Combining the Best of Both Worlds: The Role of Sequential Stereotactic Radiotherapy Boost for Spinal Metastases

Abstract

With improved survival from better systemic therapies and earlier detection with advanced diagnostic imaging, the incidence of patients with malignant spinal metastases is increasing [[1]Horn S.R. Dhillon E.S. Poorman G.W. Tishelman J.C. Segreto F.A. Bortz C.A. et al.Epidemiology and national trends in prevalence and surgical management of metastatic spinal disease.J Clin Neurosci. 2018; 53: 183-187Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Stereotactic ablative body radiotherapy (SABR) for spinal oligometastases has become a new standard of care as an alternative to radical, but often extremely morbid, surgery [[2]SABR Consortium Guidelines 2019 v6.1.0. https://www.sabr.org.uk/wp-content/uploads/2019/04/SABRconsortium-guidelines-2019-v6.1.0.pdfGoogle Scholar]. There are emerging data to support the use of SABR to treat painful spinal metastases, with Sahgal et al. [[3]Sahgal A. Myrehaug S.D. Siva S. Masucci G.L. Maralani P.J. Brundage M. et al.Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial.Lancet Oncol. 2021; 22: 1023-1033Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar] demonstrating a significant improvement in pain control at 3 months in 229 patients randomised to SABR versus conventional palliative radiotherapy. Although there are now numerous retrospective and prospective series [4Gerszten P.C. Burton S.A. Ozhasoglu C. Welch W.C. Radiosurgery for spinal metastases.Spine. 2007; 32: 193-199Crossref PubMed Scopus (567) Google Scholar, 5Guckenberger M. Mantel F. Gerszten P.C. Flickinger J.C. Sahgal A. Létourneau D. et al.Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis.Radiat Oncol. 2014; 9: 226https://doi.org/10.1186/s13014-014-0226-2Crossref PubMed Scopus (114) Google Scholar, 6Gestaut M.M. Thawani N. Kim S. Gutti V.R. Jhavar S. Deb N. et al.Single fraction spine stereotactic ablative body radiotherapy with volumetric modulated arc therapy.J Neuro-Oncol. 2017; 133: 165-172Crossref Scopus (8) Google Scholar] showing a local control benefit with SABR to spinal oligometastases, failures after treatment still occur [[7]Chang E.L. Shiu A.S. Mendel E. Mathews L.A. Mahajan A. Allen P.K. et al.Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure.J Neurosurg Spine. 2007; 7: 151-160Crossref PubMed Scopus (365) Google Scholar]. There are some commonly cited arguments against the use of SABR for metastases, including the lack of evidence to guide which patients are most likely to benefit and concerns about using tighter target volume margins. Often, the standard SABR contour for spine metastases includes only the affected vertebra [[8]Cox B.W. Spratt D.E. Lovelock M. Bilsky M.H. Lis E. Ryu S. et al.International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery.Int J Radiat Oncol Biol Phys. 2012; 83: e597-e605https://doi.org/10.1016/j.ijrobp.2012.03.009Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar] compared with traditional conformal techniques, which commonly include a vertebra above and below the affected level [[9]Barrett A. Dobbs J. Morris S. Roques T. Practical radiotherapy planning.4th edition. CRC Press, UK2009Crossref Scopus (0) Google Scholar]. Although the most frequent mechanism of spread of malignant cells to the spine is via the haematogenous route, cells can spread by contiguity, resulting in adjacent vertebrae becoming involved [[10]Maccauro G. Spinelli M.S. Mauro S. Perisano C. Graci C. Rosa M.A. Physiopathology of spine metastasis.Int J Surg Oncol. 2011; 2011: 1-8Crossref Google Scholar]. SABR techniques allow a much more rapid dose fall-off, which is utilised to minimise doses to critical structures such as the spinal cord. This inevitably results in less dose to surrounding vertebrae and may potentially increase the risk of missing adjacent undetected microscopic disease. However, it may be difficult to validate this proof of concept due to the heterogeneity of the tumour types that metastasise to the spine. For some radioresistant tumours, the low dose radiation delivered to the surrounding vertebrae may have little impact, whereas for more radiosensitive tumours it may potentially have more of a role. Another argument against the use of SABR for painful bone metastases, particularly in the spine where there is a risk of neurological compromise, is that complex stereotactic techniques take time to plan. If a patient is symptomatic, a quickly planned palliative conformal plan may be more achievable in a timely manner in busy radiotherapy departments and may give equivalent short-term pain control compared with SABR. It is important to consider the impact of the quicker ‘plan to treat’ turnover time on a patient's quality of life, especially for the ones with a poor prognosis. Last, but not least, SABR to spine metastases is suggested to be associated with an increased risk of vertebral compression fracture [[11]Sahgal A. Whyne C.M. Ma L. Larson D.A. Fehlings M.G. Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases.Lancet Oncol. 2013; 14: e310-e320Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar], which can lead to significant symptoms, most commonly pain, and cause patients to require otherwise unnecessary surgical intervention. Palliative techniques can offer an effective method of pain control without significantly increasing this risk, particularly for metastases with a high spinal instability neoplastic score where surgery may not be appropriate [[12]Fisher C.G. DiPaola C.P. Ryken T.C. Bilsky M.H. Shaffrey C.I. Berven S.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.Spine (Phila Pa 1976). 2010; 35: E1221-E1229https://doi.org/10.1097/BRS.0b013e3181e16ae2Crossref PubMed Scopus (676) Google Scholar]. Deodato et al. [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar] conducted a dose-escalation study of conventional conformal radiotherapy to the involved and adjacent vertebrae with a sequential stereotactic boost to escalate the radiation dose delivered to the metastasis. This approach aimed to obtain the potential low dose benefit to surrounding tissues with possible microscopic spread [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. Furthermore, it would allow rapid delivery of low dose radiotherapy in an emergency while still allowing subsequent SABR to be delivered to a smaller clinical target volume at a later date. The results suggested that this technique is feasible with acceptable post-radiotherapy toxicity. As yet there is little published literature related to this technique. There are only several small-scale studies using an integrated stereotactic boost to the gross tumour volume [14Pontoriero A. Iatì G. Cacciola A. Conti A. Brogna A. Siragusa C. et al.Stereotactic body radiation therapy with simultaneous integrated boost in patients with spinal metastases.Technol Cancer Res Treat. 2020; 19153303382090444Crossref Scopus (15) Google Scholar, 15van der Velden J.M. Hes J. Sahgal A. Hoogcarspel S.J. Philippens M.E.P. Eppinga W.S.C. et al.The use of a simultaneous integrated boost in spinal stereotactic body radiotherapy to reduce the risk of vertebral compression fractures: a treatment planning study.Acta Oncol. 2018; 57: 1271-1274Crossref Scopus (7) Google Scholar, 16Liu X. Li X. Zhang P. Yan H. Peng Y. Zou N. Hypofractionated stereotactic body radiation therapy with simultaneous integrated boost with flattening filter-free volumetric modulated arc therapy for spinal metastases.Int J Radiat Oncol Biol Phys. 2021; 111: e608https://doi.org/10.1016/j.ijrobp.2021.07.1621Abstract Full Text PDF PubMed Scopus (0) Google Scholar], which is different to the sequential boost approach by Deodato et al. [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. The study by Deodato et al. [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar] was a hypothesis-generating phase I maximum dose finding study considering 52 spinal oligometastases treated in 40 patients with escalation of the stereotactic boost dose. Further larger studies are needed to investigate whether this technique can offer a significant improvement in local control and symptom relief compared with SABR or palliative radiotherapy alone. The authors focused on treating patients under the oligometastatic setting, with most having relatively radiosensitive tumour subtypes. The aim was to identify the optimal safe stereotactic dose in terms of the post-radiotherapy-related toxicity for boosting spinal oligometastases. There are several hypotheses that could be investigated as a result of this trial. The first hypothesis would be that this sequential stereotactic boost technique may achieve good local control rates, improve progression-free survival and pain control, while in addition also avoiding the need for complex reirradiation of adjacent vertebrae in the future. This might allow patients with a poor prognosis or more aggressive disease to benefit from SABR while still being able to start radiotherapy quickly. This trial might be difficult to conduct given the heterogeneity of tumour types that cause spinal oligometastases. Studies involving various tumour subtypes of oligometastases, such as the landmark COMET trial [[17]Palma D.A. Olson R. Harrow S. Gaede S. Louie A.V. Haasbeek C. et al.Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-comet phase II randomized trial.J Clin Oncol. 2020; 38: 2830-2838Crossref PubMed Scopus (382) Google Scholar], or the Commissioning through Evaluation (CtE) prospective dataset [[18]Chalkidou A. Macmillan T. Grzeda M.T. Peacock J. Summers J. Eddy S. et al.Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.Lancet Oncol. 2021; 22: 98-106Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar], had successful outcomes, but there would always be criticism of such studies concerning the application to non-trial patients due to the heterogeneity of the patient populations treated. To answer the SABR oligometastases question completely, whether or not it is delivered in combination with a preceding lower palliative dose as proposed by Deodato et al. [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar], ideally such a study would focus on an individual histological tumour type and take account of the potential response to other systemic treatments. It is noted that 35 of 40 patients in the study by Deodato et al. [[13]Deodato F. Pezzulla D. Cilla S. Ferro M. Giannini R. Romano C. et al.Volumetric intensity-modulated arc stereotactic radiosurgery boost in oligometastatic patients with spine metastases: a dose-escalation study.Clin Oncol. 2023; 35: e30-e39Abstract Full Text Full Text PDF Scopus (1) Google Scholar] had oligometastases that originated either from prostate or breast cancer primaries. Typically, these are diseases with better prognosis with good systemic options available. It is important to consider the number of patients on systemic treatment at the time of follow-up as a potential confounding factor on local control when the results of this study were interpreted and generalised to current clinical practice. A second hypothesis would be to investigate whether this sequential stereotactic boost technique could be offered to patients with widespread metastatic disease and acutely painful spine metastases. The outcome measurements should include both how rapidly the pain relief can be achieved (quicker turnover time to start radiotherapy) and the duration of pain control (ablative dose to the gross tumour volume). Would achieving this reduce the need for subsequent treatments, either further radiotherapy or systemic therapy, and therefore be more convenient for patients and reduce overall longer-term treatment costs? To fully optimise the role of SABR for the management of spine metastases, it is crucial to examine the studies where SABR failed to achieve its goal. Evidence is already beginning to emerge of techniques with the aim of avoiding failure in the epidural space (where failures after SABR have been shown to occur) by trying to dose-escalate volumes within the spinal canal in close proximity to the spinal cord [[7]Chang E.L. Shiu A.S. Mendel E. Mathews L.A. Mahajan A. Allen P.K. et al.Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure.J Neurosurg Spine. 2007; 7: 151-160Crossref PubMed Scopus (365) Google Scholar]. This requires highly accurate and precise imaging of the spinal cord, both for planning and during treatment. Alternatively, the role of separation surgery followed by SABR is well established as a technique where patients have disease abutting or compressing the cord [[19]Laufer I. Iorgulescu J.B. Chapman T. Lis E. Shi W. Zhang Z. 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.J Neurosurg Spine. 2013; 18: 207-214Crossref PubMed Scopus (315) Google Scholar]. This ‘hybrid’ approach of initially using palliative radiotherapy to a larger volume encompassing the disease close to the cord with a sequential stereotactic boost at a later date can be explored as a method of managing selected patients with cord compression to allow avoidance of potentially morbid surgery [[20]Donovan E.K. Greenspoon J. Schnarr K.L. Whelan T.J. Wright J.R. Hann C. et al.A pilot study of stereotactic boost for malignant epidural spinal cord compression: clinical significance and initial dosimetric evaluation.Radiat Oncol. 2020; 15: 267https://doi.org/10.1186/s13014-020-01710-4Crossref Scopus (2) Google Scholar]. Hoskin et al. [[21]Hoskin P.J. Hopkins K. Misra V. Holt T. McMenemin R. Dubois D. et al.Effect of single-fraction vs multifraction radiotherapy on ambulatory status among patients with spinal canal compression from metastatic cancer.JAMA. 2019; 322: 2084Crossref PubMed Scopus (54) Google Scholar], in the SCORAD trial, considered ambulatory status after cord compression in patients treated with a single fraction versus a five-fraction radiotherapy regimen. Although the non-inferiority outcome was not achieved, perhaps larger radiation doses could be explored for patients with cord compression. A third hypothesis to be examined could be the application of the proposed ‘hybrid’ technique for patients with oligoprogressive disease. If most of the cancer is stable on a well-tolerated systemic therapy, would small volume, highly targeted SABR in combination with lower dose palliative radiotherapy to a larger volume offer any advantage over simply offering SABR alone to the area of oligoprogression? Despite the fact that SABR becomes more widely available and less expensive, there is still much research to be done and much to learn about the appropriate application of spinal SABR in day-to-day clinical practice. Patients with oligometastatic disease should not be offered any treatment options that may be inferior to evidence-based literature data. Patient selection for SABR remains critical and high-quality, robust clinical trials are essential to drive how we should optimally use modern radiotherapy techniques in SABR utilisation. It seems inevitable that the combination of SABR with the already well-established, highly effective palliative radiotherapy techniques in different tumour types will need to be validated further for the management of metastatic spinal disease. This highlights the important role of a multidisciplinary cancer management approach to these patients and strides have been made to establish multidisciplinary algorithms for the management of spinal metastatic disease considering the numerous permutations of this heterogeneous group [[22]Spratt D.E. Beeler W.H. de Moraes Fy Rhines L.D. Gemmete J.J. Chaudhary N. et al.An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report.Lancet Oncol. 2017; 18: e720-e730https://doi.org/10.1016/S1470-2045(17)30612-5Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. JS and YMT are the guarantors of integrity of the entire study. JS and YMT carried out the literature research. JS prepared the manuscript. JS, MA-L and YMT edited the manuscript. The authors declare no conflicts of interest. Volumetric Intensity-Modulated Arc Stereotactic Radiosurgery Boost in Oligometastatic Patients with Spine Metastases: a Dose-escalation StudyClinical OncologyVol. 35Issue 1PreviewTo report the final results of a dose-escalation study of volumetric intensity-modulated arc stereotactic radiosurgery (VMAT-SRS) boost after three-dimensional conformal radiation therapy in patients with spine metastases. Full-Text PDF