Advertisement

Advances in radiotherapy in bone metastases in the context of new target therapies and ablative alternatives: A critical review

      Highlights

      • In uncomplicated BM, SF RT produces similar overall and complete response rates to MF, butit is associated with a higher retreatment rate.
      • Complicated bone metastases can be defined as the presence of impending or existing pathologic fracture, a major soft tissue component, existing spinal cord or cauda equina compression, and neuropathic pain.
      • There are contradictory outcomes in studies reporting pain control rates and time to pain reduction when comparing stereotactic ablative radiotherapy versus conventional fractions.
      • The ideal ablative radiotherapy schedule to treat BM remains to be defined.
      • Physical activity and rehabilitation should be included in the multidisciplinary treatment of BM, with specific adaptations to improve the patient’s condition and minimise risks.

      Abstract

      In patients with bone metastases (BM), radiotherapy (RT) is used to alleviate symptoms, reduce the risk of fracture, and improve quality of life (QoL). However, with the emergence of concepts like oligometastases, minimal invasive surgery, ablative therapies such as stereotactic ablative RT (SABR), radiosurgery (SRS), thermal ablation, and new systemic anticancer therapies, there have been a paradigm shift in the multidisciplinary approach to BM with the aim of preserving mobility and function survival.
      Despite guidelines on using single-dose RT in uncomplicated BM, its use remains relatively low. In uncomplicated BM, single-fraction RT produces similar overall and complete response rates to RT with multiple fractions, although it is associated with a higher retreatment rate of 20% versus 8%.
      Complicated BM can be characterised as the presence of impending or existing pathologic fracture, a major soft tissue component, existing spinal cord or cauda equina compression and neuropathic pain. The rate of complicated BM is around 35%. Unfortunately, there is a lack of prospective trials on RT in complicated BM and the best dose/fractionation regimen is not yet established.
      There are contradictory outcomes in studies reporting BM pain control rates and time to pain reduction when comparing SABR with Conventional RT. While some studies showed that SABR produces a faster reduction in pain and higher pain control rates than conventional RT, other studies did not show differences. Moreover, the local control rate for BM treated with SABR is higher than 80% in most studies, and the rate of grade 3 or 4 toxicity is very low. The use of SABR may be preferred in three circumstances: reirradiation, oligometastatic disease, and radioresistant tumours. Local ablative therapies like SABR can delay change or use of systemic therapy, preserve patients' Qol, and improve disease-free survival, progression-free survival and overall survival. Moreover, despite the potential benefit of SABR in oligometastatic disease, there is a need to establish the optial indication, RT dose fractionation, prognostic factors and optimal timing in combination with systemic therapies for SABR.
      This review evaluates the role of RT in BM considering these recent treatment advances. We consider the definition of complicated BM, use of single and multiple fractions RT for both complicated and uncomplicated BM, reirradiation, new treatment paradigms including local ablative treatments, oligometastatic disease, systemic therapy, physical activity and rehabilitation.

      Keywords

      Bone metastases (BM) can affect quality of life (QoL) and may impact on patient survival. They require the care of a multidisciplinary team [
      • Coleman R.E.
      Clinical features of metastatic bone disease and risk of skeletal morbidity.
      ,
      • Pockett R.D.
      • Castellano D.
      • McEwan P.
      • Oglesby A.
      • et al.
      The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain.
      ,
      • Foley K.M.
      The treatment of cancer pain.
      ]. These patients are candidates for a variety of treatments, ranging from supportive care to surgery or ablative therapies, such as radiosurgery (SRS), stereotactic ablative RT (SABR) and image-guided thermal ablation [
      • Foley K.M.
      The treatment of cancer pain.
      ,
      • David S.
      • Tan J.
      • Savas P.
      • Bressel M.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: a prospective clinical trial.
      ]. In any treatment schedule involving BM patients, the overarching goal of palliative radiotherapy (RT) remains to deliver an effective, safe, and timely treatment in as few fractions as possible, recognizing the patient's life expectancy.
      The clinical management of painful BM should include optimal analgesia, osteoclast inhibitors to reduce skeletal-related complications and systemic therapy. Conventional chemotherapy can reduce pain and improve QoL in a subset of patients with BM [
      • Tannock I.F.
      • de Wit R.
      • Berry W.R.
      • Horti J.
      • et al.
      TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
      ]. For prostate cancer patients with diffuse bone pain and multiple BM, half body RT has been largely replaced by bone-targeting radioactive isotopes [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • et al.
      ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ]. Other systemic therapies may be used depending on the cancer type, including hormonal therapy, immunotherapy, and targeted therapy. These, in conjunction with the concept of radical treatment for oligometastases, have resulted in potential for improvement in the survival of selected metastatic cancer patients.

      Methods

      Between January 2021 and June 2021 a review was performed using Medline with the terms: bone metastases and radiotherapy. Specific research questions were approached by searching for combinations of the following keywords: stereotactic body radiotherapy, SBRT, stereotactic ablative RT, SABR, cyberknife, stereotactic radiosurgery, SRS, spinal metastases, non-spine bone metastases, spinal cord compression, prognostication, systemic treatment, chemotherapy, targeted therapy, hormonal therapy, immunotherapy, side effects, toxicity, spinal cord tolerance, re-irradiation, rehabilitation. Articles published in English until May 31th, 2021 were selected for relevance to the multidisciplinary management of bone metastases with surgery, radiotherapy or systemic anti-cancer treatment. All citations were evaluated for relevant content and validity.

      Radiotherapy in uncomplicated BM

      Over the last twenty years, a number of prospective randomised trials have been conducted with regards to the optimal RT dose fractionation schedule to palliate pain in uncomplicated BM, with similar pain relief response rates for single or multiple fractions RT in both intention-to-treat and per protocol assessable cohorts [

      Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004;2002:CD004721. 10.1002/14651858.CD004721.

      ,
      • Chow E.
      • Harris K.
      • Fan G.
      • Tsao M.
      • Sze W.M.
      Palliative radiotherapy trials for bone metastases: a systematic review.
      ,
      • Rich S.E.
      • Chow R.
      • Raman S.
      • Liang Zeng K.
      • et al.
      Update of the systematic review of palliative radiation therapy fractionation for bone metastases.
      ]. A systematic review and meta-analysis, with data from 29 randomized trials, found that the overall response rate was 61% for single-fraction RT (1867/3059 patients) versus 62% in RT with multiple fractions (1890/3040), and the complete response rate was also similar for both groups (23% versus 24%, respectively) providing level I evidence on the management of simple BM [
      • Rich S.E.
      • Chow R.
      • Raman S.
      • Liang Zeng K.
      • et al.
      Update of the systematic review of palliative radiation therapy fractionation for bone metastases.
      ]. In contrast, the retreatment rate was 20% in the single dose group (497/2482) versus 8% in the multiple fraction group (192/2468) (p < 0.01) [
      • Rich S.E.
      • Chow R.
      • Raman S.
      • Liang Zeng K.
      • et al.
      Update of the systematic review of palliative radiation therapy fractionation for bone metastases.
      ].
      Despite the advantages of single fraction RT in patients with uncomplicated BM, in a Medicare cohort with 7547 patients with BM from breast cancer, only 4% of patients were treated with single fraction, and 40.9% received RT with 10 or more fractions [
      • Yu J.B.
      • Pollack C.E.
      • Herrin J.
      • Zhu W.
      • et al.
      Persistent use of extended fractionation palliative radiotherapy for medicare beneficiaries with metastatic breast cancer, 2011 to 2014.
      ]. In a recent review, designed to analyse real-world data, amongst those cases with painful BM, only 12.9% were treated with a single fraction of 8 Gy [
      • Spratt D.E.
      • Mancini B.R.
      • Hayman J.A.
      • Boike T.
      • et al.
      Michigan radiation oncology quality consortium. Contemporary statewide practice pattern assessment of the palliative treatment of bone metastasis.
      ]. An evaluation of behavioural determinants in the choice of single-dose RT in uncomplicated BM found in semi structured interviews with 38 radiation oncologists from 10 different provinces in Canada, the two principal impediments to single fraction RT use were the higher risk of retreatment after single fraction RT (82%, n = 31) and worries about BM near the spine and with large target volumes (74%, n = 28) [
      • Squires J.E.
      • Asad S.
      • Varin M.D.
      • Dorrance K.
      • et al.
      Behavioral determinants of canadian radiation oncologists' use of single fraction palliative radiation therapy for uncomplicated bone metastases.
      ]. Nevertheless, implementing a radiation oncology service dedicated to palliative care increased the use of single-fraction RT from 6.4% to 22.3% (p < 0.001) [

      Skamene S, Agarwal I, Makar M, Krishnan M, et al. Impact of a dedicated palliative radiation oncology service on the use of single fraction and hypofractionated radiation therapy among patients with bone metastases. Ann Palliat Med 2018;7:186-191. 10.21037/apm.2017.11.02.

      ]. One possible reason for the increase in short course RT could be better alignment between doctors' and patients' expectations concerning treatment goals [

      Skamene S, Agarwal I, Makar M, Krishnan M, et al. Impact of a dedicated palliative radiation oncology service on the use of single fraction and hypofractionated radiation therapy among patients with bone metastases. Ann Palliat Med 2018;7:186-191. 10.21037/apm.2017.11.02.

      ]. Moreover, a comprehensive knowledge translation campaign in Manitoba increased single fraction RT use from 38% in 2016 to 59% in 2017 [
      • Shahhat S.
      • Hanumanthappa N.
      • Chung Y.T.
      • Beck J.
      • et al.
      Do coordinated knowledge translation campaigns persuade radiation oncologists to use single-fraction radiation therapy compared with multiple-fraction radiation therapy for bone metastases?.
      ].

      Radiotherapy in complicated BM

      The American Society for Radiation Oncology (ASTRO) BM consensus recognizes the need to define complicated BM more appropriately to improve the BM therapy decision process [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ]. The absence of a clear definition of complicated BM makes it difficult to determine which BM patients the prospective randomized trial results apply to. Despite some controversies, complicated BM might be described as BM with the following features: impending or existing pathologic fracture, a major soft tissue component, spinal cord or cauda equina compression, and neuropathic pain [
      • Plunkett T.A.
      • Smith P.
      • Rubens R.D.
      Risk of complications from bone metastases in breast cancer. Implications for management.
      ].
      The limitation to classifying patients as uncomplicated BM or not often comes from the lack of detailed description of radiographic evidence or clinical factors like the presence of impending pathological fracture and compression of the spinal cord and peripheral nerves [
      • Cheon P.M.
      • Wong E.
      • Thavarajah N.
      • Dennis K.
      • et al.
      A definition of “uncomplicated bone metastases” based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy.
      ,
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ]. The most common exclusion factors in these trials were fracture or its impending risk in 78% (18/23), previous RT in 78% (18/23), and the presence of neuraxis compromise in 65% (15/23) of studies [
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ]. Unfortunately, these debilitating complications are frequent and will become even more common as patient longevity increases from improvement in systemic anticancer treatment. The incidence of BM with a soft tissue or extra osseous component, pathologic fracture, or spinal cord compression has been reported as high as 31%, 35%, and 15%, respectively [
      • Delea T.
      • Langer C.
      • McKiernan J.
      • Liss M.
      • et al.
      The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer.
      ,
      • Tiwana M.S.
      • Barnes M.
      • Yurkowski E.
      • Roden K.
      • Olson R.A.
      Incidence and treatment patterns of complicated bone metastases in a population-based radiotherapy program.
      ]. One study showed that in 927 BM, 28.6% of the patients had fractures, 24.4% had soft tissue extension of the metastases, 8.7% compression in the spinal cord, and 2.9% cauda equina compression [
      • Shahhat S.
      • Hanumanthappa N.
      • Chung Y.T.
      • Beck J.
      • et al.
      Do coordinated knowledge translation campaigns persuade radiation oncologists to use single-fraction radiation therapy compared with multiple-fraction radiation therapy for bone metastases?.
      ]. A reviewing of data from 401 patients observed a 20.6% incidence of pathological fracture, 38.6% of soft tissue mass, 8.9% of prior surgery, 4.4% with previous RT, and 52 % neurological compromise of spine and medial pelvis [
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ]. When considering the more usual description of complicated BM (pathological fractures and neuraxis compromise without the other characteristics), a rate of 36.4% was described [
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ]. This rate of complicated BM is similar to the rate of 34% observed in 4127 BM treated with RT in other centres [
      • Shahhat S.
      • Hanumanthappa N.
      • Chung Y.T.
      • Beck J.
      • et al.
      Do coordinated knowledge translation campaigns persuade radiation oncologists to use single-fraction radiation therapy compared with multiple-fraction radiation therapy for bone metastases?.
      ,
      • Tiwana M.S.
      • Barnes M.
      • Yurkowski E.
      • Roden K.
      • Olson R.A.
      Incidence and treatment patterns of complicated bone metastases in a population-based radiotherapy program.
      ].
      Considering the worse median survival in complicated BM patients, it is imperative to minimize patient burden and prioritize convenience by utilizing short course RT schedules whenever possible [
      • Maranzano E.
      • Bellavita R.
      • Rossi R.
      • De Angelis V.
      • et al.
      Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial.
      ]. In terms of resources, single-dose RT is more cost-effective than more protracted RT schedules, and treatments with palliative intent can represent close to 30% of daily practice in a RT department [
      • Foro Arnalot P.
      • Fontanals A.V.
      • Galcerán J.C.
      • Lynd F.
      • et al.
      Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction.
      ,
      • Steenland E.
      • Leer J.W.
      • van Houwelingen H.
      • Post W.J.
      • et al.
      The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study.
      ]. The use of more protracted RT courses in BM patients can substantially increase the RT department workload [
      • van den Hout W.B.
      • van der Linden Y.M.
      • Steenland E.
      • Wiggenraad R.G.
      • et al.
      Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: cost-utility analysis based on a randomized trial.
      ]. In any treatment schedule involving complicated BM patients, the overarching goal of palliative RT remains delivery of an effective, safe and timely treatment in as few fractions as possible, respecting the patient's expectations.

      Impending or actual pathological fracture

      In complicated BM patients, surgery provides bone stabilization, tumour debulking, and, as a result, reduces pain and improves QoL [
      • Saravana-Bawan S.
      • David E.
      • Sahgal A.
      • Chow E.
      Palliation of bone metastases-exploring options beyond radiotherapy.
      ]. For BM in long bones, surgery is recommended for impending or pathological fracture [
      • Mirels H.
      Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures.
      ]. BM with Myrels scores ≥ 8 usually require prophylactic fixation before RT, and tumours with scores ≤ 7 can receive RT only [
      • Mirels H.
      Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures.
      ]. Post-operative RT is usually given to improve local control, reduce pain, improve bone repair and functional outcomes [
      • Drost L.
      • Ganesh V.
      • Wan B.A.
      • Raman S.
      • et al.
      Efficacy of postoperative radiation treatment for bone metastases in the extremities.
      ]. In BM with impending or pathologic fracture, several RT schedules are used in post-operative or sole treatment. There is little supporting evidence because these patients were excluded in most phase 3 trials. It is currently unknown whether one or two dose schedules are as effective as the more conventional schedules, such as 20 Gy in 5 fractions or 30 Gy in 10 fractions.
      In a retrospective study, 60 BM patients with impending or actual pathologic fractures, postoperative RT increased the probability of achieving a functional status: 53% versus 11.5% in patients with surgery alone (p < 0.01) [
      • Townsend P.W.
      • Smalley S.R.
      • Cozad S.C.
      • Rosenthal H.G.
      • Hassanein R.E.
      Role of postoperative radiation therapy after stabilization of fractures caused by metastatic disease.
      ]. With surgery alone, 15% of the fixated sites (4/26) required a subsequent orthopaedic procedure after a mean time of 12.5% versus 3% in the postoperative RT group (p = 0.03). Evaluation of best functional status and the RT course did not reveal any clear dose–response relationship, although 19 out of 26 patients received 30 Gy in the surgery plus postoperative RT arm [
      • Townsend P.W.
      • Smalley S.R.
      • Cozad S.C.
      • Rosenthal H.G.
      • Hassanein R.E.
      Role of postoperative radiation therapy after stabilization of fractures caused by metastatic disease.
      ].
      More pathologic fractures with single-fraction RT (3%) than with multiple fraction treatment (1.6%) have been reported but an associated test for heterogeneity was statistically not significant (p = 0.34) [

      Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004;2002:CD004721. 10.1002/14651858.CD004721.

      ]. Overall, the risk of developing a pathologic fracture was almost double in the single fraction arm when compared to multiple fraction RT [

      Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004;2002:CD004721. 10.1002/14651858.CD004721.

      ].

      Spinal cord compression (SCC)

      For many spinal BM patients, surgical intervention is the initial recommendation for SCC or spine instability [
      • Fisher C.G.
      • DiPaola C.P.
      • Ryken T.C.
      • Bilsky M.H.
      • et al.
      A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group.
      ]. Axial stability and indications for a surgical consultation are identified with the Spinal Instability Neoplastic Score (SINS) [
      • Fisher C.G.
      • DiPaola C.P.
      • Ryken T.C.
      • Bilsky M.H.
      • et al.
      A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group.
      ]. For SCC patients, combined therapy (surgery plus post-operative RT with conventional dose) improved outcomes with 84% (42/50) of the patients being able to walk after treatment versus 57% in the RT alone arm [
      • Patchell R.A.
      • Tibbs P.A.
      • Regine W.F.
      • Payne R.
      • et al.
      Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.
      ]. For patients who were incapable of walking, surgery resulted in a higher recovery rate in walking ability (62% versus 19%, p = 0.01) [
      • Patchell R.A.
      • Tibbs P.A.
      • Regine W.F.
      • Payne R.
      • et al.
      Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.
      ]. Patients who underwent surgery retained the ability to walk longer than in the RT alone (median 122 days versus 13 days, p = 0.03) [
      • Patchell R.A.
      • Tibbs P.A.
      • Regine W.F.
      • Payne R.
      • et al.
      Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.
      ]. Surgery techniques such as vertebroplasty or kyphoplasty do not obviate the need for adjuvant RT [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ]. In 1997, Maranzano et al treated 53 poor prognosis patients defined by radioresistant tumours or radiosensitive histologies in patients with plegia, paresis, ECOG performance status ≥ 2, and/or short life expectancy who had SCC and determined the safety profile and efficacy of 16 Gy in two fractions of 8 Gy one week apart [
      • Maranzano E.
      • Latini P.
      • Perrucci E.
      • Beneventi S.
      • et al.
      Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment.
      ]. The response rate, duration of response, and survival were similar to those observed in patients treated with 30 Gy in 8–10 fractions in a previous publication from the same group [
      • Maranzano E.
      • Latini P.
      • Perrucci E.
      • Beneventi S.
      • et al.
      Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment.
      ,
      • Maranzano E.
      • Latini P.
      Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial.
      ]. Mild oesophagitis with dysphagia for solid foods occurred in 8 of 25 patients (35%) having the thoracic spine treated, and there were few skin reactions. Moreover, 16 Gy in 2 fractions 1 week apart reduced cost to the RT centre and patient burden due to fewer treatment visits. Back pain requiring high dose opioids occurred in 3 of 33 responders who initially did not have pain or had pain controlled by minor analgesics 4 to 13-months from RT. These patients with in-field relapse underwent a second palliative course of RT and did not develop reduced ambulation. Subsequently, a phase III, randomized controlled trial examining the efficacy of short-course 8 Gy × 2, one week apart versus split-course RT (5 Gy × 3; 3 Gy × 5) in the treatment of patients with SCC and a life expectancy ≤ 6 months was performed [
      • Maranzano E.
      • Bellavita R.
      • Rossi R.
      • De Angelis V.
      • et al.
      Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial.
      ]. With 276 assessable patients, both RT courses were equally effective without severe side effects.

      Soft tissue mass

      Another relatively common clinical situation is complicated BM that present with a soft tissue mass or extra osseous component penetrating the cortical boundary. Patients in this population have traditionally had good response rates to RT [
      • Onufrey V.
      • Mohiuddin M.
      Radiation therapy in the treatment of metastatic renal cell carcinoma.
      ]. A study of 30 patients with BM extending into soft tissues included 18 treated with RT but with no details concerning dose fractionation schedules [
      • Damron T.A.
      • Heiner J.
      Distant soft tissue metastases: a series of 30 new patients and 91 cases from the literature.
      ]. In addition to these findings, our group evaluated the efficacy and safety profile of 16 Gy in 2 fractions of 8 Gy one week apart in complicated BM population cohorts [
      • Silva M.F.
      • Marta G.N.
      • Lisboa F.P.C.
      • Watte G.
      • et al.
      Hypofractionated radiotherapy for complicated bone metastases in patients with poor performance status: a phase II international trial.
      ]. In this phase II clinical trial, with 50 patients having poor performance status, 38 had an extra osseous soft tissue component, 18 needed post-surgical radiation, 3 had neuropathic pain, 3 had an impending fracture in a weight-bearing bone, and no patient had SCC [
      • Silva M.F.
      • Marta G.N.
      • Lisboa F.P.C.
      • Watte G.
      • et al.
      Hypofractionated radiotherapy for complicated bone metastases in patients with poor performance status: a phase II international trial.
      ]. At 2 months, 33 patients were alive (66%), four (12.5%) had a complete response and 12 (37.5%) had a partial response. A statistically significant improvement was seen in functional interference (p = 0.01) and psychosocial aspects (p = 0.03) of the BM22 QoL questionnaire. One patient required surgery for pathologic fracture, and another re-irradiation. 16 Gy in 2 fractions one week apart achieved satisfactory pain relief and safety results in patients with complicated BM [
      • Silva M.F.
      • Marta G.N.
      • Lisboa F.P.C.
      • Watte G.
      • et al.
      Hypofractionated radiotherapy for complicated bone metastases in patients with poor performance status: a phase II international trial.
      ]. It is important to point out the low survival rates in this group of patients, with a mean of 3.5 months after RT. This clearly supports shorter treatment and fewer visits, maintaining QoL in this group of patients.
      One other study [
      • Onufrey V.
      • Mohiuddin M.
      Radiation therapy in the treatment of metastatic renal cell carcinoma.
      ], identified five sites of soft tissue mass with no difference in response between varying fractionation schemes delivering doses which ranged from 20 to 60 Gy. This paucity of evidence has stemmed from the fact that much of the relevant literature is composed of case reports and small series [
      • Damron T.A.
      • Heiner J.
      Distant soft tissue metastases: a series of 30 new patients and 91 cases from the literature.
      ]. As such, further research into this patient population and its appropriate management with RT is warranted.

      Reirradiation

      Reirradiation is more common after treatment with single fraction RT than in patients treated with multiple fractions RT [
      • Rich S.E.
      • Chow R.
      • Raman S.
      • Liang Zeng K.
      • et al.
      Update of the systematic review of palliative radiation therapy fractionation for bone metastases.
      ]. These differences in the retreatment rate could represent a greater predisposition to repeat RT after single RT than a real need. In addition to the higher reirradiation rate, some studies suggest that patients treated with single dose RT could have more bone fractures and it has been argued that fractionated RT courses are preferable for patients with longer predicted survival [

      Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004;2002:CD004721. 10.1002/14651858.CD004721.

      ,
      • Steenland E.
      • Leer J.W.
      • van Houwelingen H.
      • Post W.J.
      • et al.
      The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study.
      ,

      8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party. Radiother Oncol 1999;52:111-21.

      ,
      • Badzio A.
      • Senkus-Konefka E.
      • Jereczek-Fossa B.
      • Adamska K.
      • et al.
      20 Gy in five fractions versus 8 Gy in one fraction in palliative radiotherapy of bone metastases: a multicenter randomized study.
      ,
      • Hartsell W.F.
      • Scott C.B.
      • Bruner D.W.
      • Scarantino C.W.
      • et al.
      Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases.
      ].
      In a large randomised study, the role of reirradiation was evaluated in 425 patients with painful BM comparing two fractionations, 8 Gy in 1 fraction and 20 Gy in five fractions. In the intention-to-treat analysis, after two months, the overall pain response rate using the Brief Pain Inventory Score was 28% in the 8 Gy group versus 32% in the 20 Gy arm (p = 0.21), and in the per-protocol analysis, it was 45% versus 51%, respectively (p = 0.17). Patients treated with 20 Gy compared with the 8 Gy arm reported more lack of appetite (66% versus 56%, p = 0.011) and diarrhoea (31% versus 23%, p = 0.018) [
      • Chow E.
      • van der Linden Y.M.
      • Roos D.
      • Hartsell W.F.
      • et al.
      Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial.
      ].

      Novel treatment paradigms in BM: systemic treatment, oligometastases, and local ablative technologies

      Systemic anti-cancer therapy and oligometastases

      Systemic anti-cancer treatment of metastatic cancer is becoming more targeted and precision-based with recent advances in molecular targeted therapies, novel hormonal agents and immunotherapy making chemotherapy no longer the only option for patients with advanced malignancies [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ]. Selection of appropriate personalized systemic treatment strategies for metastatic disease is based on identification of actionable targets including EGFR, ALK, ROS1, and TREK-fusion in NSCLC; estrogen receptor, HER-2, CDK4/6, mTOR inhibition PIK3CA in breast cancer; RAS, BRAF, VEGF in colorectal cancer; androgen dependency in prostate cancer; VEGF, MET in renal cell carcinoma, VEGF in hepatocellular carcinoma, HER-2 in gastroesophageal cancer, and, more recently, PARP inhibitors for BRCA mutation carriers, and immune check-point inhibition of PD1, PDL1, and CTLA4 in various cancer types including melanoma, NSCLC, renal and head and neck cancers. For patients who are identified with BM, the decision whether to proceed with or continue systemic therapy or to have local treatment is largely dependent on whether the patient is symptomatic with severe pain, with an imminent risk of fracture or spinal cord compression when RT or surgery should always be considered [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ,
      • Maranzano E.
      • Bellavita R.
      • Rossi R.
      • De Angelis V.
      • et al.
      Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial.
      ,
      • Maranzano E.
      • Latini P.
      • Perrucci E.
      • Beneventi S.
      • et al.
      Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment.
      ,
      • Maranzano E.
      • Latini P.
      Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial.
      ]. It is essential to assess and risk stratify the patient based on performance status, and restaging to evaluate the benefit from further systemic treatment, Fig. 1 [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ].
      Figure thumbnail gr1
      Fig. 1Initial assessment algorithm for patients with bone metastases KPS = Karnofsky performance status. EBRT = external-beam radiotherapy. MNOP = mechanical, neurological, oncological, preferred treatment. * For select patients with effective systemic therapy treatment options, systemic therapy without use of radiotherapy might be appropriate.
      The oligometastatic concept was first described in 1995 recognising a subset of patients with a more favourable prognosis due to limited metastatic disease where there might be a survival benefit with local ablative treatment, such as SABR and SRS, radiofrequency ablation (RFA) or surgery [
      • Hellman S.
      • Weichselbaum R.R.
      Oligometastases.
      ]. Recently, oligometastatic disease has been redefined as 1 to 5 metastatic lesions, with or without control of the primary tumour [
      • Lievens Y.
      • Guckenberger M.
      • Gomez D.
      • Hoyer M.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document.
      ]. The theory behind giving metastases-directed ablative therapy to oligometastatic disease is based on the observation that in some patients further metastatic progression does not occur [
      • Jamal-Hanjani M.
      • Wilson G.A.
      • McGranahan N.
      • Birkbak N.J.
      • et al.
      Tracking the evolution of non–small-cell lung cancer.
      ].
      The International Registry of Lung Metastases, with data from 13 centres in Europe and 4 in North America collected data on 5,206 patients with lung metastases over five decades [
      • Pastorino U.
      • Buyse M.
      • Friedel G.
      • Ginsberg R.J.
      • et al.
      International Registry of Lung Metastases. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases.
      ]. In cases with complete resection, the actuarial 5-year overall survival (OS) was 36%. A 5-year survival rate ranging from 28 to 58% for patients with colorectal hepatic metastasis treated with surgery is reported in four different studies with a total of 3733 patients [
      • Weichselbaum R.R.
      • Hellman S.
      Oligometastases revisited.
      ]. The improved accuracy in image methods has enabled the early detection and the characterization of different types of oligometastases: induced oligometastatic disease, genuine oligometastatic disease (repeat or de-novo oligometastases); with additional classifications (synchronous, metachronous, oligorecurrence, oligoprogression, and oligopersistence) [
      • Guckenberger M.
      • Lievens Y.
      • Bouma A.B.
      • Collette L.
      • et al.
      Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation.
      ]. Therefore, local ablative therapies can delay change or use of systemic therapy, preserve patients' Qol, and improve disease-free survival, progression-free survival, and overall survival [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ,
      • Ost P.
      • Reynders D.
      • Decaestecker K.
      • Fonteyne V.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial.
      ,
      • Siva S.
      • Bressel M.
      • Murphy D.G.
      • Shaw M.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for oligometastatic prostate cancer: a prospective clinical trial.
      ,
      • Ruers T.
      • Punt C.
      • Van Coevorden F.
      • Pierie J.P.E.N.
      • et al.
      EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
      ,
      • Mitchell K.G.
      • Farooqi A.
      • Ludmir E.B.
      • Corsini E.M.
      • et al.
      Improved overall survival with comprehensive local consolidative therapy in synchronous oligometastatic non-small-cell lung cancer.
      ].

      Oligometastases and local ablative therapy

      Recently, in the phase II Comet trial, patients with oligometastatic disease, with 1 to 5 metastases and controlled primary tumours, were randomized to SABR to all known disease sites versus palliative RT if required [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ]. In this study, bone was the second most common site of metastases, corresponding to one-third of metastases in the whole study (65/191 metastases). 35% (n = 45) of the patients in the experimental arm have BM versus 31% (n = 20) in the conventional RT arm [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ]. Patients in the SABR group had longer median overall survival (41 versus 28 months, p = 0.09) and better progression-free survival (12 versus 6 months, p = 0.001) compared with the standard of care arm [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ]. The ongoing COMET 3 and 10 trials have also included translational biomarkers: circulating tumour cells, peripheral circulating immune cells, and circulating tumour DNA [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Correa R.J.M.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of 4–10 oligometastatic tumours (SABR-COMET-10): study protocol for a randomized phase III trial.
      ,
      • Olson R.
      • Mathews L.
      • Liu M.
      • Schellenberg D.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of 1–3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.
      ].
      Cohort studies of local treatments have demonstrated benefits in oligometastatic patients in specific cancer types. In the phase II STOMP trial, prostate cancer patients receiving local treatment (metastasectomy or SABR) had an improved 5-year hormone therapy-free survival of 34% versus 8% in the observation group [
      • Ost P.
      • Reynders D.
      • Decaestecker K.
      • Fonteyne V.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial.
      ]. This is similar to a single arm study reporting a 2-year hormone therapy-free survival of 48% with SABR in metastatic prostate cancer patients without previous androgen blockage with a local progression-free survival of 97% and 93% at 1 and 2 years, respectively [
      • Siva S.
      • Bressel M.
      • Murphy D.G.
      • Shaw M.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for oligometastatic prostate cancer: a prospective clinical trial.
      ]. In patients with non-resectable colorectal liver metastases, in the European Organization for Research and Treatment of Cancer (EORTC) 40,004 trial, the addition of local therapy to systemic therapy increased the median progression-free survival (PFS) to 16.8 months versus 9.9 months with systemic therapy alone [
      • Ruers T.
      • Punt C.
      • Van Coevorden F.
      • Pierie J.P.E.N.
      • et al.
      EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
      ]. At three years, the PFS rate with local treatment was 27.6% compared to 10.6% with systemic treatment alone (p = 0.025) [
      • Ruers T.
      • Punt C.
      • Van Coevorden F.
      • Pierie J.P.E.N.
      • et al.
      EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
      ]. The observed median OS was 5 months longer in the arm with local therapy compared with chemotherapy alone after a long-term median follow-up of 9.7 years [
      • Ruers T.
      • Punt C.
      • Van Coevorden F.
      • Pierie J.P.E.N.
      • et al.
      EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
      ].
      A further study in stage IV non-small cell lung cancer (NSCLC) patients with oligoprogressive disease who received local ablative therapy for progressive or persistent metastases while receiving targeted, or immunotherapy showed survival rates that seem to show an improvement compared to patients in the literature who received systemic treatment alone [
      • Kroeze S.G.
      • Fritz C.
      • Hoyer M.
      • Lo S.S.
      • et al.
      Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review.
      ]. The median time to therapy switch was 14 months for oligoprogressive disease patients compared to 8 months for polyprogressive disease patients [
      • Kroeze S.G.
      • Fritz C.
      • Hoyer M.
      • Lo S.S.
      • et al.
      Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review.
      ]. Similarly a retrospective cohort study of oligometastatic NSCLC patients using local consolidative therapy in addition to systemic therapy, where 64% received platinum chemotherapy while 24% received angiogenesis inhibitor or targeted therapy, was associated with better survival (p = 0.034) [
      • Mitchell K.G.
      • Farooqi A.
      • Ludmir E.B.
      • Corsini E.M.
      • et al.
      Improved overall survival with comprehensive local consolidative therapy in synchronous oligometastatic non-small-cell lung cancer.
      ]. Although evidence to support the concept of targeting oligoprogressive disease while continuing systemic therapy beyond progression is limited, it is increasingly practised in the real world clinical setting.

      Ablative techniques for bone metastases

      Stereotactic irradiation techniques like SRS and SABR enable administration of ablative doses of radiation to primary or metastatic tumours sparing the surrounding healthy tissues with a rapid fall of dose outside the target. The “ablative effect” associated with high dose radiation overcomes intrinsic tumour cell radioresistance and induces indirect effects, including vascular endothelial injury and immune activation [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ]. While the ASTRO BM guideline suggests that SRS and SABR in BM should be limited to clinical trials [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ], the National Comprehensive Cancer Network (NCCN) guideline recognizes that SRS and SABR may be preferred in three circumstances: reirradiation (to reduce RT dose in the spinal cord and other critical organs), oligometastatic disease (with the purpose of tumour ablation), and in radioresistant tumours (melanoma, sarcoma, renal cell, and hepatocellular carcinoma) [

      National Comprehensive Cancer Network NCCN: Central Nervous System Cancers V3.2020 https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf Date: 2020 (september 11,2020. Accessed January 10, 2021).

      ]. In Table 1 and Table 2, the studies with different uses of such modalities and their outcomes are summarized [
      • Gerszten P.C.
      • Germanwala A.
      • Burton S.A.
      • Welch W.C.
      • et al.
      Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures.
      ,
      • Gagnon G.J.
      • Henderson F.C.
      • Gehan E.A.
      • Sanford D.
      • et al.
      Cyberknife radiosurgery for breast cancer spine metastases: a matched-pair analysis.
      ,
      • Choi C.Y.
      • Adler J.R.
      • Gibbs I.C.
      • Chang S.D.
      • et al.
      Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord.
      ,
      • Staehler M.
      • Haseke N.
      • Nuhn P.
      • Tüllmann C.
      • et al.
      Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma.
      ,
      • Garg A.K.
      • Wang X.S.
      • Shiu A.S.
      • Allen P.
      • et al.
      Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience.
      ,
      • Mahadevan A.
      • Floyd S.
      • Wong E.
      • Jeyapalan S.
      • et al.
      Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases.
      ,
      • Nikolajek K.
      • Kufeld M.
      • Muacevic A.
      • Wowra B.
      • et al.
      Spinal radiosurgery–efficacy and safety after prior conventional radiotherapy.
      ,
      • Chang U.K.
      • Cho W.I.
      • Kim M.S.
      • Cho C.K.
      • et al.
      Local tumour control after retreatment of spinal metastasis using stereotactic body radiotherapy; comparison with initial treatment group.
      ,
      • Heron D.E.
      • Rajagopalan M.S.
      • Stone B.
      • Burton S.
      • et al.
      Single-session and multisession CyberKnife radiosurgery for spine metastases University of Pittsburgh and Georgetown University experience.
      ,
      • Hunter G.K.
      • Balagamwala E.H.
      • Koyfman S.A.
      • Bledsoe T.
      • et al.
      The efficacy of external beam radiotherapy and stereotactic body radiotherapy for painful spinal metastases from renal cell carcinoma.
      ,
      • Jahanshahi P.
      • Nasr N.
      • Unger K.
      • Batouli A.
      • Gagnon G.J.
      Malignant melanoma and radiotherapy: past myths, excellent local control in 146 studied lesions at Georgetown University, and improving future management.
      ,
      • Massicotte E.
      • Foote M.
      • Reddy R.
      • Sahgal A.
      Minimal access spine surgery (MASS) for decompression and stabilization performed as an out-patient procedure for metastatic spinal tumours followed by spine stereotactic body radiotherapy (SBRT): first report of technique and preliminary outcomes.
      ,
      • Wang X.S.
      • Rhines L.D.
      • Shiu A.S.
      • Yang J.N.
      • et al.
      Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial.
      ,
      • Al-Omair A.
      • Masucci L.
      • Masson-Cote L.
      • Campbell M.
      • et al.
      Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy.
      ,
      • Laufer I.
      • Iorgulescu J.B.
      • Chapman T.
      • Lis E.
      • et al.
      Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.
      ,
      • Muacevic A.
      • Kufeld M.
      • Rist C.
      • Wowra B.
      • et al.
      Safety and feasibility of image-guided robotic radiosurgery for patients with limited bone metastases of prostate cancer.
      ,
      • Folkert M.R.
      • Bilsky M.H.
      • Tom A.K.
      • Oh J.H.
      • et al.
      Outcomes and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcomas metastasizing to the spine.
      ,
      • Amini A.
      • Altoos B.
      • Bourlon M.T.
      • Bedrick E.
      • et al.
      Local control rates of metastatic renal cell carcinoma (RCC) to the bone using stereotactic body radiation therapy: is RCC truly radioresistant?.
      ,
      • Colaco R.J.
      • Park H.S.
      • Laurans M.S.
      • Chiang V.S.
      • et al.
      Spine stereotactic body radiotherapy outcomes in patients with concurrent brain metastases.
      ,
      • Thibault I.
      • Campbell M.
      • Tseng C.L.
      • Atenafu E.G.
      • et al.
      Salvage Stereotactic Body Radiotherapy (SBRT) following in-field failure of initial SBRT for spinal metastases.
      ,
      • Ghia A.J.
      • Chang E.L.
      • Bishop A.J.
      • Pan H.Y.
      • et al.
      Single fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials.
      ,
      • Sohn S.
      • Chung C.K.
      • Sohn M.J.
      • Kim S.H.
      • et al.
      Radiosurgery compared with external radiation therapy as a primary treatment in spine metastasis from hepatocellular carcinoma: a multicenter, matched-pair study.
      ,
      • Ursino S.
      • Montrone S.
      • Cantarella M.
      • Menghini V.
      • et al.
      Stereotactic body radiotherapy of bone metastases in oligometastatic disease: prognostic factors of oncologic outcomes.
      ,
      • Mehta N.
      • Zavitsanos P.J.
      • Moldovan K.
      • Oyelese A.
      • et al.
      Local failure and vertebral body fracture risk using multifraction stereotactic body radiation therapy for spine metastases.
      ,
      • Sprave T.
      • Verma V.
      • Förster R.
      • Schlampp I.
      • et al.
      Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy.
      ,

      Ryu S, Deshmukh S, Timmerman RD, Movsas B, et al. Radiosurgery Compared To External Beam Radiotherapy for Localized Spine Metastasis: Phase III Results of NRG Oncology/RTOG 0631. Presented at ASTRO 2019 Annual Meeting, Chicago, IL. Int J Radiat Oncol Biol Phys 2019;105: Supplement, S2–S3.

      ,
      • McGee H.M.
      • Carpenter T.J.
      • Ozbek U.
      • Kirkwood K.A.
      • et al.
      Analysis of local control and pain control after spine stereotactic radiosurgery reveals inferior outcomes for hepatocellular carcinoma compared with other radioresistant histologies.
      ,
      • Nguyen Q.N.
      • Chun S.G.
      • Chow E.
      • Komaki R.
      • et al.
      Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial.
      ,
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • et al.
      CCTG SC.24/TROG 17.06: A randomized phase II/III study comparing 24Gy in 2 Stereotactic Body Radiotherapy (SBRT) fractions versus 20Gy in 5 Conventional Palliative Radiotherapy (CRT) fractions for patients with painful spinal metastases.
      ,
      • Zelefsky M.J.
      • Yamada Y.
      • Greco C.
      • Lis E.
      • et al.
      Phase 3 multi-center, prospective, randomized trial comparing single-dose 24 Gy radiation therapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer.
      ].
      Table 1Stereotactic ablative radiotherapy (SBRT) trials and type of study in bone metastases patients.
      Author, year [Ref.]SABR useStudy TypePain Response (%)Local ControlNumber of PatientsTotal Dose (Gy)Number of FractionsDeviceRT Prescription Parameters
      Gerszten, 2005
      • Gerszten P.C.
      • Germanwala A.
      • Burton S.A.
      • Welch W.C.
      • et al.
      Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures.
      POSProspective

      Single arm
      92-26mean 18

      (16 to 20)
      1CyberKnife80% isodose line
      Gagnon, 2007
      • Gagnon G.J.
      • Henderson F.C.
      • Gehan E.A.
      • Sanford D.
      • et al.
      Cyberknife radiosurgery for breast cancer spine metastases: a matched-pair analysis.
      RIR, CCRTRetrospective

      Matched-pair analysis of historical controls
      --3521–283–5CyberKnife and LinacNot mentioned
      Choi, 2010
      • Choi C.Y.
      • Adler J.R.
      • Gibbs I.C.
      • Chang S.D.
      • et al.
      Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord.
      RIRRetrospective65 (considering patients presenting with pain)73 (1y)42median 20 (10–30)median 2

      (1–5)
      CyberKnife77% isodose

      line (median)

      (range, 68–88%)
      Staehler, 2010
      • Staehler M.
      • Haseke N.
      • Nuhn P.
      • Tüllmann C.
      • et al.
      Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma.
      RRTRetrospective-94.1(1y)5520 median (19–20)1CyberKnife70% isodose

      line (median)

      (range 50–85%).
      Garg, 2011
      • Garg A.K.
      • Wang X.S.
      • Shiu A.S.
      • Allen P.
      • et al.
      Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience.
      RIRProspective-76 (1y)5927–303–5Linac80% to 90% of the target volume

      received the prescription dose
      Mahadevan, 2011
      • Mahadevan A.
      • Floyd S.
      • Wong E.
      • Jeyapalan S.
      • et al.
      Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases.
      RIRRetrospective65 (1 month after SBRT)93 (last visit)6024–303–5CyberKnifeMean prescription isodose 79% range(68–90%)
      Nikolajef, 2011
      • Nikolajek K.
      • Kufeld M.
      • Muacevic A.
      • Wowra B.
      • et al.
      Spinal radiosurgery–efficacy and safety after prior conventional radiotherapy.
      RIRRetrospectivesignificant reduction in VAS score of patients with pain (2 months)88 (1y)54median 18 (10–28)1CyberKnifeMedian prescription isodose line 70% (range 50–80%)
      Chang, 2012
      • Chang U.K.
      • Cho W.I.
      • Kim M.S.
      • Cho C.K.
      • et al.
      Local tumour control after retreatment of spinal metastasis using stereotactic body radiotherapy; comparison with initial treatment group.
      RIR, PRIRetrospective81–89 (1y)Retreatment: 81 (1y)



      Initial RT 89 (1y)
      185Retreatment: 14.7–26.5



      Initial RT: 16.6–23.2
      1CyberKnifeRetreatment: 78.3 % isodose line

      Initial RT 79.3 % isodose line
      Heron, 2012
      • Heron D.E.
      • Rajagopalan M.S.
      • Stone B.
      • Burton S.
      • et al.
      Single-session and multisession CyberKnife radiosurgery for spine metastases University of Pittsburgh and Georgetown University experience.
      PRIRetrospective88 MF vs 100 SF96 MF vs 70 SF (2y)228MF:

      20.6 (9–26.3)



      SF:

      16.3 (6–20) 1
      MF: 3–5



      SF: 1
      CyberKnifeMF: 80% isodose line (range 70%–95%)

      SF: 72% isodose line (range 50%–85%)
      Hunter, 2012
      • Hunter G.K.
      • Balagamwala E.H.
      • Koyfman S.A.
      • Bledsoe T.
      • et al.
      The efficacy of external beam radiotherapy and stereotactic body radiotherapy for painful spinal metastases from renal cell carcinoma.
      CCRT, RRTRetrospectiveCRT: 68 - SBRT:62 (overall)-1108–301–10LinacCRT: prescribed to a depth, or the isocentre

      SBRT: not mentioned
      Jahanshahi, 2012
      • Jahanshahi P.
      • Nasr N.
      • Unger K.
      • Batouli A.
      • Gagnon G.J.
      Malignant melanoma and radiotherapy: past myths, excellent local control in 146 studied lesions at Georgetown University, and improving future management.
      RRT, OLIRetrospective-72–100 (1y)50mean 24.1 (7.7–54)1–5CyberKnifeMean prescription isodose 78.7%
      Massicote, 2012
      • Massicotte E.
      • Foote M.
      • Reddy R.
      • Sahgal A.
      Minimal access spine surgery (MASS) for decompression and stabilization performed as an out-patient procedure for metastatic spinal tumours followed by spine stereotactic body radiotherapy (SBRT): first report of technique and preliminary outcomes.
      POS, RRTRetrospectiveMedian improvement on VAS was 6 points

      (5 months)
      7010median 24 (18–35)1–5Linac80–90% of CTV coverage
      Wang, 2012
      • Wang X.S.
      • Rhines L.D.
      • Shiu A.S.
      • Yang J.N.
      • et al.
      Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial.
      PRI, RIR, POSProspectiveIncrease in patients without 26.2 vs 53.9

      (6 months)
      80.514927–303LinacNot mentioned
      Al-Omair, 2013
      • Al-Omair A.
      • Masucci L.
      • Masson-Cote L.
      • Campbell M.
      • et al.
      Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy.
      POS, RRTRetrospective-84 (1y)80median 24

      (18–40)
      median 2

      (1–5)
      LinacMedian CTV V80 in 90% of the patients
      Laufer, 2013
      • Laufer I.
      • Iorgulescu J.B.
      • Chapman T.
      • Lis E.
      • et al.
      Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.
      POS, RRTRetrospective-83,6 (1y)18618–361–6-Not mentioned
      Muacevic, 2013
      • Muacevic A.
      • Kufeld M.
      • Rist C.
      • Wowra B.
      • et al.
      Safety and feasibility of image-guided robotic radiosurgery for patients with limited bone metastases of prostate cancer.
      OLI, RRTProspective-95 (1y)40median 20 (16.5–22)1CyberKnifeMedian peripheral isodose 70% (60–80)
      Folker, 2014
      • Folkert M.R.
      • Bilsky M.H.
      • Tom A.K.
      • Oh J.H.
      • et al.
      Outcomes and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcomas metastasizing to the spine.
      RRT, OLIRetrospective-87.9 (1y)8818–361–6LinacMedian prescription D95% coverage 95% of PTV
      Amini, 2015
      • Amini A.
      • Altoos B.
      • Bourlon M.T.
      • Bedrick E.
      • et al.
      Local control rates of metastatic renal cell carcinoma (RCC) to the bone using stereotactic body radiation therapy: is RCC truly radioresistant?.
      RRT, CCRTRetrospective74.9 SBRT, 39,9 Conv (1y)74.1 S − 45,1C (1y)468–401–12LinacNot mentioned
      Colaco, 2015
      • Colaco R.J.
      • Park H.S.
      • Laurans M.S.
      • Chiang V.S.
      • et al.
      Spine stereotactic body radiotherapy outcomes in patients with concurrent brain metastases.
      OLIRetrospective-89 (1y)7810–171–3Linac and Gamma KnifeNot mentioned
      Thibault, 2015
      • Thibault I.
      • Campbell M.
      • Tseng C.L.
      • Atenafu E.G.
      • et al.
      Salvage Stereotactic Body Radiotherapy (SBRT) following in-field failure of initial SBRT for spinal metastases.
      RIRRetrospective-81 (1y)4020–351–5LinacAimed to cover > 80% of the PTV minus the CNT with 95–100% dose.
      Ghia, 2016
      • Ghia A.J.
      • Chang E.L.
      • Bishop A.J.
      • Pan H.Y.
      • et al.
      Single fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials.
      RRT, POSCRT-82 (1y)4324–301–5Linacisodose was normalized to the isocenter and the dose prescribed to the volume included by the 90% isodose line
      Sohn, 2016
      • Sohn S.
      • Chung C.K.
      • Sohn M.J.
      • Kim S.H.
      • et al.
      Radiosurgery compared with external radiation therapy as a primary treatment in spine metastasis from hepatocellular carcinoma: a multicenter, matched-pair study.
      CCRTRetrospectivePost-treatment VAS scores were lower in both groups32 conv, 59 SBRT (1y)56Mean 31–35Mean 4–10CyberKnife and LinacTumor volume covered by the prescription dose was more than 90% (mean, 96%).
      Ursino, 2016
      • Ursino S.
      • Montrone S.
      • Cantarella M.
      • Menghini V.
      • et al.
      Stereotactic body radiotherapy of bone metastases in oligometastatic disease: prognostic factors of oncologic outcomes.
      OLIRetrospective-90.2 (1y)4024–271–3LinacNot mentioned
      Mehta, 2018
      • Mehta N.
      • Zavitsanos P.J.
      • Moldovan K.
      • Oyelese A.
      • et al.
      Local failure and vertebral body fracture risk using multifraction stereotactic body radiation therapy for spine metastases.
      POS, PRI, OLI, RIRRetrospective-84% (1y)83median 24 (14–44)median 3 (2–5)CyberKnifePlans were optimized to try to keep the prescription isodose line ≥ 80%.
      Sprave, 2018
      • Sprave T.
      • Verma V.
      • Förster R.
      • Schlampp I.
      • et al.
      Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy.
      CCRTProspective52,6 SBRT vs 10 Conv VAS complete response (6 months)-5524–301–10Linac and TomoTherapySBRT PTV covered by 80% isodose.
      Ryu, 2019

      Ryu S, Deshmukh S, Timmerman RD, Movsas B, et al. Radiosurgery Compared To External Beam Radiotherapy for Localized Spine Metastasis: Phase III Results of NRG Oncology/RTOG 0631. Presented at ASTRO 2019 Annual Meeting, Chicago, IL. Int J Radiat Oncol Biol Phys 2019;105: Supplement, S2–S3.

      CCRTProspectiveNo difference in pain response (3 months)-3398, 16–181-Not mentioned
      McGee, 2019
      • McGee H.M.
      • Carpenter T.J.
      • Ozbek U.
      • Kirkwood K.A.
      • et al.
      Analysis of local control and pain control after spine stereotactic radiosurgery reveals inferior outcomes for hepatocellular carcinoma compared with other radioresistant histologies.
      PRI, RRT, POSRetrospective93 in patients with pain41 vs 85 (1y)41/9614–181Linacdose prescribed to the 100% isodose line, and normalization values ranged from 90% to 113.5%.
      Nguyen, 2019
      • Nguyen Q.N.
      • Chun S.G.
      • Chow E.
      • Komaki R.
      • et al.
      Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial.
      CCRTProspective77 SBRT, 46 conv

      (9 months)
      100 vs 90.5 (1y)16012–16, 301, 10LinacMixed radiotherapy techniques from conventional (2d) to SBRT.
      Sahgal, 2020
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • et al.
      CCTG SC.24/TROG 17.06: A randomized phase II/III study comparing 24Gy in 2 Stereotactic Body Radiotherapy (SBRT) fractions versus 20Gy in 5 Conventional Palliative Radiotherapy (CRT) fractions for patients with painful spinal metastases.
      CCRTProspective33 SBRT vs 16 conv

      (6 months)
      69 vs 7522920–241–5-Not mentioned
      Zelefsky, 2021
      • Zelefsky M.J.
      • Yamada Y.
      • Greco C.
      • Lis E.
      • et al.
      Phase 3 multi-center, prospective, randomized trial comparing single-dose 24 Gy radiation therapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer.
      PRI, OLIProspective-94.2 vs 78 (3y)11721–241–3Linac100% isodose line
      Abbreviations: POS, postoperative SBRT; CCRT, comparing with conventional RT; RIR, reirradiation; OLI, bone and or visceral oligometastases; PRI, primary treatment, and RRT, radioresistant tumors; CTV, the clinical target volume; PTV, planning target volume; CNT, critical neural tissues.The selection criteria data for each trial is available in Table 2
      A systematic review of SABR for BM analysed 38 studies evaluating pain response and 45 reporting local control. The local control rate was higher than 80% in most studies, and a >75% pain response was seen in more than half the studies with few high-grade toxicities [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ]. In the largest study in this series, with Patient Reported Outcomes in 149 cases, there were 12 grade 3 events (fatigue, pain, gastrointestinal disorder, and diaphoresis); spinal myelopathy was not reported, and reported low-grade toxicities were nausea, vomiting, and temporary numbness and tingling [
      • Wang X.S.
      • Rhines L.D.
      • Shiu A.S.
      • Yang J.N.
      • et al.
      Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial.
      ]. Ten trials with 676 patients prospectively registered toxicity and reported a 0.03% rate of grade 3 or 4 toxicity (n = 19) [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ]. In the 28 studies evaluating toxicity retrospectively, the rate of grade 3 or 4 toxicity was very low as well (5 cases in 2033 patients) [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ]. The median survival in these studies (ranging, 8–47 months), is longer than observed in conventional RT phase 3 trials in BM (median, 7 months) suggesting patient selection [
      • Steenland E.
      • Leer J.W.
      • van Houwelingen H.
      • Post W.J.
      • et al.
      The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study.
      ,
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ].
      A meta-analysis included 3237 patients with 4911 spinal oligometastases treated with SRS (43.8%), SABR (19.7%), or conventional RT (36.5%) [
      • Singh R.
      • Lehrer E.J.
      • Dahshan B.
      • Palmer J.D.
      • et al.
      Single fraction radiosurgery, fractionated radiosurgery, and conventional radiotherapy for spinal oligometastasis (SAFFRON): a systematic review and meta-analysis.
      ]. SRS treatment was associated with increased 1-year local control compared with conventional RT (92.9% versus 81.0% respectively, p = 0.007), and there was no difference in local control between conventional RT and SABR (81.0 % versus 82.1%, p = 0.86) [
      • Singh R.
      • Lehrer E.J.
      • Dahshan B.
      • Palmer J.D.
      • et al.
      Single fraction radiosurgery, fractionated radiosurgery, and conventional radiotherapy for spinal oligometastasis (SAFFRON): a systematic review and meta-analysis.
      ]. The overall grade 3–5 toxicity rate was low in all the groups, 0.4%, 0.2%, and none for SRS, SABR, and conventional RT, respectively. Nevertheless, SRS was associated with a higher risk of vertebral collapse fractures than SABR (19.5% versus 9.6%, respectively, p = 0.039) without an apparent dose effect [
      • Singh R.
      • Lehrer E.J.
      • Dahshan B.
      • Palmer J.D.
      • et al.
      Single fraction radiosurgery, fractionated radiosurgery, and conventional radiotherapy for spinal oligometastasis (SAFFRON): a systematic review and meta-analysis.
      ]. In contrast another review found doses per fraction ≥ 20 Gy were associated with increased vertebral fracture risk [
      • Loi M.
      • Nuyttens J.J.
      • Desideri I.
      • Greto D.
      • Livi L.
      Single-Fraction Radiotherapy (SFRT) for bone metastases: patient selection and perspectives.
      ].
      A randomized phase II study of 55 patients with painful spinal BM, reported that treatment with SRS (24 Gy/1 fraction) produced a faster reduction in pain than conventional RT (30 Gy/10 fractions) [
      • Sprave T.
      • Verma V.
      • Förster R.
      • Schlampp I.
      • et al.
      Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy.
      ]. A higher pain response at 6 months was also described, 73.7% with SRS versus 35% with conventional RT (p = 0.003); however, there were no differences in analgesic intake at 3 and 6 months) [
      • Sprave T.
      • Verma V.
      • Förster R.
      • Schlampp I.
      • et al.
      Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy.
      ].
      Another randomized phase II study showed higher pain control with SABR (24 Gy in 2 fractions) than with conventional RT (20 Gy in 5 fractions) [
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • et al.
      CCTG SC.24/TROG 17.06: A randomized phase II/III study comparing 24Gy in 2 Stereotactic Body Radiotherapy (SBRT) fractions versus 20Gy in 5 Conventional Palliative Radiotherapy (CRT) fractions for patients with painful spinal metastases.
      ]. At 3 months, the complete pain response rate was 36% (40/114) in the SABR arm versus 14% (16/115) in the conventional RT arm (p < 0.001). This difference persisted at 6 months, with 33% (37/114) complete pain response in the SABR group versus 16% (18/115) with conventional RT (p = 0.004) [
      • Sahgal A.
      • Myrehaug S.D.
      • Siva S.
      • Masucci L.
      • et al.
      CCTG SC.24/TROG 17.06: A randomized phase II/III study comparing 24Gy in 2 Stereotactic Body Radiotherapy (SBRT) fractions versus 20Gy in 5 Conventional Palliative Radiotherapy (CRT) fractions for patients with painful spinal metastases.
      ].
      However, in the early results of the phase 2/3 RTOG 0631 study, SABR did not improve pain response in patients with one to three spinal BM compared to conventional RT [

      Ryu S, Deshmukh S, Timmerman RD, Movsas B, et al. Radiosurgery Compared To External Beam Radiotherapy for Localized Spine Metastasis: Phase III Results of NRG Oncology/RTOG 0631. Presented at ASTRO 2019 Annual Meeting, Chicago, IL. Int J Radiat Oncol Biol Phys 2019;105: Supplement, S2–S3.

      ]. 209 patients were treated with SRS (16–18 Gy) and 130 received conventional external RT (8 Gy/1 fraction) and there were no differences in pain scores at 3 months (p = 0.99). Other important outcome measures when using SRS or SABR are complete response in terms of metastatic disease control and a consequent survival improvement which have yet to be reported [

      Ryu S, Deshmukh S, Timmerman RD, Movsas B, et al. Radiosurgery Compared To External Beam Radiotherapy for Localized Spine Metastasis: Phase III Results of NRG Oncology/RTOG 0631. Presented at ASTRO 2019 Annual Meeting, Chicago, IL. Int J Radiat Oncol Biol Phys 2019;105: Supplement, S2–S3.

      ].
      Comparison of single-dose SABR (24 Gy) with fractionated SABR (27 Gy in 3 fractions) found that single-dose SABR was associated with a lower local relapse rate at 2 and 3 years, 2.7% and 5.1%, respectively, compared with 9.1% and 22% with fractionated SABR (p = 0.0048) [
      • Zelefsky M.J.
      • Yamada Y.
      • Greco C.
      • Lis E.
      • et al.
      Phase 3 multi-center, prospective, randomized trial comparing single-dose 24 Gy radiation therapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer.
      ]. Furthermore, there was also a difference in progression with distant metastases in favour of single-dose SABR 5.3%, compared with 22.5% with SABR in 3 fractions in 3 years (p = 0.010) [
      • Zelefsky M.J.
      • Yamada Y.
      • Greco C.
      • Lis E.
      • et al.
      Phase 3 multi-center, prospective, randomized trial comparing single-dose 24 Gy radiation therapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer.
      ]. A consensus guideline has acknowledged the role of SABR after surgery in spine BM with tumours restricted to 1–2 vertebral levels, radioresistant disease, and previous RT [
      • Redmond K.J.
      • Lo S.S.
      • Soltys S.G.
      • Yamada Y.
      • et al.
      Consensus guidelines for postoperative stereotactic body radiation therapy for spinal metastases: results of an international survey.
      ].
      Reports on nonspine bone metastases (NSBM) are limited. In a systematic review by Spencer et al, only 8 of the 57 reviewed studies included NSBM and only 2 studied a population consisting exclusively of NSBM patients [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ]. There appears to be significant heterogeneity in the delivery of NSBM-SABR globally in terms of treatment technique and dose prescription. An expert consensus report on bone SABR, found complete agreement for a dose delivering a BED of ≤100 Gy10, and more than half of the panelists selected dose fractionations that had a BED of 60 Gy10 [
      • Nguyen T.K.
      • Sahgal A.
      • Dagan R.
      • Eppinga W.
      • et al.
      Stereotactic body radiation therapy for nonspine bone metastases: international practice patterns to guide treatment planning.
      ]. The majority would de-escalate the dose for re-irradiation with SABR and in weight-bearing bones with significant cortical erosion [
      • Nguyen T.K.
      • Sahgal A.
      • Dagan R.
      • Eppinga W.
      • et al.
      Stereotactic body radiation therapy for nonspine bone metastases: international practice patterns to guide treatment planning.
      ]. The lower bone SABR dose compared to other conventional SABR sites such as liver and lung where a BED > 100 Gy10 would usually be recommended reflects effective local control with lower doses and concern over RT-induced fracture. Single institution study have reported local control rates of 95% and 87% at 6 months and 24 months using SABR 30–35 Gy/5fr for NSBM, respectively [
      • Erler D.
      • Brotherston D.
      • Sahgal A.
      • Cheung P.
      • et al.
      Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases.
      ]. Another study used a wider range of SABR doses (15 Gy/1fr–50 Gy/5fr) and reported a 1- year LC rate of 92% [
      • Owen D.
      • Laack N.N.
      • Mayo C.S.
      • Garces Y.I.
      • et al.
      Outcomes and toxicities of stereotactic body radiation therapy for non-spine bone oligometastases.
      ].

      Immunotherapy and SABR

      Programmed death ligand 1 expression level is known to be correlated with response to immune checkpoint inhibitors (ICI) with PD1/PDL1 inhibitors. RT may be able to induce PDL-1 expression, improve response to immune checkpoint inhibition, and prevent development of resistance to immunotherapy [
      • Bauml J.M.
      • Mick R.
      • Ciunci C.
      • Aggarwal C.
      • et al.
      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
      ,
      • de Goeje P.L.
      • Smit E.F.
      • Waasdorp C.
      • Schram M.T.B.
      • et al.
      Stereotactic ablative radiotherapy induces peripheral T-cell activation in patients with early-stage lung cancer.
      ,
      • Evans J.D.
      • Morris L.K.
      • Zhang H.
      • Cao S.
      • et al.
      Prospective immunophenotyping of CD8+ T cells and associated clinical outcomes of patients with oligometastatic prostate cancer treated with metastasis-directed SBRT.
      ]. In a single arm phase 2 trial with oligometastatic (≤4 metastases) NSCLC patients, the use of pembrolizumab following a local ablative treatment to all tumour sites was associated with a significant improvement in the median progression-free survival of 19.1 versus 6.6 months when compared with historical data (p = 0.005) [
      • Bauml J.M.
      • Mick R.
      • Ciunci C.
      • Aggarwal C.
      • et al.
      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
      ].
      A small nonrandomized observational study in patients with early-stage NSCLC, treated with surgery (n = 13) or SABR (n = 10), demonstrated that SABR induces systemic blood T-cell activation in a major subgroup of patients [
      • de Goeje P.L.
      • Smit E.F.
      • Waasdorp C.
      • Schram M.T.B.
      • et al.
      Stereotactic ablative radiotherapy induces peripheral T-cell activation in patients with early-stage lung cancer.
      ]. Moreover, a study of 37 prostate cancer patients with oligometastatic (≤3 metastases) treated with SABR, reported that an increase in the CD8+ tumour-reactive cells decreased the risk of local progression (p = 0.032) [
      • Evans J.D.
      • Morris L.K.
      • Zhang H.
      • Cao S.
      • et al.
      Prospective immunophenotyping of CD8+ T cells and associated clinical outcomes of patients with oligometastatic prostate cancer treated with metastasis-directed SBRT.
      ]. In contrast, an increase in the CD8+ T central memory cells, which may result in a tumour-bearing state limiting tumoricidal cytotoxic activity, was connected to the risk of death (p = 0.033) [
      • Evans J.D.
      • Morris L.K.
      • Zhang H.
      • Cao S.
      • et al.
      Prospective immunophenotyping of CD8+ T cells and associated clinical outcomes of patients with oligometastatic prostate cancer treated with metastasis-directed SBRT.
      ]. These observations strengthen the need to perform clinical trials combining SABR with immunotherapies [
      • de Goeje P.L.
      • Smit E.F.
      • Waasdorp C.
      • Schram M.T.B.
      • et al.
      Stereotactic ablative radiotherapy induces peripheral T-cell activation in patients with early-stage lung cancer.
      ].

      Toxicities of combining SABR with systemic treatment

      Toxicity data for concurrent treatment of SABR and systemic treatment is limited and mostly reported for cranial SABR. Concurrent treatment is mostly well tolerated in cranial SABR, but higher rates of severe toxicity were observed when combined with BRAF-inhibitors [
      • Kroeze S.G.
      • Fritz C.
      • Hoyer M.
      • Lo S.S.
      • et al.
      Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review.
      ]. In a systematic review, the authors reported a scarce literature on extra-cranial SABR but a potential risk of increased toxicity when SABR is combined with EGFR-targeting tyrosine kinase inhibitor, and bevacizumab, which was not observed for cranial SRT [
      • Kroeze S.G.
      • Fritz C.
      • Hoyer M.
      • Lo S.S.
      • et al.
      Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review.
      ]. Patients receiving SABR targeting the liver and concurrent use of sorafenib also seemed to experience more toxicities [
      • Kroeze S.G.
      • Fritz C.
      • Hoyer M.
      • Lo S.S.
      • et al.
      Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review.
      ].These findings concurred with a systematic review, which found increased toxicities when RT is combined with bevacizumab, cetuximab, and tyrosine kinase inhibitors [
      • Belgioia L.
      • Desideri I.
      • Errico A.
      • Franzese C.
      • et al.
      Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: a literature review.
      ].
      Although several trials have shown that the addition of antiangiogenic agents to conventionally fractionated radiation therapy is well tolerated, other reports have demonstrated increased luminal gastrointestinal toxicity with the combination, especially in patients on anticoagulation [
      • Crane C.H.
      • Eng C.
      • Feig B.W.
      • Das P.
      • et al.
      Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer.
      ,
      • Small Jr, W.
      • Mulcahy M.F.
      • Rademaker A.
      • Bentrem D.J.
      • et al.
      Phase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer.
      ,
      • Chen S.W.
      • Lin L.C.
      • Kuo Y.C.
      • Liang J.A.
      • et al.
      Phase 2 study of combined sorafenib and radiation therapy in patients with advanced hepatocellular carcinoma.
      ,
      • Spigel D.R.
      • Hainsworth J.D.
      • Yardley D.A.
      • Raefsky E.
      • et al.
      Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab.
      ,
      • Choe K.S.
      • Jani A.B.
      • Liauw S.L.
      External beam radiotherapy for prostate cancer patients on anticoagulation therapy: how significant is the bleeding toxicity?.
      ,
      • D'Amico A.V.
      • Manola J.
      • McMahon E.
      • Loffredo M.
      • et al.
      A prospective evaluation of rectal bleeding after dose-escalated three-dimensional conformal radiation therapy using an intrarectal balloon for prostate gland localization and immobilization.
      ]. Bevacizumab appears to be more associated with GI toxicity than some of the other agents such as sunitinib and sorafenib [
      • Elice F.
      • Rodeghiero F.
      • Falanga A.
      • Rickles F.R.
      Thrombosis associated with angiogenesis inhibitors.
      ]. It is believed that SABR is more likely to result in GI mucosal injury by preventing normal tissue recovery in the post-SABR period and thus make SABR-related toxicity more likely [
      • Pollom E.L.
      • Deng L.
      • Pai R.K.
      • Brown J.M.
      • et al.
      Gastrointestinal toxicities with combined antiangiogenic and stereotactic body radiation therapy.
      ]. EGFR and ALK tyrosine kinase inhibitors are generally safe, but caution is required around potential lung toxicity with interstitial pneumonitis while on tyrosine kinase inhibitors, especially when the concomitant RT volume includes lung [
      • Pellegrino B.
      • Facchinetti F.
      • Bordi P.
      • Silva M.
      • et al.
      Lung toxicity in non-small-cell lung cancer patients exposed to ALK inhibitors: report of a peculiar case and systematic review of the literature.
      ].
      In metastatic breast cancer, BM are commonly seen in hormone receptor positive tumours and the treatment of choice would be hormonal therapy such as tamoxifen, aromatase inhibitor, or fulvestrant in combination with CDK4/6 inhibitors (ribociclib, palbociclib or abemaciclib) [
      • Molnár I.A.
      • Molnár B.Á.
      • Vízkeleti L.
      • Fekete K.
      • et al.
      Breast carcinoma subtypes show different patterns of metastatic behavior.
      ,
      • Cristofanilli M.
      • Turner N.C.
      • Bondarenko I.
      • Ro J.
      • et al.
      Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
      ,
      • Goetz M.P.
      • Toi M.
      • Campone M.
      • Sohn J.
      • et al.
      MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.
      ,
      • Tripathy D.
      • Im S.A.
      • Colleoni M.
      • Franke F.
      • et al.
      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.
      ]. For patients with previous GI toxicity using CDK4/6 inhibitors, RT should be highly conformed to spare the GI mucosa [
      • Ippolito E.
      • Greco C.
      • Silipigni S.
      • Dell'Aquila E.
      • et al.
      Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: preliminary assessment of toxicity.
      ]. For HER-2 positive breast cancer patients, anti-HER2 agents such as trastuzumab, pertuzumab, T-DM1 and tyrosine kinase inhibitors such as lapatinib, neratinib and tucatinib are generally safe when given with RT and may contribute to a radiosensitizing effect on tumour cells [
      • Bese N.S.
      • Umay C.
      • Serdengecti S.
      • Kepil N.
      • et al.
      The impact of trastuzumab on radiation-induced pulmonary fibrosis: results of an experimental study.
      ,
      • Sambade M.J.
      • Kimple R.J.
      • Camp J.T.
      • Peters E.
      • et al.
      Lapatinib in combination with radiation diminishes tumour regrowth in HER2+ and basal-like/EGFR+ breast tumour xenografts.
      ,
      • Adams S.R.
      • Yang H.C.
      • Savariar E.N.
      • Aguilera J.
      • et al.
      Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.
      ]. Anti-androgens used in prostate cancer such as abiraterone, and enzalutamide are found to be generally safe when given with RT and may contribute to a radiosensitizing effect on tumour cells [
      • Cho E.
      • Mostaghel E.A.
      • Russell K.J.
      • Liao J.J.
      • et al.
      External beam radiation therapy and abiraterone in men with localized prostate cancer: safety and effect on tissue androgens.
      ,
      • Bitting R.L.
      • Healy P.
      • George D.J.
      • Anand M.
      • et al.
      Phase II trial of enzalutamide and androgen deprivation therapy with salvage radiation in men with high-risk prostate-specific antigen recurrent prostate cancer: the STREAM trial.
      ].
      The use of immune-checkpoint inhibitors with ablative RT is generally found to be safe. No difference in adverse events was noted among patients who received combination therapy compared to those who received either modality alone [
      • Tazi K.
      • Hathaway A.
      • Chiuzan C.
      • Shirai K.
      Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery.
      ,
      • Kwon E.D.
      • Drake C.G.
      • Scher H.I.
      • Fizazi K.
      • et al.
      CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
      ,
      • Patel K.R.
      • Shoukat S.
      • Oliver D.E.
      • Chowdhary M.
      • et al.
      Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases.
      ,
      • Qin R.
      • Olson A.
      • Singh B.
      • Thomas S.
      • et al.
      Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab.
      ,
      • Ahmed K.A.
      • Stallworth D.G.
      • Kim Y.
      • Johnstone P.A.
      • et al.
      Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy.
      ,
      • Qian J.M.
      • Yu J.B.
      • Kluger H.M.
      • Chiang V.L.
      Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.
      ,
      • Aboudaram A.
      • Modesto A.
      • Chaltiel L.
      • Gomez-Roca C.
      • et al.
      Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination.
      ,
      • Koller K.M.
      • Mackley H.B.
      • Liu J.
      • Wagner H.
      • et al.
      Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone.
      ].
      In castration resistant prostate cancer patients who received at least one course of bone-directed RT with 8 Gy in one fraction with or without Ipilimumab had no adverse effects [
      • Kwon E.D.
      • Drake C.G.
      • Scher H.I.
      • Fizazi K.
      • et al.
      CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
      ]. In combination treatment, dual immune checkpoint inhibitors (ICPI) using a PD1/PDL1 inhibitor with a CTLA4 inhibitor, combinations with chemotherapy or anti-VEGF agents are likely to be more toxic when used concomitantly with SABR, especially anti-VEGF agents and precautions need to be taken if triple modalities are to be given together [
      • Long J.
      • Lin J.
      • Wang A.
      • Wu L.
      • et al.
      PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.
      ]. Using combination immunotherapy with nivolumab and ipilimumab increased toxicity is reported with more than 45% grade 3 and 4 immune-related adverse events (irAEs) [
      • Long J.
      • Lin J.
      • Wang A.
      • Wu L.
      • et al.
      PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.
      ,
      • Kooshkaki O.
      • Derakhshani A.
      • Hosseinkhani N.
      • Torabi M.
      • et al.
      Combination of ipilimumab and nivolumab in cancers: from clinical practice to ongoing clinical trials.
      ]. IrAEs can generally be managed using corticosteroids from 0.5 to >2 mg/kg/day and other immunosuppressants if the AEs do not resolve with steroids. It is controversial whether corticosteroids, commonly given before RT to the bone especially for malignant cord compression, would dampen ICI efficacy. Adjustment of schedules and doses of ipilimumab were found minimise irAEs using reduced dose and extended dosing intervals to every 6 or 12 weeks [
      • Warner A.B.
      • Postow M.A.
      Combination controversies: checkpoint inhibition alone or in combination for the treatment of melanoma?.
      ,
      • Trinh S.
      • Le A.
      • Gowani S.
      • La-Beck N.M.
      Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines.
      ].

      Interventional radiological local ablative techniques

      Thermal ablation consists of several techniques, the most commonly used include radiofrequency, cryotherapy, laser, and microwave thermal ablation [
      • Errani C.
      • Bazzocchi A.
      • Spinnato P.
      • Facchini G.
      • et al.
      What's new in management of bone metastases?.
      ].In Dupuy et al’s study, CT-guided RFA of BM effectively reduced pain at 1 and 3 months post-treatment. Adverse events related to RFA occurred in approximately 5% with neurological damage and neuropathic pain related to heat-related damage to nerves adjacent to the ablated region [
      • Dupuy D.E.
      • Liu D.
      • Hartfeil D.
      • Hanna L.
      • et al.
      Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial.
      ]. RFA can be combined with cement injection to add value in pain relief and bone stabilization at various skeletal sites including the vertebral bodies and long bones. [
      • Errani C.
      • Bazzocchi A.
      • Spinnato P.
      • Facchini G.
      • et al.
      What's new in management of bone metastases?.
      ]. The effectiveness of pain palliation is related to the size of the lesion [
      • Dupuy D.E.
      • Liu D.
      • Hartfeil D.
      • Hanna L.
      • et al.
      Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial.
      ]. Tumour local control can be achieved in 70–80% at 1 year and multiple lesions can be treated in the same session avoiding ionizing radiation [
      • Wallace A.N.
      • Tomasian A.
      • Vaswani D.
      • Vyhmeister R.
      • et al.
      Radiographic local control of spinal metastases with percutaneous radiofrequency ablation and vertebral augmentation.
      ,
      • Barral M.
      • Auperin A.
      • Hakime A.
      • Cartier V.
      • et al.
      Percutaneous thermal ablation of breast cancer metastases in oligometastatic patients.
      ].
      A newer ablative technique includes magnetic resonance imaging-guided high-intensity focused ultrasound (HIFU), also known as MR imaging-guided focused ultrasound surgery (MRgFUS). In a phase 3 trial, with 147 patients, self-reported pain score had a response rate of 64% compared with 20% for placebo [
      • Hurwitz M.D.
      • Ghanouni P.
      • Kanaev S.V.
      • Iozeffi D.
      • et al.
      Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.
      ]. The most common adverse effect was sonication pain occurring in 32.1% of MRgFUS patients. Other adverse events include pathological fractures in two patients, third-degree skin burn in one patient, and neuropathy in one patient. Most AEs were short-lived and resolved in 60.3% of patients on the first treatment day [
      • Hurwitz M.D.
      • Ghanouni P.
      • Kanaev S.V.
      • Iozeffi D.
      • et al.
      Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.
      ]. MRgFUS can be used as salvage therapy in patients not suitable for re-irradiation.
      Embolization is a palliative treatment option for BM either alone or in combination with other treatments specifically for hypervascular tumors such as renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma demonstrating effective control of pain and neurological symptoms [
      • Rossi G.
      • Mavrogenis A.F.
      • Casadei R.
      • Bianchi G.
      • et al.
      Embolisation of bone metastases from renal cancer.
      ,
      • Owen R.J.
      Embolization of musculoskeletal bone tumors.
      ,
      • Cazzato R.L.
      • Arrigoni F.
      • Boatta E.
      • Bruno F.
      • et al.
      Percutaneous management of bone metastases: state of the art, interventional strategies and joint position statement of the Italian College of MSK Radiology (ICoMSKR) and the Italian College of Interventional Radiology (ICIR).
      ]. One report of selective and super-selective embolizations in 243 patients with bone metastases achieved a pain reduction in 97% of patients with a mean duration of pain relief for 8.1 month [
      • Keilani M.
      • Kainberger F.
      • Pataraia A.
      • Hasenöhrl T.
      • et al.
      Typical aspects in the rehabilitation of cancer patients suffering from metastatic bone disease or multiple myeloma.
      ]. Embolization can also be used to devascularize the tumour before thermal ablation to reduce the heat/cold-sink effect of ablation [
      • Crevenna R.
      • Kainberger F.
      • Wiltschke C.
      • Marosi C.
      • et al.
      Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.
      ].

      Bone modifying agents

      Bone modifying agents are systemic agents that can be used to treat osteoporosis, or in the case of BM to control pain and prevent skeletal-related events (SRE). Bisphosphonates and denosumab are commonly used in clinical practice. In the adjuvant setting, the EBCTCG study demonstrated that adjuvant bisphosphonates reduced the rate of breast cancer distant recurrence, bone recurrence, and breast cancer mortality, especially in postmenopausal women [

      Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015;386(10001):1353-1361. 10.1016/S0140-6736(15)60908-4.

      ].
      In the setting of BM, denosumab has been found to be at least non-inferior compared to zoledronic acid in delaying SRE in solid tumours and multiple myeloma in various studies [
      • Stopeck A.T.
      • Lipton A.
      • Body J.J.
      • Steger G.G.
      • et al.
      Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
      ,
      • Henry D.H.
      • Costa L.
      • Goldwasser F.
      • Hirsh V.
      • et al.
      Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
      ,
      • Fizazi K.
      • Carducci M.
      • Smith M.
      • Damião R.
      • et al.
      Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.
      ]. Some early studies have even demonstrated an overall survival benefit, but phase 3 randomized trials have failed to confirm this [
      • Scagliotti G.V.
      • Hirsh V.
      • Siena S.
      • Henry D.H.
      • et al.
      Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.
      ,
      • Peters S.
      • Danson S.
      • Hasan B.
      • Dafni U.
      • et al.
      A randomized open-label phase III trial evaluating the addition of denosumab to standard first-line treatment in advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR trial.
      ].
      In EGFR mutated adenocarcinoma of lung, treatment of osteolytic lesions using tyrosine kinase inhibitors has shown accelerated re-ossification of lytic lesions and together with bisphosphonates, could improve overall survival [
      • Zhang G.
      • Cheng R.
      • Zhang Z.
      • Jiang T.
      • et al.
      Bisphosphonates enhance antitumour effect of EGFR-TKIs in patients with advanced EGFR mutant NSCLC and bone metastases.
      ,
      • Garfield D.
      Increasing osteoblastic lesions as a manifestation of a major response to gefitinib.
      ]. When an EGFR TKI was omitted, there was an increased and earlier risk of SRE which could ultimately impact survival [
      • Sun J.M.
      • Ahn J.S.
      • Lee S.
      • Kim J.A.
      • et al.
      Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases.
      ]. In the age of immunotherapy, beyond its supportive role, bone is a haematopoietic organ consisting of lymphoid tissue that modulates the immune system. Metastatic NSCLC patients who received nivolumab with bone metastases were found to have a lower overall response rate, shorter progression-free-survival and overall survival compared to patients who did not have BM [
      • Landi L.
      • D'Incà F.
      • Gelibter A.
      • Chiari R.
      • et al.
      Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer.
      ]. There are several studies that have found the combination of ICI with denosumab, a RANKL inhibitor, can enhance objective response to more than 50%, and prolong PFS and OS by possibly priming the tumour microenvironment to respond to RANKL blockade and improving antitumour activity [
      • Liede A.
      • Hernandez R.K.
      • Wade S.W.
      • Bo R.
      • et al.
      An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer.
      ,
      • Afzal M.Z.
      • Shirai K.
      Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a tertiary care center.
      ,
      • Angela Y.
      • Haferkamp S.
      • Weishaupt C.
      • Ugurel S.
      • et al.
      Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases.
      ].

      Physical activity, exercise, and rehabilitation in patients with BM

      When treating pain related to BM, physical activity, exercise, physical medical modalities (eg. transcutaneous electrical nerve stimulation) are often perceived as contraindicated due to possible pathological fractures and spinal cord compression [
      • Keilani M.
      • Kainberger F.
      • Pataraia A.
      • Hasenöhrl T.
      • et al.
      Typical aspects in the rehabilitation of cancer patients suffering from metastatic bone disease or multiple myeloma.
      ]. Regular physical activity, exercise and other physical modalities should be incorporated into the multidisciplinary and multimodality treatment of BM. Modalities increasing local blood flow like ultrasound therapy, thermotherapy, massage, and various electrotherapy options should not be performed near the tumour site [
      • Crevenna R.
      • Kainberger F.
      • Wiltschke C.
      • Marosi C.
      • et al.
      Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.
      ]. Physical activity and exercise should be encouraged aiming to improve muscle strength, endurance capacity, sensorimotor functions, flexibility, and functional status [
      • Crevenna R.
      • Kainberger F.
      • Wiltschke C.
      • Marosi C.
      • et al.
      Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.
      ]. Such rehabilitation programmes should be individually tailored and adapted to maintain the patient’s condition and to minimise risks [
      • Crevenna R.
      • Kainberger F.
      • Wiltschke C.
      • Marosi C.
      • et al.
      Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.
      ]. A review of studies that prescribed exercise for patients living with metastatic cancer reported good patient acceptance, tolerance, and adherence [
      • Sheill G.
      • Guinan E.M.
      • Peat N.
      • Hussey J.
      Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review.
      ]. Statistically significant and clinically meaningful improvements were found in exercise behaviour, muscle mass, muscle strength, and endurance capacity [
      • Sheill G.
      • Guinan E.M.
      • Peat N.
      • Hussey J.
      Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review.
      ]. Most importantly, few adverse events related to exercise interventions were reported [
      • Sheill G.
      • Guinan E.M.
      • Peat N.
      • Hussey J.
      Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review.
      ,
      • Galvão D.A.
      • Taaffe D.R.
      • Spry N.
      • Cormie P.
      • et al.
      Exercise preserves physical function in prostate cancer patients with bone metastases.
      ]. A controlled study evaluated the efficacy and safety of an exercise programme consisting of aerobic, resistance, and flexibility exercise in prostate cancer patients with bone metastases and found patient-reported improvement in physical functioning and lower body muscle strength with no complications or increase in skeletal pain [
      • Galvão D.A.
      • Taaffe D.R.
      • Spry N.
      • Cormie P.
      • et al.
      Exercise preserves physical function in prostate cancer patients with bone metastases.
      ].
      Patient autoregulation during exercise programmes allows self-determination of exercise capabilities according to their fitness [
      • Sheill G.
      • Guinan E.M.
      • Peat N.
      • Hussey J.
      Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review.
      ]. It is important to note when prescribing resistance exercise the location of BM to ensure affected regions are not targeted and mechanical and sheer force at areas of metastases are minimized [
      • Sheill G.
      • Guinan E.M.
      • Peat N.
      • Hussey J.
      Considerations for exercise prescription in patients with bone metastases: a comprehensive narrative review.
      ].
      For patients with stable BM, physical activity using isometric exercise can maintain painless mobility. Braces can be used to stabilize the vertebral column and peripheral joints, either for mechanical stabilization after surgery or as a preventive measure for unstable bone metastases that are medically or surgically inoperable in combination with other treatment modalities such as systemic anti-cancer treatment, radiotherapy, and bone modifying agents for the treatment of bone metastases [
      • Keilani M.
      • Kainberger F.
      • Pataraia A.
      • Hasenöhrl T.
      • et al.
      Typical aspects in the rehabilitation of cancer patients suffering from metastatic bone disease or multiple myeloma.
      ].
      According to the American College of Sports Medicine, if patients show no contraindications for active exercise, regular physical activity includes: 150 min per week of moderate intensity or 75 min per week of vigorous intensity activity or an equivalent combination and muscle strengthening activities of at least moderate intensity for at least 2 days per week for each major muscle group with stretching of major muscle groups and tendons [
      • Schmitz K.H.
      • Courneya K.S.
      • Matthews C.
      • Demark-Wahnefried W.
      • et al.
      American College of Sports Medicine. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      ].
      Other areas that may be important during the rehabilitation process include adequate patient and carer information and education in relation to physical activities; BM specific nutritional programmes to maintain muscle mass, and psychological assessment for patients becoming newly disabled [
      • Crevenna R.
      • Kainberger F.
      • Wiltschke C.
      • Marosi C.
      • et al.
      Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.
      ].

      Discussion

      The decision making process in the management of BM remains complex. Several publications have described strategies to guide clinicians on the management of spinal metastases including the NOMS framework, the LMNOP system, and the integrated multidisciplinary algorithm by the International Spine Oncology Consortium group [
      • Laufer I.
      • Rubin D.G.
      • Lis E.
      • Cox B.W.
      • et al.
      The NOMS framework: approach to the treatment of spinal metastatic tumors.
      ,
      • Paton G.R.
      • Frangou E.
      • Fourney D.R.
      Contemporary treatment strategy for spinal metastasis: the “LMNOP” system.
      ,
      • Spratt D.E.
      • Beeler W.H.
      • de Moraes F.Y.
      • Rhines L.D.
      • et al.
      An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.
      ]. The initial assessment algorithm for patients with spinal metastases evaluates patients based on 4 aspects: performance status, systemic burden of disease, control of systemic disease, and available systemic treatment options and their efficacy which would stratify patients according to prognosis, Fig. 1 [
      • Spratt D.E.
      • Beeler W.H.
      • de Moraes F.Y.
      • Rhines L.D.
      • et al.
      An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.
      ]. Another important factor to consider in the patient stratification of available treatment options is resource, which includes the institution, the patient and their carer, and financial resources which may limit available treatment options. If the patient satisfies all 5 areas required to proceed with aggressive surgical, RT, or systemic treatment, then the MNOP (Mechanical, Neurological, Oncological, Preferred treatment) algorithm should be considered [
      • Spratt D.E.
      • Beeler W.H.
      • de Moraes F.Y.
      • Rhines L.D.
      • et al.
      An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.
      ]. The algorithm proposed by the International Spine Oncology Consortium can also be applied in nonspine BM including complicated bone metastases using the same principle but instead of using the spinal instability neoplastic score, one would assess mechanical stability of the bone metastases by using the Mirel’s score or other factors such as the size of the soft tissue mass adjacent to the BM to review a patient’s risk of pathological fracture and whether surgical intervention may be indicated.
      It is important to note that various prognostic models have been developed to estimate patient prognosis and survival from spinal metastases [
      • Zucker A.
      • Tsai C.J.
      • Loscalzo J.
      • Calves P.
      • Kao J.
      The NEAT predictive model for survival in patients with advanced cancer.
      ,
      • Westhoff P.G.
      • de Graeff A.
      • Monninkhof E.M.
      • Bollen L.
      • et al.
      An easy tool to predict survival in patients receiving radiation therapy for painful bone metastases.
      ,
      • Alcorn S.R.
      • Fiksel J.
      • Wright J.L.
      • Elledge C.R.
      • et al.
      Developing an improved statistical approach for survival estimation in bone metastases management: the Bone Metastases Ensemble Trees for Survival (BMETS) model.
      ,
      • Balain B.
      • Jaiswal A.
      • Trivedi J.M.
      • Eisenstein S.M.
      • et al.
      The Oswestry Risk Index: an aid in the treatment of metastatic disease of the spine.
      ,
      • Aoude A.
      • Amiot L.P.
      A comparison of the modified Tokuhashi and Tomita scores in determining prognosis for patients afflicted with spinal metastasis.
      ,
      • Tokuhashi Y.
      • Uei H.
      • Oshima M.
      • Ajiro Y.
      Scoring system for prediction of metastatic spine tumor prognosis.
      ]. However, these models are seldom used in clinical practice because of limited accuracy when applied to the individual.
      It is essential to consider that several of the trials assessing conventional RT for simple BM lack detailed radiological and clinical details relating to factors leading to complications, and the evaluation of local control with serial imaging is rarely used [
      • Cheon P.M.
      • Wong E.
      • Thavarajah N.
      • Dennis K.
      • et al.
      A definition of “uncomplicated bone metastases” based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy.
      ,
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ]. Furthermore, few of these trials evaluated patient performance status, and heterogeneity in the assessment of toxicity makes comparison across studies difficult [
      • Cheon P.M.
      • Wong E.
      • Thavarajah N.
      • Dennis K.
      • et al.
      A definition of “uncomplicated bone metastases” based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy.
      ,
      • Alcorn S.R.
      • Elledge C.R.
      • Wright J.L.
      • Smith T.J.
      • et al.
      Frequency of complicated symptomatic bone metastasis over a breadth of operational definitions.
      ].
      Despite the advantages in time, convenience, and cost-effectiveness, the use of single-fraction RT with conventional dose remains low even in patients with uncomplicated BM [
      • Yu J.B.
      • Pollack C.E.
      • Herrin J.
      • Zhu W.
      • et al.
      Persistent use of extended fractionation palliative radiotherapy for medicare beneficiaries with metastatic breast cancer, 2011 to 2014.
      ,
      • Spratt D.E.
      • Mancini B.R.
      • Hayman J.A.
      • Boike T.
      • et al.
      Michigan radiation oncology quality consortium. Contemporary statewide practice pattern assessment of the palliative treatment of bone metastasis.
      ]. Most BM phase 3 trials were performed prior to the development of modern ablative techniques like SABR and the introduction of improved systemic therapy including immunotherapy, targetted therapy, and radiopharmaceuticals [
      • Lutz S.
      • Balboni T.
      • Jones J.
      • Lo S.
      • et al.
      Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline.
      ].
      Furthermore, there is a paradigm shift in systemic anticancer treatment with the increasing use of immune-checkpoint inhibition in patients with metastatic cancer. [
      • Liede A.
      • Hernandez R.K.
      • Wade S.W.
      • Bo R.
      • et al.
      An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer.
      ,
      • Afzal M.Z.
      • Shirai K.
      Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a tertiary care center.
      ,
      • Angela Y.
      • Haferkamp S.
      • Weishaupt C.
      • Ugurel S.
      • et al.
      Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases.
      ]. Clinical and pre-clinical data demonstrates that SABR is also able to modulate the immune system shown in circulating immune cells in peripheral blood [
      • de Goeje P.L.
      • Smit E.F.
      • Waasdorp C.
      • Schram M.T.B.
      • et al.
      Stereotactic ablative radiotherapy induces peripheral T-cell activation in patients with early-stage lung cancer.
      ,
      • Evans J.D.
      • Morris L.K.
      • Zhang H.
      • Cao S.
      • et al.
      Prospective immunophenotyping of CD8+ T cells and associated clinical outcomes of patients with oligometastatic prostate cancer treated with metastasis-directed SBRT.
      ]. In patients with oligometastases, local ablative therapies may improve disease-free survival [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ,
      • Ost P.
      • Reynders D.
      • Decaestecker K.
      • Fonteyne V.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial.
      ,
      • Siva S.
      • Bressel M.
      • Murphy D.G.
      • Shaw M.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for oligometastatic prostate cancer: a prospective clinical trial.
      ,
      • Ruers T.
      • Punt C.
      • Van Coevorden F.
      • Pierie J.P.E.N.
      • et al.
      EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).
      ,
      • Mitchell K.G.
      • Farooqi A.
      • Ludmir E.B.
      • Corsini E.M.
      • et al.
      Improved overall survival with comprehensive local consolidative therapy in synchronous oligometastatic non-small-cell lung cancer.
      ]. SABR in BM appears to be safe, with good rates of pain and local control, including fast relief of the pain, and with a small probability of severe complications [
      • Spencer K.L.
      • van der Velden J.M.
      • Wong E.
      • Seravalli E.
      • et al.
      Systematic review of the role of stereotactic radiotherapy for bone metastases.
      ,
      • Singh R.
      • Lehrer E.J.
      • Dahshan B.
      • Palmer J.D.
      • et al.
      Single fraction radiosurgery, fractionated radiosurgery, and conventional radiotherapy for spinal oligometastasis (SAFFRON): a systematic review and meta-analysis.
      ,
      • Loi M.
      • Nuyttens J.J.
      • Desideri I.
      • Greto D.
      • Livi L.
      Single-Fraction Radiotherapy (SFRT) for bone metastases: patient selection and perspectives.
      ]. In spinal BM, SABR with single doses higher than 20 Gy can increase vertebral fracture risk [
      • Loi M.
      • Nuyttens J.J.
      • Desideri I.
      • Greto D.
      • Livi L.
      Single-Fraction Radiotherapy (SFRT) for bone metastases: patient selection and perspectives.
      ]. A good dose–response relationship was recognized with 12–16 Gy in a single fraction particularly in radioresistant tumours [
      • Loi M.
      • Nuyttens J.J.
      • Desideri I.
      • Greto D.
      • Livi L.
      Single-Fraction Radiotherapy (SFRT) for bone metastases: patient selection and perspectives.
      ]. However, the occurrence of three deaths (4.5%) in the interventional arm in the SABR-COMET study highlights the need for caution using high doses per fraction with SABR in patients with oligometastatic disease [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
      ].
      BM studies should describe pain scores, low and high-grade toxicities, at baseline and regular intervals, with standardized methods, including physician and patient-reported outcomes measurements. QoL and cost effectiveness also need to be studied in future studies. In addition, trials in BM and oligometastases should analyze overall survival, disease-free and progression-free survival, survival without systemic therapy, local control with serial images, and also study the benefit of combined therapy. Like SABR-COMET 3 and 10, future SABR trials should investigate translational biomarkers to define oligometastatic disease better, identify new predictors of prognosis, and improve understanding of the effect of SABR in the immune system [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Correa R.J.M.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of 4–10 oligometastatic tumours (SABR-COMET-10): study protocol for a randomized phase III trial.
      ,
      • Olson R.
      • Mathews L.
      • Liu M.
      • Schellenberg D.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of 1–3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.
      ]. Data from additional clinical trials in progress is available in Table 3.
      Most systemic therapies appear to be safe to use in combination with palliative RT, but some drugs deserve further research. For patients with previous GI toxicity using CDK4/6 inhibitors, radiotherapy should be highly conformed to spare the GI mucosa [
      • Ippolito E.
      • Greco C.
      • Silipigni S.
      • Dell'Aquila E.
      • et al.
      Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: preliminary assessment of toxicity.
      ]. Antiangiogenic agents can increase GI toxicity, and special attention is required in anticoagulated patients treated with SABR [
      • Choe K.S.
      • Jani A.B.
      • Liauw S.L.
      External beam radiotherapy for prostate cancer patients on anticoagulation therapy: how significant is the bleeding toxicity?.