive either 223Ra or placebo alongside best supportive care. Those patients who received 223Ra had an improved overall survival of three and a half months to 14.9 months. They also had 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 myelo-suppression and few adverse events.11
Stereotactic body radiotherapy: stereotactic body radiotherapy (SBRT) is a special method of external beam radiotherapy using high doses to precise targets whilst minimizing the dose to adjacent normal structures. It is delivered in one or a small number of fractions. It is particularly useful in the treatment of spinal metastases causing spinal cord compression due to the sensitivity of normal surrounding tissues to radiation and consequent concern with regard to late toxicity. Tumours that are traditionally radioresistant such as melanoma or renal carcinomas may also benefit from this technique and patients who require re-irradiation.8 SBRT is not yet in routine use nor is it funded in the UK for treatment of metastatic disease as it is still under investigation.
Bisphosphonates Bisphosphonates are a group of compounds that are stable analogues of naturally occurring inorganic pyrophosphate. They are potent inhibitors of osteoclast-mediated bone resorption by affecting differentiation and maturation of osteoclasts and also they also have a direct apoptotic effect on osteoclasts. Bisphosphonates also have a direct effect on cancer cells by inhibiting tumour cell invasion and adhesion to bone matrix. In animal models bisphosphonates can inhibit the development of bone metastases. There are ongoing trials in humans looking at their role in preventing bone metastases. There are three generations of bisphosphonates available, from first generation clodronate to second generation pamidronate and more recently third generation zoledronic acid and ibandronate. With succeeding generations of bisphosphonates the in-vitro potency significantly increases. Many studies have confirmed the effectiveness of bisphosphonates in treating hyper-calcaemia of malignancy and in preventing skeletal related events in patients known to have bone metastases (secondary prophylaxis). Most supportive evidence is for patients with breast cancer, multiple myeloma and prostate cancer. (Table 1). A systematic review by Ross et al.12 included 21 randomized controlled trials (RCTs) of patients with bone metastases from myeloma and solid malignancies, predominantly breast and prostate cancer. Primary end-points were time to first SRE and
Hemi-body irradiation (HBI): bone metastases are frequently multiple and patients may complain of poorly localized pain that flits around. Attempts to ‘chase’ the cause of pain may lead to multiple localized radiotherapy treatments with unsatisfactory results. HBI can be an alternative option for such patients. HBI was traditionally considered as upper or lower hemi-body radiotherapy with the ‘cut off’ at the umbilicus. Today it is planned as a large field of external beam radiotherapy covering the areas of painful bone metastases either in the upper or lower body. A typical linear accelerator will be able to produce a radiation field size of 40 40 cm. Treatment to the upper hemibody is 6 Gy in a single fraction and to the lower hemi-body is typically 8 Gy in a single fraction. HBI has also been shown to delay the appearance of new painful bone metastases in the treatment field.9 When treating large volumes with radiotherapy, acute toxicity can be a major problem especially gastrointestinal toxicity and bone marrow toxicity. Prophylactic 5HT3 antagonist
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Bisphosphonates are considered the normal standard of care for breast cancer patient with bone metastases who have a reasonable prognosis. Grade 1 evidence from five RCTs and three systematic reviews conclude that bisphosphonates reduce the risk of predefined SRE. 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.13 However, there was no improvement in overall survival. Intravenous pamidronate, zoledronic acid and ibandronate and oral ibandronate have all been shown to reduce SRE. Recent NICE guidelines for advanced breast cancer are that bisphosphonates should be considered for patients with newly diagnosed bone metastases to prevent SRE and reduce pain, but do not make recommendations on which bisphosphonate to use.
Drugs that reduce skeletal related events in metastatic bone disease Primary tumour Bisphosphonate
Breast
Prostate
Myeloma
Other solid tumours
Pamidronate Zoledronic acid Ibandronate Denosumab
þ þ þ þ
þ e þ but not approved
þ þ þ but not approved
þ þ
Table 1
reduction in skeletal morbidity. It did not assess pain relief. The risk of developing an SRE e.g. vertebral fracture or hypercalcaemia was significantly improved compared with patients receiving radiotherapy. There was no benefit seen with regards to spinal cord compression. Time to SRE was also reduced with bisphosphonates. The review concluded that patients needed to be on bisphosphonates for at least 24 months before there was a significant reduction in the need for orthopaedic surgery, twelve months before hyper-calcaemia and non-vertebral fractures were reduced, and six months before there was a reduction in the need for radiotherapy. Studies giving less than six months of bisphosphonates showed no significant benefit in any end-point. Treating patients with a prognosis of less than six months, is probably therefore not beneficial or cost-effective. Evidence for the use of bisphosphonates for pain control from bone metastases is inconsistent. Several trials support the effectiveness of these drugs in providing some pain relief for bone metastases but there is insufficient data to recommend them as first line treatment. There is insufficient data to conclude which bisphosphonate was most efficacious for pain or to say which primary tumour type benefits most. Bisphosphonates are generally well tolerated but do cause acute phase reactions including nausea and electrolyte imbalances. They can also cause osteonecrosis of the jaw and patients must be counselled accordingly and consideration made of any dental treatment that may be needed before or during treatment. One of the major difficulties in comparing the results of trials that look at different treatments for bone metastases is the varying primary end-points and inconsistent timings of these events. Biochemical surrogate markers have therefore been sought to try and make assessment more objective. Urinary and blood markers of bone remodeling can be useful in the assessment of bisphosphonates efficacy.
Bisphosphonates in myeloma Myeloma is a malignancy of plasma cells characterized by osteolytic bone destruction throughout the skeleton resulting in pain, pathological fractures and hyper-calcaemia. Cytokines such as interleukins and tumour necrosis factor produced by the myeloma cells and the stroma of the bone marrow stimulate osteoclastic resorption of bone without accompanying bone formation leading to purely osteolytic metastases. For patients with at least one lytic bone lesion, four-weekly Pamidronate in addition to chemotherapy is recommended. Berensen et al. reported that the time to first SRE and the number of patients sustaining an SRE were significantly reduced for those receiving a bisphosphonate (41% of patients in the placebo group versus 24% in the pamidronate group).14 Bone pain was significantly reduced with pamidronate but there was no difference in overall survival between the two groups. 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 recent guidelines from the USA have recommended against the use of zoledronic acid in myeloma patients. Bisphosphonates in prostate cancer It was initially thought that purely osteoblastic (sclerotic) bone metastases would not respond to bisphosphonates. Skeletal metastases from prostatic cancer are usually osteoblastic but it is now known that there is an element of increased bone resorption in metastatic prostate cancer. This probably explains the response seen to zoledronic acid which is the only bisphosphonate that has been demonstrated to confer clinical benefit in reducing SRE in this patient group.15 Compared to placebo, three weekly intravenous doses of zoledronic acid reduced the risk of SRE by 11% and significantly prolonged the time to first SRE by 5.5 months.
Bisphosphonates in breast cancer Approximately 70% of patients with advanced breast cancer will develop bone metastases. They are predominantly osteolytic but some may be osteoblastic. 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. Systemic treatment options for metastatic breast cancer patients with bone metastases include analgesia, hormone treatments, chemotherapy, biological agents e.g. trastuzumab, and bisphosphonates.
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Bisphosphonates in other solid malignancies There is less evidence about the efficacy of bisphosphonates in other types of malignancy. In the UK only patients with breast, prostate cancer and myeloma patients are routinely prescribed bisphosphonates. However, a large RCT comparing zoledronic acid with placebo in patients with metastases from lung, renal and a variety of other primary cancers concluded that zoledronic acid was beneficial.16 A significantly lower proportion of patients
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receiving zoledronic acid had an SRE and in those that did, there was a longer time to first SRE. Based on these data, zoledronic acid is the only bisphosphonate to have worldwide regulatory approval for patients with bone metastases from solid tumours other than breast cancer.
theoretical, benefits of neo-adjuvant chemotherapy are that micro-metastases can be treated earlier, the tumour may shrink making surgery easier, and chemotherapy may sterilize the surgical bed making contamination less of a concern at the time of surgery. The risks of neo-adjuvant chemotherapy are that it delays definitive treatment and if the cancer does not respond to chemotherapy a potentially curable cancer may become inoperable. Neo-adjuvant chemotherapy also allows an in vivo drug trial to determine the chemo-sensitivity of the tumour. A good response, defined as 90% or greater tumour cell necrosis, indicates a five year survival between 70 and 80%. In patients with less tumour necrosis the 5 year survival rate is significantly lower at 45e60%. The POG trial 8651 randomized patients with high grade osteosarcoma to surgery and adjuvant chemotherapy or 10 weeks of neo-adjuvant chemotherapy followed by surgery. There was no statistically significant difference between five year recurrence-free survival in the two arms: 65% for the adjuvant arm versus 61% in the neo-adjuvant arm.18 Currently the standard treatment for patients with localized high grade osteosarcoma is two/three cycles of cisplatin and doxorubicin and high dose methotrexate (the 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 is controversial although there seems to be more benefit in younger patients. This is a highly toxic regimen which needs to be administered as an inpatient via a central line (Table 2). The recent 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 (randomized to continue Cisplatin/Doxorubicin or switch to Ifosfamide/Etoposide), and whether maintenance Interferon improves survival (patients with good response randomized to two years of Interferon or observation.) The only data available so far is from an analysis of the 715 patients in the ‘good response’ arm which showed the addition of Interferon to MAP did not confer a statistically superior event free survival (77 vs 74%).19 The benefit of adding a fourth drug to the MAP combination pre-operatively has not yet been established. There may be some increased response rates but at the cost of increase toxicity and as yet no benefit in survival. Post-operatively the immune stimulant muramyl-tripeptide (Mifamurtide) has shown an improvement in overall survival but strangely not disease free survival.20 It has been granted a European license and is now NICE approved in the adjuvant setting alongside standard multi-agent chemotherapy. Osteosarcoma is relatively radio-resistant, thus radiotherapy has a very small role in its treatment. The only indication for adjuvant radiotherapy is after an incomplete surgical resection where further surgery is not possible when 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 is indicative of a poor prognosis. The only potential for long term survival for patients with lung metastases is metastatectomy and chemotherapy and this should be considered in all patients with
New agents to treat bone metastases Denosumab is a fully humanized monoclonal antibody that binds to and neutralises RANK (Receptor Activator of Nuclear Factor kB) ligand, resulting in inhibition of osteoclast function and bone resorption. It is given as a subcutaneous injection every four weeks. Combined analyses of three large randomized trials examining Denosumab in metastatic bone disease has shown superiority compared to zoledronic acid with increased time to first (on study) SRE by 8.2 months and reducing the risk of developing an SRE by 17%. It is well tolerated but does cause more hypocalcaemia than bisphosphonates.17 It has now been approved by NICE for use in metastatic bone disease where a bisphosphonate would otherwise be considered (other than prostatic).
Primary musculoskeletal tumours Malignant primary bone and connective tissue tumours are rare, accounting for about 1e2% of all new cancers diagnosed in the UK annually. In England all patients presenting with a suspected primary bone sarcoma should be referred to a specialist bone sarcoma centre for their surgical treatment. Less than 0.2% of all cancers are primary bone malignancies. The most common is osteosarcoma, then chondrosarcoma and Ewing’s disease. In 2011 there were 559 new cases in the UK of primary bone sarcoma and there were 3272 new diagnoses of soft tissue sarcomas. In comparison, there were over 50 000 new cases of breast cancer and 43 000 new lung tumours.1 The treatment of soft tissue sarcoma is very different from the treatment of primary bone tumours and the treatment of each subtype of sarcoma is different. For the purposes of this review the main principles for the more common tumours will be discussed. Osteosarcoma There are two peaks in the age-related incidence of osteosarcoma. The first is in adolescents and young adults and there is a second smaller peak in older adults. Teenagers and young adults (under 24) should be offered treatment in an oncology centre with a specialised teenage and young adult oncology department to provide physical, psychological and social support. For some patients this may mean travelling a significant distance. Until the 1970s surgical resection, which usually meant amputation, was the sole radical treatment for osteosarcoma. Despite good local control, 80e90% of patients subsequently died of metastatic disease, due to subclinical micro-metastases present at presentation. Thus a systemic approach to treatment is required with chemotherapy in addition to surgery to improve survival. Uncertainty remains as to whether pre-operative (neo-adjuvant) or post-operative (adjuvant) chemotherapy is superior. Neo-adjuvant chemotherapy became popular as limb salvage surgery was introduced to give patients treatment while allowing time for a customized endo-prosthesis to be made. Other,
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Toxicities associated with chemotherapy regimes used to treat sarcoma patients Doxorubicin
Doxorubicin and ifosfamide
Sarcoma type STS STS Common toxicities Nausea, vomiting, mucositis, As doxorubicin þ CNS toxicity alopecia, myelosuppression, diarrhoea, fatigue, skin necrosis, nail changes
Rare but serious toxicities
Cardiotoxicity, infertility, liver toxicity
Doxorubicin and cisplatin
Osteosarcoma Nausea, vomiting, mucositis, alopecia, myelosuppression, diarrhoea, renal impairment, hearing loss, peripheral neuropathy, nail changes, fatigue, skin necrosis þ bladder, renal and liver toxicity, Cardiotoxicity, infertility, infertility, second malignancy liver toxicity
VIDE Ewings Nausea, vomiting, mucositis, alopecia, myelosuppression, diarrhoea, constipation, fatigue, skin necrosis, nail changes, CNS toxicity Cardiotoxicity, infertility, bladder, renal and liver toxicity. Second malignancy
Table 2
depends on the site of the primary and the presence and distribution of any metastatic disease. Most patients’ treatment will consist of six cycles of in-patient vincristine, ifosfamide, doxorubicin and etoposide (VIDE). If there is localized operable disease, then the treatment is surgery and or radiotherapy followed by further chemotherapy. If there is more than 90% necrosis of the tumour after initial chemotherapy, the prognosis is improved which is similar in principle to osteosarcoma. Further chemotherapy decisions are dependent on the degree of tumour necrosis. Ewing’s sarcoma is a far more radiosensitive tumour than osteosarcoma and most soft tissues sarcomas. Lower doses of radiotherapy are needed, usually around 50e55 Gy. Postoperative radiotherapy is given if there are positive surgical margins or <90%necrosis, 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. If the position of the primary tumour makes surgery impossible then radiotherapy alone without surgery can be used as radical treatment to the primary. Patients with metastatic disease at presentation have a worse prognosis with five year survival of 20e30%. 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. Patients with other sites of metastatic disease who respond well to conventional chemotherapy regimens may be considered for high dose chemotherapy with stem cell rescue (i.e. transplant). The evidence to support this approach is small and is currently being reviewed in the ongoing analysis of the international ‘EuroEwings 99’ trial protocol.
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. Radiofrequency ablation (RFA) is a new method to treat lung metastases. It is a minimally invasive technique used when surgical resection is not an option. An electrode is placed into the area to be treated and causes tissue destruction with thermal energy. While good early results have been obtained, there is as yet no evidence from randomized controlled trials comparing RFA to surgery. 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 an unresectable tumour at presentation, treatment is aimed at palliation. Options include various combinations of chemotherapy and palliative radiotherapy for bone or obstructing lung metastases. Patients may be considered for 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 particular malignancy to establish early efficacy data for the drug. Ewing’s sarcoma Ewing’s sarcoma is the second most common primary bone malignancy of childhood and adolescence. Treatment in a specialist paediatric or teenage and young adult department is as important as for osteosarcoma. The tumour arises from the neural crest and is one of the small round blue cell family of tumours. The diagnosis can be confirmed by cytogenetic testing which shows 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 and without systemic treatment more than 90% of patients die from secondary metastases.21 Since the 1970s aggressive chemotherapy has increased survival rates to 55e65% for local disease and up to 35% in primary metastatic disease. Treatment a patient receives
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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 20e27% of primary bone malignancies. Approximately 90% are low or intermediate grade and are treated by surgery alone. High grade and the rarer mesenchymal chondrosarcomas have a high
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grade sarcomas the ten year local recurrence rates were 4% versus 33% in favour of radiotherapy. There was no benefit in overall survival for either low or high grade sarcomas with radiotherapy. Traditionally the standard of care has been adjuvant radiotherapy for patients with either high grade, >5 cm in size or deep tumours. Patients who have positive margins after surgery in whom further surgery is not possible should also receive postoperative radiotherapy. To plan radiotherapy treatment the oncologist needs to outline on a CT planning scan of the site of the original tumour, add a margin for possible subclinical spread, and a margin to allow for patient movement and daily radiotherapy set up error. They need to have the pre-operative imaging, histopathology report, and surgical operation notes. Ideally, the sarcoma surgeon will have placed clips around the tumour bed which can be seen on imaging. It also helps if the oncologist sees the patient preoperatively and can talk to the surgeon after surgery about what the intra-operative appearances of the tumour were to ascertain which margins the surgeon might be concerned about. Patients typically are treated daily, for 6e7 weeks with a dose of 60e66 Gy in 33 fractions. Historically, large volumes of tissue were irradiated with margins of 5e7 cm superiorly and inferiorly to the site of the original tumour. Irradiating such large volumes can cause significant morbidity and there is evidence that local recurrences occur much closer to the initial tumour. The Vortex study was a National Cancer Research Network trial to ascertain whether such large treatment margins are necessary. Results are awaited. There is now an increasing body of evidence to support the use of neo-adjuvant radiotherapy. There are potential benefits from both approaches. An RCT comparing pre- and postoperative radiotherapy was designed to assess differences in the incidence of wound complications.24 The trial was stopped prematurely because of increased acute wound complications in the pre-operative treatment arm. 35% of patients developed wound complications in the pre-operative arm versus 17% in the post-operative arm (p ¼ 0.01). Updated data from this trial however, with a median follow up of 6.9 years show over 90% local control in both arms but the post-operative radiotherapy arm had significantly more patients with late toxicity (86% versus 68%). In the UK now there is a changing emphasis on when to use radiotherapy with much more pre-operative treatment being given particularly for those tumours in the extremities that are radiosensitive such as myxoid liposarcomas. Patients have repeat imaging and then surgery within 6e8 weeks of completing radiotherapy. A post-operative boost of radiotherapy is recommended for those patients who have positive margins after resection. Radiation toxicity varies dependent on the site being treated, the volume being irradiated and a patient’s individual sensitivity to radiotherapy (Table 3). Acute wound complications can generally be managed whilst late toxicities such as loss of subcutaneous tissue and fibrosis are generally irreversible. Patient education and physiotherapy are important to aid recovery after surgery and radiotherapy in order for patients to recover to their maximum potential. With regard to adjuvant chemotherapy there have been many trials showing conflicting results with regards to improvements in Progression Free Survival (PFS) and overall survival. Several meta-analyses and a recent pooled analysis of two large European trials have shown no overall benefit for adjuvant
metastatic potential and less than 30% ten year survival. 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. De-differentiated chondrosarcomas are highly aggressive and have an additional component of high grade soft tissue sarcoma. The prognosis is very poor and patients are offered neo-adjuvant and adjuvant chemotherapy with cisplatin and doxorubicin.22 Solitary plasmacytoma of the bone A solitary plasmacytoma is a proliferation of monoclonal plasma cells which usually presents with a bony lesion, neurological compression or pain. They are most common in the axial skeleton and in the spine they can cause spinal cord compression. Before the diagnosis of solitary plasmacytoma can be made, multiple myeloma needs to be excluded, by bone marrow aspirate, skeletal survey, urine Bence-Jones protein, immunoglobulin levels, serum calcium, renal function and full blood count. MRI of the spine is necessary to confirm that the lesion is truly solitary. These tumours are radiosensitive and should be treated with radical radiotherapy with a dose 45e50 Gy. Local control rates are above 90% and median survival is 10 years. However, over half of these patients will go on to develop multiple myeloma usually within two to five years but even after 20 years. There is no strong evidence at present that adjuvant chemotherapy is of benefit. Primary lymphoma of bone Primary non Hodgkin lymphoma of bone accounts for about 3% of primary bone malignancies. The vast majority are diffuse large B cell lymphomas. Presentation is usually with pain and about half will have a palpable mass secondary to soft tissue around the bone. B symptoms (night sweats, fever and weight loss) may be present. NHL is both chemo- and radiosensitive. Treatment consists of ReCHOP chemotherapy i.e. rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone. Chemotherapy is often followed by radiotherapy to the primary bone site with a dose of 40e45 Gy but treatment is individualized based on extent and site of disease.
Soft tissue sarcoma Soft tissue sarcomas (STS) can occur in any part of the body where there is mesenchymal tissue and there are over 50 different histological types in the WHO sarcoma classification. The non-surgical treatment for the majority of these is similar. For some sub-types such as rhabdomyosarcoma, Gastro Intestinal Tumours (GISTs) and Kaposi’s sarcoma, the treatment is very different and beyond the scope of this article. The goal of treatment for localized extremity STS is a functioning limb without local recurrence. In the 1980s it became clear that wide local excision (limb conservation) and adjuvant radiotherapy could produce local control rates similar to amputation without prejudicing overall survival. Yang et al. randomized patients with STS to adjuvant radiotherapy or not, after wide excision.23 In high grade sarcomas the ten year local recurrence rate was 0% versus 22% in favour of radiotherapy. In the low
ORTHOPAEDICS AND TRAUMA --:-
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approximately 30e40% but at the cost of considerably more toxicity, the need for inpatient treatment and no benefit in overall survival. In 2007 Trabectedin, a novel DNA binding compound derived from the marine creature Ecteinascidia turbinata, the mangrove tunicate, was licensed for treatment of STS. This was the first newly licensed drug for STS in over 20 years. Studies have shown Trabectedin can stop tumour growth or induce a partial response in 50% of patients with one year survival rates of 50%. It is now commonly used as second line treatment particularly for leiomyosarcomas and liposarcoma. Other drug options include chemotherapy with Gemcitabine based combinations or alone, and Pazopanib, a multi-targeted tyrosine kinase inhibitor that improves PFS compared to placebo by 3 months. Inevitably like most cases of metastatic cancer, patients will deteriorate and need active symptom control and palliative care. Palliative radiotherapy can be very effective in locally advanced STS to control symptoms of bleeding, pain or compression. Occasionally palliative surgery can be a useful treatment for intractable local symptoms.
Comparing neo-adjuvant and adjuvant radiotherapy in STS
For
Against
Pre-op radiotherapy
Post-op radiotherapy
Smaller volume treated Easier to delineate tumour in situ Lower dose of radiotherapy Acute wound complications Delay in definitive treatment
Known histology Already had definitive treatment
Late toxicity impacting on function
Table 3
chemotherapy.25 In the UK adjuvant chemotherapy is rarely used outside the setting of clinical trials. Occasionally neo-adjuvant chemotherapy is given in an attempt to make a surgical excision possible or to attempt to avoid amputation. There are however no data from randomized controlled trials to support this approach. Patients with localized but inoperable disease or co-morbidity can be treated radically with radiotherapy alone. Doses in excess of 66 Gy need to be used with reasonable local control rates. 50% of patients with STS will either present with, or develop locally advanced or metastatic disease. When they do, the median survival is around 12 months. As with bone sarcomas, the commonest site of metastatic disease is the lung and the possibility of metastatectomy should always be considered as this is the only way to achieve long term survival (Figure 1) For the majority of patients the aim of treatment is palliation intent. Chemotherapy with doxorubicin alone or in combination with ifosfamide is the standard option. Response rates for doxorubicin alone are approximately 20%. Ifosfamide and doxorubicin together have a higher response rate of
Conclusion Malignancy affects the musculo-skeletal system in many ways. The incidence of metastatic bone disease is much higher than that of primary musculo-skeletal malignancy. There are many treatment options for metastatic disease, but it is almost always for palliation. Primary bone or soft tissue malignancy is rare and can be challenging to treat. Bone sarcomas still have a disappointingly poor prognosis even for localized disease, particularly as patients are often young. Other primary bone tumours such as NHL and plasmacytoma have a much better prognosis. Patients should be offered the opportunity to take part in clinical trials at all parts of their disease course if appropriate. For all patients with these conditions there is a need for a truly multidisciplinary approach in order to ensure they are diagnosed and treated to the highest possible level. A REFERENCES 1 Cancer Research UK. www.cancerreasearchuk.org. (Accessed Feb 2015). 2 Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12(20 suppl). 3 Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy e a systematic review of randomized trials. Clin Oncol 2003; 15: 345e52. 4 Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007; 25: 1423e36. 5 Wu JSY, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2006; 55: 594e605. 6 Dennis K, Makhani L, Xang L, Lam H, Chow E. Single fraction conventional external beam radiation therapy for bone metastases; a systematic review of randomized controlled trails. Radiother Oncol 2013; 106: 5e14. 7 Hird A, Chow E, Zhang L, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three Canadian cancer centres. Int J Radiat Oncol Biol Phys 2009; 75: 193e7.
Figure 1 Chest radiograph of a patient with a metastatic soft tissue sarcoma who had a left pneumonectomy for metastatic disease and five years later has a metastasis in her right lung.
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17 Lipton A, Fizazi K, Stopeck AT, et al. Superiority of Denosumab to Zoledronic acid for prevention of skeletal-related events; a combined analysis of three pivitol, randomized, phase III trials. Eur J Cancer 2012; 48: 3082e92. 18 Goorin AM, Schwartzentruber DJ, Devidas M, et al. Pre-surgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for non metastatic osteosarcoma: pediatric Oncology Group Study POG-8651. J Clin Oncol 2003; 21: 1574e80. 19 Bielak SS, Smeland S, Whelan J, et al. MAP plus maintenance pagylated Interferon alpha-2b (MAPIfn) versus MAP alone in patients with resectable high grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 “good response” randomization (abstract). J Clin Oncol 2013; 31 (suppl; abst 10504). 20 Bielak SS, CArrle D, Casali PG. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(suppl 4): 137. 21 Patricio MB, Vilhena M, Neves M, et al. Ewings’ Sarcoma in children: twenty five years of experience at the Instituto Portuges do Oncologia de Francisico Gentil. J Surg Oncol 1991; 47: 37e40. 22 Mitchell AD, Ayoub K, Mangham DC, et al. Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Jt Surg 2000; 82B: 55e61. 23 Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1988; 16: 197e203. 24 O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359: 2235e41. 25 Le Cesne A, Ouali M, Leahy MG, et al. Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma; pooled analysis of two STBSGEORTC phase III clinical trials. Ann Oncol 2014; 25: 2425e32.
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