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Stereotactic body radiation therapy for spine and non-spine bone metastases. GETUG (french society of urological radiation oncologists) recommendations using a national two-round modified Delphi survey

Open AccessPublished:August 08, 2022DOI:https://doi.org/10.1016/j.ctro.2022.08.006

      Abstract

      Backround and purpose

      The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) remains to be demonstrated through phase III trials. Multiple SBRT procedures have been published potentially resulting in a disparity of practices. Therefore, the french society of urological radiation oncolgists (GETUG) recognized the need for joint guidelines for metastasis-directed SBRT in order to standardize practice in trials carried out by the group.

      Materials and methods

      After a comprehensive litterature review, 97 recommandation statements were created regarding planning and delivery of spine bone (SBM) and non-spine bone metastases (NSBM) SBRT. These statements were then submitted to a national online two-round modified Delphi survey among main GETUG investigators. Consensus was achieved if a statement received ≥ 75 % agreements, a trend to consensus being defined as 65–74 % agreements. Any statement without consensus at round one was re-submitted in round two.

      Results

      Tweny-one out of 29 (72.4%) surveyed GETUG investigators responded to both rounds. Consensus was achieved for 91/97 statements (93.8%) allowing the edition of comprehensive guidelines encompassing all aspects of SBM and NSBM SBRT planning and delivery: patients selection (19 statements), treatment preparation (14 statements), target volume delineation (18 statements), dose and fractionation (11 statements), prescription and dose objectives (9 statements), organs at risk dose constraints (15 statements) and image guided radiation therapy (11 statements).

      Conclusion

      GETUG guidelines for SBM and NSBM SBRT were agreed upon using a validated modified Delphi approach. These guidelines will be used as per-protocol recommendations in ongoing and further GETUG clinical trials.

      Keywords

      1. Introduction

      The prevalent use of functional imaging for disease assessment and the improvement of life expectancy driven by recent therapeutic advances make urological cancer patients more likely to be in an oligometastatic state at the time of diagnosis (synchronous) or recurrence (metachronous).[
      • Lievens Y.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
      ,
      • Guckenberger M.
      • Lievens Y.
      • Bouma A.B.
      • Collette L.
      • Dekker A.
      • deSouza N.M.
      • 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.
      ] The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) has been prospectively assessed in phase II randomized studies.[
      • Ost P.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II Trial.
      ,
      • Palma D.A.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ,
      • Phillips R.
      • et al.
      Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The ORIOLE phase 2 randomized clinical trial.
      ] Aside from excellent local control with limited toxicity, the level of evidence for oncological benefits remains low.[
      • Zaorsky N.G.
      • Lehrer E.J.
      • Kothari G.
      • Louie A.V.
      • Siva S.
      Stereotactic ablative radiation therapy for oligometastatic renal cell carcinoma (SABR ORCA): a meta-analysis of 28 studies.
      ,
      • Marvaso G.
      • et al.
      Oligorecurrent prostate cancer and stereotactic body radiotherapy: Where are we now? A systematic review and meta-analysis of prospective studies.
      ].
      SBRT is often proposed to target oligometastases in the field of castration-sensitive prostate cancer or to treat metastases from renal cell carcinoma in order to postpone initiation or change of systemic therapies.[
      • Ost P.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II Trial.
      ,
      • Palma D.A.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ,
      • Schoenhals J.E.
      • et al.
      Stereotactic ablative radiation therapy for oligoprogressive renal cell carcinoma.
      ] By inducing presentation of cancer antigens to the immune system, SBRT is also believed to stimulate a tumor-targeted immune response (bystander and abscopal effects) and to improve the therapeutic efficiency of immunotherapies (STAR effect).[
      • Tubin S.
      • Ashdown M.
      • Jeremic B.
      Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment.
      ,
      • Solanki A.A.
      • et al.
      Combining immunotherapy with radiotherapy for the treatment of genitourinary malignancies.
      ,
      • Torok J.A.
      • Salama J.K.
      Combining immunotherapy and radiotherapy for the STAR treatment.
      ] In addition, a new era of therapeutic indications proposes the use of SBRT for pain relief for multimetastatic patients, as opposed to standard palliative irradiation.[
      • Sahgal A.
      • 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.
      ] Nevertheless, inclusion of patients in large phase III trials is still warranted to better understand the true benefits of metastasis-directed SBRT.
      A large number of SBRT procedures has been published with significant differences in terms of delineation, dose prescription, fractionation and dose objectives, potentially resulting in a disparity of practices.[
      • Soltys S.G.
      • et al.
      Stereotactic body radiation therapy for spinal metastases: Tumor control probability analyses and recommended reporting standards.
      ] As approximately-one-third of cancer patients will develop bone metastases, of which 70 % will experience spinal metastases[
      • De Bari B.
      • et al.
      Spinal metastases: Is stereotactic body radiation therapy supported by evidences?.
      ], the french society of urological radiation oncolgists (GETUG) recognized the need for joint consensus guidelines for metastasis-directed SBRT in order to guarantee a consistent practice in ongoing and further clinical trials carried out by the group.
      Using a modified Delphi approach[
      • Loblaw D.A.
      • Prestrud A.A.
      • Somerfield M.R.
      • Oliver T.K.
      • Brouwers M.C.
      • Nam R.K.
      • et al.
      American society of clinical oncology clinical practice Guidelines: formal systematic review-based consensus methodology.
      ], a representative panel of GETUG radiation oncologists was interviewed to assess the level of consensus regarding recommendations for all aspects of SBRT in spine bone metastases (SBM) and non-spine bone metastases (NSBM).

      2. Materials and methods

      2.1 Building of a first proposal of statements by a GETUG task force

      A GETUG task force of six radiation oncologists and four medical physicists specialized in the treatment of urological malignancies and SBRT was created. Three members of the task force (FV, PG, DP) conducted a Pubmed search for relevant English-language articles, published within the last 10 years and providing pratical recommendations for treatment planning and delivery of bone metastasis-directed SBRT. Other members of the task force were asked to add to the list of publications as they deemed necessary. Following article selection, the task force conducted a litterature review session to decide the main steps for planning bone metastasis-directed SBRT. Conclusions were summarized in a written document and a list of 97 recommendation statements was edited to be submitted to GETUG investigators through a two-round modified Delphi survey. These statements were structured around seven main topics: patient selection, treatment preparation (patient immobilization and imaging modalities), target volume delineation, dose and fractionation, modality of prescription and dose objectives, organs at risk, image guided radiation therapy (IGRT).

      2.2 Respondents

      The main active investigators of GETUG clinical trials were contacted by e-mail to answer the survey. If the participants felt it appropriate, they could forward the survey to the member of their department with a higher expertise in SBRT. Respondents were encouraged to answer the survey in collaboration with a physicist. Physicians who accepted to respond to the first round were invited to the second round and were offered authorship.

      2.3 Two-round modified Delphi survey

      To assess the consensus level for each of the 97 statements, an online questionnaire was generated using the Google Form plateform (Google, Alphabet Inc, Mountain View, USA) and was used to conduct a two-round survey through a modified Delphi approach. [
      • Loblaw D.A.
      • Prestrud A.A.
      • Somerfield M.R.
      • Oliver T.K.
      • Brouwers M.C.
      • Nam R.K.
      • et al.
      American society of clinical oncology clinical practice Guidelines: formal systematic review-based consensus methodology.
      ] Prior to the first round, the document summarizing the task force literature review was sent to all respondents.
      In round one, respondents were asked to rate their degree of agreement for each statement using a 7-point Likert scale. Answers were grouped as follow: disagreement including answers “strongly disagree” and “disagree” (votes 1–2), neutral (votes 3–5), agreement including answers “agree” and “strongly agree” (votes 6–7). Participants were encouraged to explain their disagreement in a free text box. Statements with 75 % agreement (votes 6–7) were considered to have met consensus and those statements were not redistributed for ranking in a second round. [
      • Loblaw D.A.
      • Prestrud A.A.
      • Somerfield M.R.
      • Oliver T.K.
      • Brouwers M.C.
      • Nam R.K.
      • et al.
      American society of clinical oncology clinical practice Guidelines: formal systematic review-based consensus methodology.
      ].
      In round two, the results from the first round were shared. Respondents were then asked to reevaluate each statement that had not achieved consensus in round one. At this point, to ensure a consistent interpretation of the statements, any statement that had been identified as unclear was slightly reworked and accompanied by an explanation. For a limited number of statements, the Likert scale was replaced by close-ended response options.
      At the end of round two, statements with < 75 % agreement were considered to have failed to achieve consensus. Nervertheless, statements with 65–74 % agreement were considered to have achieved a trend to consensus.

      3. Results

      Twenty-nine radiation oncologists were asked to participate. Twenty-one (72.4 %) completed the first round survey. The same 21 also completed the second round. The invitation to round one was sent April 5th, 2021 and votes for round two closed Ocotber 10th, 2021.
      Of the 97 recommendation statements submited to vote, 75 achieved consensus at round one. The 22 remaining statements were submitted to revote and 16 of them achieved consensus at round two making a total rate of consensus of 94 % (91/97). Among the 6 remaining statements that failed to achieve consensus, 5 achieved a trend to consensus (statements 12, 19, 53, 71, 79) and 1 lacked any sort of consensus (statement 7).
      Content of each statement and the correponding voting from the two-round survey are presented in Table 1. Statements that achieved consensus are in bold. Organs at risk dose constraints put to vote are presented in Table 2.
      Table 1Results of the two-round survey (statements that achieved consensus are bolded).
      StatementsnRoundAgreeNeutralDisagreeConsensus
      Patient selection
      1. To offer SBRT to an oligometastatic patient, his life expectancy must be ≥ 6 months21180.9 %19.1 %0 %Yes
      2. To offer SBRT to an oligometastatic patient, his WHO performance status must be ≤ 221185.7 %14.3 %0 %Yes
      3. For PET-avid primary tumors (prostate adenocarcinoma, urothelial carcinoma), the oligometastatic state must be attested by PET-CT and not only using conventional imaging (CT-scan, bone scan)21185.7 %14.3 %0 %Yes
      4. The oligometastatic state is defined by a maximum of 5 metastases total21176.2 %0 %23.8 %Yes
      5. The oligometastatic state is defined by maximum of 3 metastases total21123.8 %0 %76.2 %No
      6. Published data support the use of SBRT for treatment of metachronous oligometastases21171.4 %23.8 %4.8 %No
      21285.6 %9.6 %4.8 %Yes
      7. Published data support the use of SBRT for treatment of synchronous oligometastases21138.1 %23.8 %38.1 %No
      21228.6 %9.6 %61.8 %No
      8. Published data support the use of SBRT for pain relief for multimetastatic patients in the field of palliative care21138.1 %38.1 %23.8 %No
      21276.2 %14.3 %9.5 %Yes
      9. For SBM, GTV must be ≤ 5 cm21185.7 %9.5 %4.8 %Yes
      10. For SBM, a maximum of 2 contiguous vertebrae can be treated simultaneously21195.2 %4.8 %0 %Yes
      11. For SBM, Bislky grading system must be < 1c and / or the GTV-to-spinal-cord distance should be ≥ 23 mm in order to allow adequate dose fall off21166.7 %33.3 %0 %No
      21295.2 %0 %4.8 %Yes
      12. If the GTV-to-spinal cord distance is not sufficient, a spinal cord separation surgery (i.e. the epidural part of the tumor is resected without significant vertebral body resection) can be proposed before SBM SBRT21138 %52.4 %9.6 %No
      21266.6 %9.6 %23.8 %No (trend)
      13. The Spinal Instability Neoplastic Score (SINS) scoring system must be used to evaluate vertebral mechanical instability before SBM SBRT.21190.5 %9.5 %0 %Yes
      14. A SINS score > 7 requires a neurosurgical advise to discuss pre-SBRT vertebral stabilization21185.7 %14.3 %0 %Yes
      15. SBM SBRT after kyphoplasty or vertebral osteosynthesis is safe21166.7 %33.3 %0 %No
      21290.5 %9.5 %0 %Yes
      16. For NSBM, the Mirels scoring system should be used to assess the risk of post-SBRT fracture21161.9 %33.3 %4.8 %No
      21285.7 %9.5 %4.8 %Yes
      17. For NSBM, a Mirels score ≥ 9 requires orthopedic advise for bone stabilization surgery21176.2 %23.8 %0 %Yes
      18. For NSBM, ≥30 % circumferential cortical infiltration requires orthopedic advise for bone stabilization surgery20190 %10 %0 %Yes
      19. As no evidence exists for safety of SBRT after NSBM osteosynthesis, indication for bone stabilization surgery precludes the use of SBRT21133.4 %42.8 %23.8 %No
      21271.4 %14.3 %14.3 %No (trend)
      Treatment preparation (immobilization and imaging modalities)
      20. A customized immobilization device is mandatory (except if an image-guided tracking robotic system that provides minimal residual intra-fraction error is used)21195.5 %0 %4.8 %Yes
      21. The treatment planning will be performed on a planning CT-scan (≤2mm slice thickness) without contrast21185.6 %9.6 %4.8 %Yes
      22. For SBM, accuracy of ≤ 1 mm translational and ≤ 1° rotational setup errors must be ensured21195.2 %4.8 %0 %Yes
      23. For SBM, the planning CT-scan should cover at least 2 vertebrae above and below PTV21195.5 %4.8 %0 %Yes
      24. For SBM, the imaging modalities used for the treatment planning must include spine MRI (≤3mm slice thicknesswith contrast21190.4 %9.6 %0 %Yes
      25. For SBM, the MRI should at least include (SPINO recommandations) axial T2-weighted (for spinal cord identification),a T1-weighted and gadolium-enhenced T1-weighted (for GTV localization) sequences21176.2 %23.8 %0 %Yes
      26. For SBM, an automatic planning-CT/MRI rigid registration (focused on the region of interest) must be performed followed by a carefull medical validation before starting volumes delineation21185.6 %9.6 %4.8 %Yes
      27. For SBM, It is highly recommended but not mandatory for the spine MRI to be acquired in the treatment position using the patient’s customized immobilization device21161.9 %33.3 %4.8 %No
      21280.9 %14.3 %4.8 %Yes
      28. For SBM, as an option, a diagnostic spine MRI (i.e. not acquired with the patient's customized immobilizaton device) can be used but must be<3-week-old and fulfilll SPINO recommandations21171.4 %28.6 %0 %No
      21295.2 %0 %4.8 %Yes
      29. For NSBM, accuracy of ≤ 3 mm translational and ≤ 2° rotational setup errors must be ensured20190.4 %9.6 %0 %Yes
      30. For NSBM, the planning CT-scan should cover at least 10 cm above and below PTV and include the metastatic bone in it's entirety21185.7 %14.3 %0 %Yes
      31. For mobile targets (eg. ribs), a 4D-planning CT-scan must be performed21190.5 %9.5 %0 %Yes
      32. For NSBM, a bone MRI and/or a PET-CT can be registered (optional) to the planning-CT to help for the delineation of GTV21190.5 %9.5 %0 %Yes
      33. For NSBM, if a planning-CT/MRI registration is performed, a diagnostic MRI (i.e. not acquired with the patient's customized immobilization device) can be used if<3-week-old21190.5 %9.5 %0 %Yes
      Target volume delineation
      34. For SBM, GTV = macroscopic disease as assessed on planning (CT) and diagnostic (MRI+/- PET) imaging211100 %0 %0 %Yes
      35. For SBM, GTV must include epidural and paraspinal tumor expansion21190.4 %9.6 %0 %Yes
      36. For SBM, after debulking surgery: GTV = residual macroscopic disease only21180.8 %9.6 %9.6 %Yes
      37. For SBM, CTV = GTV + anatomical sections of the vertebra at risk for microscopic spread211100 %0 %0 %Yes
      38. For SBM, CTV delineation should follow guidelines for vertebral [Cox et al. IJROBP 2012;83(5):e597-605] and sacral [Dunne et al. Radiother Oncol. 2020;145:21–9] metastases21195.2 %4.8 %0 %Yes
      39. For SBM, CTV with a “donut” shape should be avoided19168.4 %31.6 %0 %No
      21285.6 %4.8 %9.6 %Yes
      40. For SBM, after debulking surgery: CTV = residual GTV + preoperative bony and epidural extent of the disease + adjacent sections of the vertebra at risk for microscopic spread [Redmond et al. IJROBP 2017;97(1):64–74].21195.2 %4.8 %0 %Yes
      41. For SBM, after debulking surgery, a preoperative-MRI/postoperative-planning-CT registration is highly recommended to help for the delineation of CTV21190.4 %9.6 %0 %Yes
      42. For SBM, PTV = CTV + 12 mm (institution-dependant)21195.2 %4.8 %0 %Yes
      43. For SBM, PTV will be partially amputated to create a volume called “restricted PTV” (labelled PTV!) in order to coerce the inverse planning system into decreasing the dose distribution in areas of close vicinity between PTV and major OARs (e.g. PTV! = PTV minus the spinal canal and any area of PTV/PRVs overlap)211100 %0 %0 %Yes
      44. For SBM, the final treatment planning approval (dose objectives achievement) must rely on the adequate coverage of PTV! – following SABR UK guidelines21128.6 %0 %71.4 %No
      21295.2 %0 %4.8 %Yes
      45. For SBM, PTV (and not PTV!) must be used for dose reporting – following ICRU guidelines21185.7 %14.3 %0 %Yes
      46. For NSBM, GTV = macroscopic disease as assessed on planning (CT) and diagnostic (MRI+/- PET) imaging21195.2 %4.8 %0 %Yes
      47. For NSBM, GTV must include extra-bone and medullary tumor expansions21195.2 %4.8 %0 %Yes
      48. For mobile targets: ITV = sum of each GTV from the different phases of a 4D planning CT21195.2 %4.8 %0 %Yes
      49. For NSBM, CTV = GTV (or ITV) + 35 mm21185.7 %14.3 %0 %Yes
      50. For NSBM, CTV must be manually adjusted to be kept inside the cortical bone (unless the tumor expanses in surrounding soft tissues)21190.5 %9.5 %0 %Yes
      51. For NSBM, PTV = CTV + 35 mm (institution-dependant)211100 %0 %0 %Yes
      Dose and fractionation
      52. For SBM, In case of multiple fractions, the treatment must be delivered every other day21180.9 %14.3 %4.8 %Yes
      StatementsnRoundAgreeNeutralDisagreeConsensus
      53. For SBM from primary renal cell carcinoma (radioresistant), 24 Gy in 1 fraction is a valid treatment option21161.9 %33.4 %4.8 %No
      21271.4 %4.8 %23.8 %No (trend)
      54. For SBM from primaries other than renal cell carcinoma, multiple fractions should be favored21185.7 %4.8 %9.6 %Yes
      55. For SBM, 30 Gy in 3 fractions (10 Gy/fraction) is a valid prescription scheme20190 %5 %5 %Yes
      56. For SBM, 27 Gy in 3 fractions (9 Gy/fraction) is a valid prescription scheme21185.7 %9.5 %4.8 %Yes
      57. For SBM, 35 Gy in 5 fractions (7 Gy/fraction) is a valid prescription scheme21185.7 %14.3 %0 %Yes
      58. For SBM, 30 Gy in 5 fractions (6 Gy/fraction) is a valid prescription scheme21166.7 %23.8 %9.5 %No
      21295.2 %0 %4.8 %Yes
      59. For SBM, after debulking surgery the same prescription schemes as the ones mentioned above should be used20185 %10 %5 %Yes
      60. For NSBM, multiple fractions should be favored over ultrahigh-dose single-fraction21180.9 %14.4 %4.8 %Yes
      61. For NSBM, the same prescription schemes as the ones used for SBM can be used21190.4 %4.8 %4.8 %Yes
      21152 %38 %10 %No
      62. For NSBM, it is possible (option) to deliver the treatment every day instead of every other day as long as a gap of 24 h between two fractions is provided.202100 %0 %0 %Yes
      Prescription and dose objectives
      63. The “prescription dose” is defined as the dose deemed to enclose an optimal percentage of the volume of PTV (ideally 95 % of PTV)21195.2 %4.8 %0 %Yes
      64. The treatment planning should promote a significant dose heterogeneity within PTV with an increase in dose beyond 107 % of the prescription dose19173.7 %0 %26.3 %No
      21295.2 %0 %4.8 %Yes
      65. The maximum dose can reach up to:
      − 107 % of the prescription dose19126.3 %0 %73.7 %No
      − 130 % of the prescription dose2120 %0 %100 %No
      19173.7 %0 %26.3 %No
      − 140 % of the prescription dose212100 %0 %0 %Yes
      19157.9 %0 %42.1 %No
      − 150 % of the prescription dose21285.8 %0 %14.2 %Yes
      19110.5 %0 %89.5 %No
      − 160 % of the prescription dose21214.3 %0 %85.7 %No
      1910 %0 %100 %No
      2124.8 %0 %95.2 %No
      66. As an option, a simultaneous integrated boost technique can be used to confine the maximal dose inside GTV21147.6 %38.1 %14.3 %No
      21290.5 %9.5 %0 %Yes
      67. For SBM, main dose objective for PTV is as follow: ≥95 % PTV should receive ≥ 100 % of the prescription dose21190.5 %9.5 %0 %Yes
      68. For SBM, if required for the respect of OARs dose constraints, PTV dose objective can be lowered to ≥ 90 % PTV should receive ≥ 100 % of the prescription dose, provided that ≥ 98 % GTV receives ≥ 21 Gy in 3 fractions or ≥ 23 Gy in 5 fractions [Bishop et al. IJROBP 2015;92(5):1016–26.]21180.9 %19.1 %0 %Yes
      69. Fot SBM from primary renal cell carcinoma (radioresistant) it is mandated that ≥ 98 % GTV receives ≥ 18 Gy in 1 fraction, 24 Gy in 3 fractions or 30 Gy in 5 fractions [Wang et al. IJROBP 2017;98(1):91–100]21176.2 %23.8 %0 %Yes
      70. For NSBM, main dose objective for PTV is as follow: ≥95 % PTV should receive ≥ 100 % of the prescription dose20195 %5 %0 %Yes
      71. For NSBM, PTV dose objective should not be lowered (motive: GTV to PTV disctance is narrow)21152.3 %38.1 %9.6 %No
      21266.6 %0 %33.4 %No (trend)
      Organs at risk
      72. Neurological OARs (brainstem, spinal cord, cauna equida, plexus) are delineated using the axial T2-weighted MRI sequence21195.2 %4.8 %0 %Yes
      73. For neurological OARs (brainstem, spinal cord, cauna equida, plexus), dose constraints will be applied to a PRV21190.5 %9.5 %0 %Yes
      74. The same margin as the one used from CTV to PTV is applied around neurological OARs (brainstem, spinal cord, cauna equida, plexus) to create their corresponding PRV21195.2 %4.8 %0 %Yes
      75. The thecal sac as assessed on MRI can be used as a surrogate for spinal cord PRV or cauda equina PRV21180.9 %14.3 %4.8 %Yes
      76. In rare cases, when the patient has MRI contraindication and on the condition GTV does not reach the edges of the spinal canal, it is acceptable to use the spinal canal as a surrogate for spinal cord or cauna equida PRV21176.2 %23.8 %0 %Yes
      77. The esophagus is a serial OAR potentially in close vicinity with PTV. Thus, a margin should be applied around the esophagus to create a PRV.21176.1 %4.8 %19.1 %Yes
      78. PRV is not mandated for OARs other than neurological structures or esophagus21157.1 %23.8 %19.1 %No
      21281 %0 %19 %Yes
      79. When emerging via the intervertebral foramina, a root of a brachial or sacral plexus cuts throughout PTV
      -To avoid major PTV underdosage, that root will not be delineated so that no dose constraint will be applied to it21157.1 %0 %42.9 %No
      -That root will be delineated as part of the corresponding plexus and PTV underdosage will be allowed to provide the respect of the same dose constraints as for the plexus2129.5 %0 %90.5 %No
      21142.9 %0 %57.1 %No
      21219 %0 %81 %No
      -That root will be delineated as a single volume in order to avoid the maximal dose to be delivered in that area but without compromising adequate dose delivery to PTV (no undertreatment)212*71.5 %0 %28.5 %No (trend)
      80. Brainstem dose constraints (see Table 2)21195.2 %4.8 %0 %Yes
      81. Spinal Cord dose constraints (see Table 2)21190.4 %9.6 %0 %Yes
      82. Cauda Equina dose constraints (see Table 2)21195.2 %4.8 %0 %Yes
      83. Plexus dose constraints (see Table 2)20195 %5 %0 %Yes
      84. Esophagus dose constraints (see Table 2)21195.2 %4.8 %0 %Yes
      85. Large Vessels dose constraints (see Table 2)21180.9 %14.3 %4.8 %Yes
      86. Skin dose constraints (see Table 2)21176.2 %14.3 %9.6 %Yes
      Image Guided Radiation Therapy (IGRT)
      87. The use of IGRT with online correction is required for every fraction20195 %5 %0 %Yes
      88. Orthogonal kV images provide adequate positioning precision only if using the Cyberknife© image guided tracking system or the Exatrac© system20190 %5 %5 %Yes
      89. For SBM SBRT, the ability to correct any displacement with a 6-degree of freedom couch is required21190.4 %9.6 %0 %Yes
      90. KiloVoltage cone beam CT (kV-CBCT) must be taken before every fraction for inaugural positioning (does not apply to Cyberknife©)19184.2 %10.6 %5.2 %Yes
      91. In the case of coplanar beam plans, the use of kiloVoltage cone beam CT (kV-CBCT) provides enough precision for patient positioning. The use of the Exactrac® system is optional (does not apply to Cyberknife©)21185.6 %4.8 %9.6 %Yes
      92. In the case of non-coplanar beam plans, as the use of kiloVoltage cone beam CT (kV-CBCT) is not possible, patient positioning must be checked using adequate on-board imaging such as the Exactrac® system (does not apply to Cyberknife©)21195.2 %4.8 %0 %Yes
      93. Patient positioning control must be repeated after any couch displacement19189.4 %10.6 %0 %Yes
      94. Intrafraction patient positioning controls are not mandatory if the treatment is fast (<2 min)19184.2 %15.8 %0 %Yes
      95. Post-fraction kV-CBCT is optional19194.7 %5.3 %0 %Yes
      96. Couch shifts must be applied in case of > 1 mm translational or > 1° rotational setup error for SBM SBRT19178.9 %15.8 %5.3 %Yes
      97. Couch shifts must be applied in case of > 1 mm translational or > 1° rotational setup error for NSBM SBRT21190.4 %9.6 %0 %Yes
      SBRT: stereotactic body radiation therapy; SBM: spine bone metastases; NSBM: non-spine bone metastases.
      * Third option added at the time of the second round.
      Table 2Organs at risk dose constraints.
      Organs at Risk1 fraction3 fractions5 fractions
      Brainstem*D0.1 cc < 15 GyD0.1 cc < 23.1 GyD0.1 cc < 31 Gy
      D1cc < 10 GyD1cc < 18 GyD1cc < 26 Gy
      Spinal Cord*D0.1 cc < 14 GyD0.1 cc < 21.9 GyD0.1 cc < 30 Gy
      D0.35 cc < 10 GyD0.35 cc < 18 GyD0.35 cc < 22.5 Gy
      D1.2 cc < 7 GyD1.2 cc < 12.3 GyD1.2 cc < 14.5 Gy
      Cauda Equina*D0.1 cc < 16 GyD0.1 cc < 24 GyD0.1 cc < 32 Gy
      D5cc < 14 GyD5cc < 21.9 GyD5cc < 30 Gy
      Plexus*D0.035 cc < 17.5 GyD0.035 cc < 24 GyD0.035 cc < 32 Gy
      D3cc < 14 GyD3cc < 22.5 GyD3cc < 30 Gy
      Esophagus*D0.035 cc < 16 GyD0.5 cc < 25.2 GyD0.5 cc < 34 Gy
      D5cc < 11.9 GyD5cc < 21 GyD5cc < 27.5 Gy
      Large VesselsD0.035 cc < 37 GyD0.5 cc < 45 GyD0.5 cc < 53 Gy
      D10cc < 31 GyD10cc < 39 GyD10cc < 47 Gy
      SkinD0.035 cc < 26 GyD0.5 cc < 33 GyD0.5 cc < 39.5 Gy
      D10cc < 23 GyD10cc < 30 GyD10cc < 36.5 Gy
      * Dose constraints must be applied to the planning organ at risk volume (PRV).
      The voting resulted in creation of step-by-step consensus guidelines for SBM and NSBM that can be found in Supplementary Material 1.

      4. Discussion

      We used a two-round survey through a modified Delphi approach to develop GETUG guidelines regarding SBRT for treatment of SBM and NSBM.[
      • Loblaw D.A.
      • Prestrud A.A.
      • Somerfield M.R.
      • Oliver T.K.
      • Brouwers M.C.
      • Nam R.K.
      • et al.
      American society of clinical oncology clinical practice Guidelines: formal systematic review-based consensus methodology.
      ] A high rate of consensus allowed for the creation of a comprehensive list of recommendations from patient selection to treatment planning and delivery. These guidelines will be used as per-protocole recommendations to ensure a consistent approach for investigators’ practice in ongoing and further GETUG trials, the final objectives being to encourage adoption of trials protocols, improve inclusion rates and limit major deviations.
      Interestingly, among the six statements that did not achieve consensus, half were related to patient selection. Agreement was notable for defining the oligometastatic state as a maximum of five metastases - eventhough 24 % of respondents would lower the limit to three - and for offering metastasis-directed ablative therapies to metachronous oligometastatic patients. On the contrary, a majority of respondents considered that current knowledge does not allow for routinely offering that option to synchronous oligometastatic patients.
      Actually, the relevance of metastasis-directed ablative therapies remains to be demonstrated. SBRT has been mainly reported through retrospective series, as well as a limited number of small phase II randomized studies.[
      • Ost P.
      • et al.
      Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II Trial.
      ,
      • Palma D.A.
      • et al.
      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
      ,
      • Phillips R.
      • et al.
      Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The ORIOLE phase 2 randomized clinical trial.
      ] Aside from excellent local control and good tolerance, it appears that overall survival could be improved and the need for starting a new systemic treatment postponed.[
      • Zaorsky N.G.
      • Lehrer E.J.
      • Kothari G.
      • Louie A.V.
      • Siva S.
      Stereotactic ablative radiation therapy for oligometastatic renal cell carcinoma (SABR ORCA): a meta-analysis of 28 studies.
      ,
      • Marvaso G.
      • et al.
      Oligorecurrent prostate cancer and stereotactic body radiotherapy: Where are we now? A systematic review and meta-analysis of prospective studies.
      ] Nevertheless, inclusion of patients in large phase III trials is still highly warranted. Moreover, the oligometastatic state encompasses a vast variety of clinical situations. The “de novo” oligometastatic disease can be synchronous or metachronous depending if it is diagnosed at the time or long after the primary cancer diagnosis. The “repeat” oligometastatic disease happens after prior history of oligometastatic disease. The “induced” oligometastatic disease is a polymetastatic disease that was once controlled for a varying length of time under systemic therapies and finally progresses in a limited number of sites.[
      • Lievens Y.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
      ,
      • Guckenberger M.
      • Lievens Y.
      • Bouma A.B.
      • Collette L.
      • Dekker A.
      • deSouza N.M.
      • 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.
      ] All these situations should be separately assessed in clinical trials.
      Because the epidural space is a major site of local failure after spinal SBRT [
      • Redmond K.J.
      • Lo S.S.
      • Fisher C.
      • Sahgal A.
      Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine Metastases: A Critical Review to Guide Practice.
      ,
      • Chan M.W.
      • et al.
      Patterns of epidural progression following postoperative spine stereotactic body radiotherapy: implications for clinical target volume delineation.
      ,
      • Bishop A.J.
      • et al.
      Outcomes for spine stereotactic body radiation therapy and an analysis of predictors of local recurrence.
      ], the gross tumor extension in that area must be radiologically assessed by spinal magnetic resonance imaging (MRI) using the Bilsky epidural disease grading system[
      • Bilsky M.H.
      • et al.
      Reliability analysis of the epidural spinal cord compression scale.
      ,
      • Jabbari S.
      • et al.
      Stereotactic body radiotherapy for spinal metastases: practice guidelines, outcomes, and risks.
      ,
      • Thibault I.
      • Chang E.L.
      • Sheehan J.
      • Ahluwalia M.S.
      • Guckenberger M.
      • Sohn M.-J.
      • et al.
      Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.
      ]. In case of epidural contact (Bilsky 1c-3), or if GTV-to-spinal cord distance is deemed too short to allow sufficent dose fall-off to ensure adequate target volumes coverage while respecting spinal cord dose constraints (typically, 2–3 mm are required), GETUG members agreed to propose an inaugural mini-invasive spinal cord separation surgery before SBRT [
      • Redmond K.J.
      • Lo S.S.
      • Fisher C.
      • Sahgal A.
      Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine Metastases: A Critical Review to Guide Practice.
      ,
      • Rothrock R.
      • Pennington Z.
      • Ehresman J.
      • Bilsky M.H.
      • Barzilai O.
      • Szerlip N.J.
      • et al.
      Hybrid therapy for spinal metastases.
      ]. Obviously, access to such a highly specialised approach is limited due to its technicity and should be considered with caution in the view of the benefit-risk balance when treating asymptomatic metastatic patients.
      Delivering SBRT after stabilisation surgery or kyphoplasty appeared consensual for SBM. Responses were indeed more disparate regarding the acceptance of delivering SBRT to NSBM after osteosynthesis. This is explained by the lack of evidence for the safety of that approach with concern regarding potential cancer cells spread in the medullary space of a tubular bone. The risk of fracture after NSBM SBRT is around 8 % (up to 25 %), with the majority occuring during the first month post-treatment [
      • Erler D.
      • et al.
      Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases.
      ]. As the Spine Instability Scoring System (SINS) allows safe selection of patients to prevent post-SBRT vertebral compression fracture [
      • 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.
      ], for NSBM SBRT we propose to use, in addition to the Mirels score, the percentage of tumoral circumferential cortical infiltration. A surrogate of 30 % has been associated with a 100 % sensitivity for post-SBRT fracture risk of long bones [
      • Tatar Z.
      • et al.
      Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: a retrospective study.
      ,
      • Mirels H.
      Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures.
      ].
      Statements for treatment preparation were consensual especially for the need to provide setup intrafraction accuracy ≤ 1 mm/1° for SBM and ≤ 3 mm/2° for NSBM. Thus, a customized immobilization device is mandatory except if an image-guided tracking robotic system that provides minimal residual intra-fraction error is used. Of note, after round two, GETUG members agreed on the use of a diagnostic MRI (as opposed to a dedicated MRI acquired in the treatment position) for treatment planning as long as it is a volumetric imaging<3-week-old and meets all quality criteria as defined by SPINO guidelines (axial T1-weighted and T2-weighted, slice sickness ≤ 3 mm) [
      • Thibault I.
      • Chang E.L.
      • Sheehan J.
      • Ahluwalia M.S.
      • Guckenberger M.
      • Sohn M.-J.
      • et al.
      Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.
      ]. This is a practical approach reflecting the fact that most departments still don’t have dedicated access to MRI. In rare cases, when the patient has a contraindication to MRI and on the condition that the spine metastasis does not reach the edges of the spinal canal, it seems acceptable to use the spinal canal as a surrogate for planning organ at risk volume (PRV) of the spinal cord or the cauna equida.
      GETUG members agreed on relying on edited consensus contouring guidelines regarding target volume delineation for SBM SBRT [
      • Cox B.W.
      • et al.
      International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery.
      ,
      • Dunne E.M.
      • et al.
      International consensus recommendations for target volume delineation specific to sacral metastases and spinal stereotactic body radiation therapy (SBRT).
      ,
      • Redmond K.J.
      • et al.
      Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine.
      ]. Notably, the irradiation should not be restricted to the macroscopic disease but should include full vertebra segments to account for microscopic spread. Such recommandations were so far only based on experts opinions but were recently reinforced by the report by Chen et al. of an improvement in local control. [
      • Chen X.
      • LeCompte M.C.
      • Kleinberg L.R.
      • Ryan D.M.
      • Lo L.
      • Sciubba D.M.
      • et al.
      Deviation from consensus contouring guidelines predicts inferior local control after spine stereotactic body radiotherapy.
      ] As a counterpart for NSBM, GETUG members proposed to apply a 3–5 mm margin around the gross target volume (GTV) while keeping that extension inside the cortical bone (unless the tumor extends into surrounding soft tissues). This proposal is in accordance with recently published recommendations by Nguyen et al. [
      • Nguyen T.K.
      • et al.
      Stereotactic body radiation therapy for nonspine bone metastases: international practice patterns to guide treatment planning.
      ] As level 1 evidence is lacking for strong recommendations regarding NSBM SBRT, guidelines are subject to evolve with future publications.
      Regarding SBM SBRT, a highly anticipated challenge arises due to the close vicinity of the clinical target volume (CTV) and some organs at risk (OARs) such as the spinal cord and the oesophagus for instance. This is even more challenging when margins are applied to create the corresponding PTV and PRVs that can then overlap. Drawing on SABR UK guidelines [

      Home. SABR Consortium https://www.sabr.org.uk/.

      ], the GETUG members agreed on the generation of an intermediate target volume called “restricted PTV” (labelled PTV!) defined as the PTV minus the spinal canal and any area of PTV/PRVs overlap. The final treatment planning approval will then rely on the adequate coverage of PTV! by the prescription isodose. This coerces the planning system to lower dose distribution in specific areas of PTV - consented limited areas of local underdosage - with sharp dose gradient to adequately avoid major OARs. Nevertheless, in respect with ICRU guidelines, the final dose reporting will provide an information on the dose actually delivered to PTV.
      A broad spectrum of dose fractionation schedules have been published. [
      • Soltys S.G.
      • et al.
      Stereotactic body radiation therapy for spinal metastases: Tumor control probability analyses and recommended reporting standards.
      ] GETUG members agreed on the following in order of priority: 30 Gy in 3 fractions of 10 Gy, 27 Gy in 3 fractions of 9 Gy, 35 Gy in 5 fractions of 7 Gy and 30 Gy in 5 fractions of 6 Gy for both NSBM and SBM including after prior surgery. A single dose of 24 Gy reached a trend to consensus for treating SBM from primary renal cell carcinoma with respect to its radioresistant status and the richness of its neovascularization.
      Recently, a phase III trial established a better local control after metastasis-directed SBRT (mainly bone metastases) using a single fraction of 24 Gy versus 27 Gy in 3 fractions, resulting in less distant metastatic progressions with no increase in toxicity. [
      • Zelefsky M.J.
      • 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.
      ] Although exciting, these results should not yet be broadly applied as they were achieved in a highly selected population treated in a center of excellence with limited follow-up and as ultrahigh-dose single-fraction SBRT might cause serious long-term side effects. [
      • Biswas T.
      • Spratt D.E.
      Dose escalation for oligometastatic disease: Is more better?.
      ].
      Results from another phase III trial were recently published by Sahgal et al. comparing SBRT 24 Gy in 2 fractions to conventional irradiation 20 Gy in 5 fractions for the treatment of painful SBM. The study did not focus on oligometastatic disease as patients could be included irrespective of the total tumor burden unless life expectancy was > 3 months. With a median follow-up of 6.7 months, SBRT improved complete pain response (primary endpoint) at 3 months (p = 0.0002) and 6 months (p = 0·0036). It provided a 6-month local progression free survival of 75 % which was not greater than conventional irradiation (p = 0.34). Overall, 11 % of SBRT patients had a vertebral compression fracture mainly of low severity (grade 1). Those results validate the schedule of 24 Gy in two fractions for the palliative treatment of painful SBM [
      • Sahgal A.
      • 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.
      ].
      In order to allow for the generation of a sharp dose gradient, GETUG members agreed that the prescription dose should be prescribed on the isodose line that encompasses ≥ 95 % of PTV and that the dose distribution inside PTV should be kept heterogeneous beyond 107 % and up to 140 % of the prescription dose. As an option, a simultaneous integrated boost technique can be used to keep the maximal dose inside GTV. Anticipating the need for acceptance of minor deviations and in accordance with Bishop et al. recommandations, GETUG members agreed that, if required for the respect of OARs dose constraints, when delivering SBM SBRT the dose objectives can be lowered to ≥ 90 % PTV receives ≥ 100 % of the prescription dose providing that ≥ 98 % GTV receives ≥ 21 Gy in 3 fractions or ≥ 23 Gy in 5 fractions. [
      • Bishop A.J.
      • et al.
      Outcomes for spine stereotactic body radiation therapy and an analysis of predictors of local recurrence.
      ] In the case of SBM from primary renal cell carcinoma, ≥98 % GTV should receive ≥ 18 Gy in 1 fraction, 24 Gy in 3 fractions or 30 Gy in 5 fractions. [
      • Wang C.J.
      • et al.
      Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases.
      ] For NSBM SBRT, lowering PTV dose objectives didn’t reach the same consensus but remains an option depending on clinical situations. Although criticizable, we sense that the acceptance of minor deviations is a pragmatic view that provides a satisfactory balance between effectiveness and risk.
      As SBRT is often proposed to asymptomatic long-term survivors, it is consensual that complications threatening major vital functions as well as quality of life must be avoided. As such, GETUG members agreed for the application of a margin around the spinal cord, brachial/sacral plexus and oepsophagus to generate a PRV on which dose constraints will apply. This choice can differ from other reports, some authors considering that treatment delivery is accurate enough so that dose constraints should be applied to OARs with no margin [
      • Benedict S.H.
      • et al.
      Stereotactic body radiation therapy: the report of AAPM Task Group 101.
      ] when others put security first and promote generation of PRVs. [
      • Wang H.
      • et al.
      Dosimetric effect of translational and rotational errors for patients undergoing image-guided stereotactic body radiotherapy for spinal metastases.
      ,
      • Sahgal A.
      • et al.
      Spinal cord dose tolerance to stereotactic body radiation therapy.
      ] The GETUG members agreed on the use of OARs dose constraints issued from major international expert-based recommendations (Table 2). [
      • Benedict S.H.
      • et al.
      Stereotactic body radiation therapy: the report of AAPM Task Group 101.
      ,
      • Timmerman R.D.
      An overview of hypofractionation and introduction to this issue of seminars in radiation oncology.
      ,
      • Hanna G.G.
      • et al.
      UK Consensus on normal tissue dose constraints for stereotactic radiotherapy.
      ] It is noteworthy that the HyTEC (High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic) recently published somewhat more restrictive recommendations regarding the spinal cord point maximum dose (Dmax) based on mathematical and biological models (12.4 to 14.0 Gy in 1 fraction, 20.3 Gy in 3 fractions, 25.3 Gy in 5 fractions). [
      • Sahgal A.
      • et al.
      Spinal cord dose tolerance to stereotactic body radiation therapy.
      ] Yet, the paper clearly stated that all edited tolerance limits are suggestions and are not absolute. The GETUG members agreed that the HyTEC recommendations should be viewed as an optimal goal but should not prevent from delivering SBM SBRT provided that expert-based recommendations are reached (Table 2).
      As roots of the brachial plexus (anterior rami of C5-T1 spinal nerves) or the sacral plexus (anterior rami of L4-S4 spinal nerves) leave the spinal canal via the intervertebral foramina, it may happen that they run throughout PTV. Enforcing rigorous dose constraints to these substructures may then lead to major PTV underdosage. Neither the proposition of omitting the delineation of those roots nor the proposition of applying to them the same dose constraints as for the plexus were validated. A trend to agreement was observed for delineating the roots as single volumes and to avoid delivering hot spots (maximal dose) to them without compromising the adequate coverage of PTV.
      GETUG members agreed that the use of daily image-guided radiation therapy with online setup correction is required. High precision orthogonal 2D kV images such as Cyberknife© image guided tracking robotic system or ExacTrac© system are considered adequate for pre-treatment and intra-fraction positioning control. [
      • Ho A.K.
      • Fu D.
      • Cotrutz C.
      • Hancock S.L.
      • Chang S.D.
      • Gibbs I.C.
      • et al.
      A study of the accuracy of cyberknife spinal radiosurgery using skeletal structure tracking.
      ,
      • Yang J.
      • Wang X.
      • Zhao Z.
      • Brown P.
      SU-E-T-410: Spine radiosurgery imaging guidance using exactrac and CT on rails.
      ] In case of coplanar fields, the use of kiloVoltage cone-beam CT (kV-CBCT) provides enough precision for pre-treatment positioning as well. Aware that the risk of significant intra-fraction movements increases with treatment duration, GETUG members agreed that pausing treatment for intra-fraction kV-CBCT re-assessment is not mandatory as long as the fraction lasts<2 min. [
      • Wu J.
      • et al.
      Frequency of large intrafractional target motions during spine stereotactic body radiation therapy.
      ] Post-treatment kvCBCT is optional.
      GETUG members call for couch shifts to be applied for any > 1 mm translational or > 1° rotational setup error for both SBM or NSBM. The ability to acquire a 6-degree of freedom (DOF) positioning verification and to correct any displacement with a 6-DOF couch is required for SBM SBRT.
      Current indications of metastasis-directed SBRT remain limited to selected oligometastatic patients. [
      • Palma D.A.
      • et al.
      Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET Phase II Randomized Trial.
      ] Ongoing clinical trials are likely to enhance those indications in the future [

      Palma, D. A Randomized Phase III Trial of Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of 4-10 Oligometastatic Tumors (SABR-COMET 10). https://clinicaltrials.gov/ct2/show/NCT03721341 (2021).

      ,

      Olson, R. Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 Metastases) Cancer (SABR-COMET-3). https://clinicaltrials.gov/ct2/show/NCT03862911 (2021).

      ,

      European Organisation for Research and Treatment of Cancer - EORTC. Stereotactic Body Radiotherapy in Addition to Standard of Care Treatment in Patients With Rare Oligometastatic Cancers (OligoRARE): a Randomized, Phase 3, Open-label Trial. https://clinicaltrials.gov/ct2/show/NCT04498767 (2021).

      ] and recent developments tend to position SBRT as a more palliative treatment as well. Sahgal et al. proposed to extend indications to the setting of pain relief for SBM, irrespective of the total tumor burden unless patient life expectancy is > 3 months. Complete pain response was improved using SBRT compared to conventional radiotherapy. [
      • Sahgal A.
      • 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.
      ] Whilst not yet considered practice-changing, these results pave the way for an exponential increment in therapeutic applications raising the question of risk-taking in generalizing a treatment that is anything but trivial. [
      • van der Velden J.M.
      • van der Linden Y.M.
      Spinal stereotactic radiotherapy for painful spinal metastasis.
      ] As more accidental exposures are expected, the radiation oncology community faces the great challenge of generalizing a highly precise technique without compromising patients’ safety. [
      • Ortiz López P.
      • et al.
      ICRP publication 112. A report of preventing accidental exposures from new external beam radiation therapy technologies.
      ] We therefore believe that providing group guidelines using a rigorous methodology is of major interest. However, the main limitation remains the low level of evidence available in the literature, many of the studies being retrospective with limited population. Thus, many of the statements remain at the opinion level of GETUG investigators.

      5. Conclusion

      Consensus guidelines covering the main aspects of planning and delivery of SBRT for the treatment SBM and NSBM were provided using a validated two-round survey modified Delphi approach. These guidelines will be used as per-protocole recommendations to standardize investigators’ practice in ongoing and further clinical trials carried out by the GETUG.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Lievens Y.
        • et al.
        Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
        Radiother Oncol J Eur Soc Ther Radiol Oncol. 2020; 148: 157-166
        • Guckenberger M.
        • Lievens Y.
        • Bouma A.B.
        • Collette L.
        • Dekker A.
        • deSouza N.M.
        • 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.
        Lancet Oncol. 2020; 21: e18-e28
        • Ost P.
        • et al.
        Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II Trial.
        J Clin Oncol Off J Am Soc Clin Oncol. 2018; 36: 446-453
        • Palma D.A.
        • et al.
        Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.
        Lancet Lond Engl. 2019; 393: 2051-2058
        • Phillips R.
        • et al.
        Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The ORIOLE phase 2 randomized clinical trial.
        JAMA Oncol. 2020; 6: 650-659
        • Zaorsky N.G.
        • Lehrer E.J.
        • Kothari G.
        • Louie A.V.
        • Siva S.
        Stereotactic ablative radiation therapy for oligometastatic renal cell carcinoma (SABR ORCA): a meta-analysis of 28 studies.
        Eur Urol Oncol. 2019; 2: 515-523
        • Marvaso G.
        • et al.
        Oligorecurrent prostate cancer and stereotactic body radiotherapy: Where are we now? A systematic review and meta-analysis of prospective studies.
        Eur Urol Open Sci. 2021; 27: 19-28
        • Schoenhals J.E.
        • et al.
        Stereotactic ablative radiation therapy for oligoprogressive renal cell carcinoma.
        Adv Radiat Oncol. 2021; 6100692
        • Tubin S.
        • Ashdown M.
        • Jeremic B.
        Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment.
        Radiat Oncol Lond Engl. 2019; 14: 220
        • Solanki A.A.
        • et al.
        Combining immunotherapy with radiotherapy for the treatment of genitourinary malignancies.
        Eur Urol Oncol. 2019; 2: 79-87
        • Torok J.A.
        • Salama J.K.
        Combining immunotherapy and radiotherapy for the STAR treatment.
        Nat Rev Clin Oncol. 2019; 16: 666-667
        • Sahgal A.
        • 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: 1023-1033
        • Soltys S.G.
        • et al.
        Stereotactic body radiation therapy for spinal metastases: Tumor control probability analyses and recommended reporting standards.
        Int J Radiat Oncol Biol Phys. 2021; 110: 112-123
        • De Bari B.
        • et al.
        Spinal metastases: Is stereotactic body radiation therapy supported by evidences?.
        Crit Rev Oncol Hematol. 2016; 98: 147-158
        • Loblaw D.A.
        • Prestrud A.A.
        • Somerfield M.R.
        • Oliver T.K.
        • Brouwers M.C.
        • Nam R.K.
        • et al.
        American society of clinical oncology clinical practice Guidelines: formal systematic review-based consensus methodology.
        J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 3136-3140
        • Redmond K.J.
        • Lo S.S.
        • Fisher C.
        • Sahgal A.
        Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine Metastases: A Critical Review to Guide Practice.
        Int J Radiat Oncol Biol Phys. 2016; 95: 1414-1428
        • Chan M.W.
        • et al.
        Patterns of epidural progression following postoperative spine stereotactic body radiotherapy: implications for clinical target volume delineation.
        J Neurosurg Spine. 2016; 24: 652-659
        • Bishop A.J.
        • et al.
        Outcomes for spine stereotactic body radiation therapy and an analysis of predictors of local recurrence.
        Int J Radiat Oncol Biol Phys. 2015; 92: 1016-1026
        • Bilsky M.H.
        • et al.
        Reliability analysis of the epidural spinal cord compression scale.
        J Neurosurg Spine. 2010; 13: 324-328
        • Jabbari S.
        • et al.
        Stereotactic body radiotherapy for spinal metastases: practice guidelines, outcomes, and risks.
        Cancer J Sudbury Mass. 2016; 22: 280-289
        • Thibault I.
        • Chang E.L.
        • Sheehan J.
        • Ahluwalia M.S.
        • Guckenberger M.
        • Sohn M.-J.
        • et al.
        Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.
        Lancet Oncol. 2015; 16: e595-e603
        • Rothrock R.
        • Pennington Z.
        • Ehresman J.
        • Bilsky M.H.
        • Barzilai O.
        • Szerlip N.J.
        • et al.
        Hybrid therapy for spinal metastases.
        Neurosurg Clin N Am. 2020; 31: 191-200
        • Erler D.
        • et al.
        Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases.
        Radiother Oncol J Eur Soc Ther Radiol Oncol. 2018; 127: 304-309
        • 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. 2010; 35: E1221-1229
        • Tatar Z.
        • et al.
        Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: a retrospective study.
        Radiat Oncol. 2014; 9: 227
        • Mirels H.
        Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures.
        Clin Orthop. 1989; 249: 256???264
        • Cox B.W.
        • 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-e605
        • Dunne E.M.
        • et al.
        International consensus recommendations for target volume delineation specific to sacral metastases and spinal stereotactic body radiation therapy (SBRT).
        Radiother Oncol. 2020; 145: 21-29
        • Redmond K.J.
        • et al.
        Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine.
        Int J Radiat Oncol Biol Phys. 2017; 97: 64-74
        • Chen X.
        • LeCompte M.C.
        • Kleinberg L.R.
        • Ryan D.M.
        • Lo L.
        • Sciubba D.M.
        • et al.
        Deviation from consensus contouring guidelines predicts inferior local control after spine stereotactic body radiotherapy.
        Int J Radiat Oncol Biol Phys. 2021; 111: S101
        • Nguyen T.K.
        • et al.
        Stereotactic body radiation therapy for nonspine bone metastases: international practice patterns to guide treatment planning.
        Pract Radiat Oncol. 2020; 10: e452-e460
      1. Home. SABR Consortium https://www.sabr.org.uk/.

        • Zelefsky M.J.
        • 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.
        Int J Radiat Oncol Biol Phys. 2021; 110: 672-679
        • Biswas T.
        • Spratt D.E.
        Dose escalation for oligometastatic disease: Is more better?.
        Int J Radiat Oncol Biol Phys. 2021; 110: 680-681
        • Wang C.J.
        • et al.
        Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases.
        Int J Radiat Oncol Biol Phys. 2017; 98: 91-100
        • Benedict S.H.
        • et al.
        Stereotactic body radiation therapy: the report of AAPM Task Group 101.
        Med Phys. 2010; 37: 4078-4101
        • Wang H.
        • et al.
        Dosimetric effect of translational and rotational errors for patients undergoing image-guided stereotactic body radiotherapy for spinal metastases.
        Int J Radiat Oncol Biol Phys. 2008; 71: 1261-1271
        • Sahgal A.
        • et al.
        Spinal cord dose tolerance to stereotactic body radiation therapy.
        Int J Radiat Oncol Biol Phys. 2021; 110: 124-136
        • Timmerman R.D.
        An overview of hypofractionation and introduction to this issue of seminars in radiation oncology.
        Semin Radiat Oncol. 2008; 18: 215-222
        • Hanna G.G.
        • et al.
        UK Consensus on normal tissue dose constraints for stereotactic radiotherapy.
        Clin Oncol R Coll Radiol G B. 2018; 30: 5-14
        • Ho A.K.
        • Fu D.
        • Cotrutz C.
        • Hancock S.L.
        • Chang S.D.
        • Gibbs I.C.
        • et al.
        A study of the accuracy of cyberknife spinal radiosurgery using skeletal structure tracking.
        Neurosurgery. 2007; 60: 147-156
        • Yang J.
        • Wang X.
        • Zhao Z.
        • Brown P.
        SU-E-T-410: Spine radiosurgery imaging guidance using exactrac and CT on rails.
        Med Phys. 2012; 39: 3799
        • Wu J.
        • et al.
        Frequency of large intrafractional target motions during spine stereotactic body radiation therapy.
        Pract Radiat Oncol. 2020; 10: e45-e49
        • Palma D.A.
        • 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 Off J Am Soc Clin Oncol. 2020; 38: 2830-2838
      2. Palma, D. A Randomized Phase III Trial of Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of 4-10 Oligometastatic Tumors (SABR-COMET 10). https://clinicaltrials.gov/ct2/show/NCT03721341 (2021).

      3. Olson, R. Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 Metastases) Cancer (SABR-COMET-3). https://clinicaltrials.gov/ct2/show/NCT03862911 (2021).

      4. European Organisation for Research and Treatment of Cancer - EORTC. Stereotactic Body Radiotherapy in Addition to Standard of Care Treatment in Patients With Rare Oligometastatic Cancers (OligoRARE): a Randomized, Phase 3, Open-label Trial. https://clinicaltrials.gov/ct2/show/NCT04498767 (2021).

        • van der Velden J.M.
        • van der Linden Y.M.
        Spinal stereotactic radiotherapy for painful spinal metastasis.
        Lancet Oncol. 2021; S1470–2045: 00268https://doi.org/10.1016/S1470-2045(21)00268-0
        • Ortiz López P.
        • et al.
        ICRP publication 112. A report of preventing accidental exposures from new external beam radiation therapy technologies.
        Ann ICRP. 2009; 39: 1-86