Bony M - Stereotactic Ablative Radiotherapy (SABR) of Bony Metastases in Patients With Oligometastatic Disease - A Phase II Study
Phase: NA
Conditions: Oligometastatic Disease, Bone Metastases, Stereotactic Body Radiotherapy
Sponsor: Gitte Fredberg Persson MD PhD

Protocol version 1.1, 01 MAY 2020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 
   
BONY-M   
Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with oligometastatic 
disease - A phase II study 
 
 
 
Study protocol 
Protocol version:  Version 1.1 
Document Date: 01 MAY 2020 
Identifier: NCT05101824 
 
 
Primary Investigator and sponsor:  
Associate professor Gitte Fredberg Persson, MD PhD 
Herlev and Gentofte Hospital Copenhagen University 
Department of Oncology 
Herlev Ringvej 75 
2730 Herlev 
Phone: +45 38689299 
Email: gitte.persson@regionh.dk 
 
 
 
 
 
 
 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Trial management committee 
 
The trial management committee is responsible for maintaining protocol updates, quality assurance of the treatment 
plans collected in the data base and handle all serious adverse events (SAE) as reported from the participating centres. 
 
Trial management committee 
Associate professor Gitte Fredberg Persson, MD PhD 
Professor Ivan Richter Vogelius PhD DMSc  
Professor Olfred Hansen, MPO, PhD  
Mette Felter MD 
Morten Suppli MD PhD 
Medical physicist Mirjana Josipovic PhD 
Medical physicist Tine Bjørn Nielsen PhD 
Medical physicist Claus Behrens PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Herlev and Gentofte Hospital 
Onkologisk afdeling 
Herlev Ringvej 75 
2730 Herlev 
 
 
Local investigator: Mette van Overeem Felter, MD 
 
Sub-investigators: Consultant Poul Geertsen MD PhD, 
Consultant Eva Serup-Hansen MD PhD, Consultant Jon 
Alexander Lykkegaard Andersen MD, Consultant 
Henriette Lindberg MD PhD, Staff Specialist Jesper 
Andreas Palshof MD PhD, Staff Specialist Louise 
Wichmann Matthiessen MD PhD 
Odense Universitetshospital  
Onkologisk afdeling R 
Sdr. Boulevard 29, Indgang 99 
5000 Odense 
 
Local investigator: Professor Olfred Hansen, MPO, 
PhD 
Medical physicist: Wiviann Ottosson, PhD; Fatma 
Gaard-Petersen. 
 
Medical physicist: Tine Bjørn Nielsen, PhD 
  
Rigshospitalet, Københavns Universitet 
Onkologisk klinik 5073 
Blegdamsvej 7-9 
2100 København Ø 
 
Local investigator: Morten Hiul Suppli, MD PhD 
 
Sub-investigators: Mette Pøhl, MD PhD 
 
Medical physicist: Mirjana Josipovic, PhD 
 
 
Århus Universitets Hospital 
Onkologisk Afdeling 
Palle Juul-Jensens Boulevard 99 
8200 Aarhus N  
 
Local investigator: Simon Buus, MD PhD 
 
 
 
 
 
 
St Olavs Universitetssykehus, Trondheim 
Avd. Stråleterapi, Kreftklinikken 
 
Local investigator: Jan Boris Sten 
 
Medical physicist: Josefine Ståhl Kornerup, Ph.D. 
 
 
 
 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Table of contents ................................................................................................................. 
1 
 Background........................................................................................................................ 1 
 
The oligometastatic state 
1 
 
Stereotactic ablative body radiotherapy (SABR) 
2 
 
Bone metastases and SABR 
3 
1.3.1 
Bone metastases .................................................................................................................................................. 3 
1.3.2 
Local control rate .................................................................................................................................................. 3 
1.3.1 
SABR versus palliative fractionation schemes ...................................................................................................... 4 
1.3.2 
Pain relief .............................................................................................................................................................. 5 
 
SABR – what’s left to explore 
5 
2 
Bony-M .............................................................................................................................. 6 
3 
Endpoints ........................................................................................................................... 6 
3.1      Primary endpoint 
6 
 
Secondary endpoints 
6 
 
Exploratory studies 
7 
 
Definition of endpoint-related concepts 
7 
 
Pain assessment and the Numeric pain rating scale (NPRS) 
8 
4 
Study design, sample size calculation and timeframe .......................................................... 9 
 
Study design 
9 
 
Sample size 
9 
 
Sample size calculation for primary endpoint 
10 
 
Timeframe 
11 
5 
Visits and follow-up procedure ......................................................................................... 11 
 
Visits 
11 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
Toxicity assessment. 
11 
 
Blood sampling 
12 
 
Scanning procedure 
14 
 
Response evaluation 
14 
 
Supplemental treatment 
15 
 
EuroQol EQ-5D-5L Index 
15 
 
Systemic therapy 
15 
6 
Participants ...................................................................................................................... 16 
 
Inclusion criteria 
16 
 
Exclusion criteria 
17 
 
Enrolment 
18 
 
Withdrawal from the study 
19 
7 
Radiotherapy planning ...................................................................................................... 19 
 
Simulation 
19 
 
Dose prescription 
20 
 
Treatment delivery technique and position verification 
21 
 
Quality assurance 
22 
8 
Target and organs at risk ................................................................................................... 22 
 
Target definition 
22 
 
Organ at risk (OAR) definition 
23 
8.2.1 
OAR: none-spine ................................................................................................................................................. 23 
8.2.2 
OAR - Spine ......................................................................................................................................................... 23 
 
Previous RT 
24 
9 
Safety assessment ............................................................................................................ 24 
 
Adverse events (AE) 
24 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
Serious adverse events (SAE) 
25 
 
Trial management committee 
27 
10 Ethical aspects .................................................................................................................. 27 
 Ethical considerations 
27 
 Toxicity 
28 
10.2.1 
Risk of fracture ................................................................................................................................................... 28 
10.2.2 
Risk of joint stiffness ........................................................................................................................................... 29 
10.2.3 
Radiation Myelopathy (RM) ............................................................................................................................... 29 
10.2.4 
Pain flare............................................................................................................................................................. 30 
 Imaging 
30 
 Contrast agents and blood tests 
31 
 Pregnancy 
31 
 Insurance 
31 
11 Data management ............................................................................................................ 32 
12 Protocol handling and economy ........................................................................................ 32 
13 Feasibility ......................................................................................................................... 33 
14 Perspectives ..................................................................................................................... 33 
 
Bilsky score ........................................................................................................ 34 
 
Constraints ........................................................................................................ 35 
 
Dunne - Target delineation in the sacrum ........................................................... 37 
 
Cox - CTV delineation guidelines ........................................................................ 39 

Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
DcmCollab export .............................................................................................. 40 
 
Numeric Pain Rating Scale (NPRS) ...................................................................... 41 
 
Spine instability neoplastic score (SINS) ............................................................. 42 
 
EQ-5D-5L ............................................................................................................ 43 
 
CTCAE v. 5.0 ....................................................................................................... 46 
References ............................................................................................................................... 52 
 
 

1 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
1  Background 
 The oligometastatic state 
Historically, patients with metastatic cancer are considered incurable and treated with palliative 
therapies. However, some of these patients have long disease-free survival when treated with 
ablative treatment strategies to all metastatic sites. The existence of an oligometastatic state 
between locoregional - and metastatic disease were first proposed by Hellman and Weichselbaum. 
They presented the idea of an oligometastatic state in 1995 describing a hypothetical intermediate 
state between localized and widespread metastatic disease [1]. They hypothesized that certain 
tumours have not fully developed their metastatic potential and show a slow natural history. Factors 
that favour a truly oligometastatic state include a long interval between the treatment of the 
primary tumour and the appearance of metastases, and a high ratio of the metastasis growth rate 
compared to that of the primary tumour. Withers and Lee summaries this idea as “The more 
micrometastatic doubling times elapsing between removal of the primary and the clinical detection 
of the 'leader' metastasis, the higher the probability of an oligometastatic distribution” [2].  
The identification of patients with truly oligometastatic disease (OMD) is however difficult and a 
clear definition does not exist. It is likely cancer type dependent and best defined biologically [3]. 
Most studies have focused on up to five metastases, but some have included patients with up to 
eight metastases. These categories of OMD have been proposed:  
• Patients with few metastases at diagnosis have de novo OMD. 
• Patients with widespread disease that becomes oligometastatic after treatment have 
induced OMD. 
• Patients in complete remission who develop oligometastatic recurrence.  
• Patients with widespread disease receiving systemic therapy that progress in a limited 
number of sites have oligo-progressive disease (OPD). 
The introduction of targeted therapies and immune checkpoint inhibitors to control micro- 
metastatic disease together with advances in local therapy strategies, lead us to believe that a more 
aggressive approach to these patients may be meaningful.  

2 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Evidence is emerging, that definitive treatment of the oligometastatic categories is beneficial. A 
significantly prolonged survival in patients with oligometastatic disease compared with patients 
with more widely disseminated disease have been documented [4]. That statement has led some 
authors to conclude, that patients with oligometastatic disease will probably live long enough to 
benefit from the high rates of prolonged local control (LC) reported after an ablative strategy.  
An oligometastatic treatment strategy has been established in respect to surgery and shown 
superior survival outcome [5-9] . Surgery has therefore become standard procedure in the 
treatment of patients and is increasingly used for oligometastatic lung-, colorectal- and kidney 
cancer. However, not all patients are eligible for surgery and not all metastases are resectable.   
 Stereotactic ablative body radiotherapy (SABR) 
Radiotherapeutic challenges have historically been to deliver a truly ablative radiation dose without 
causing toxicity to the surrounding tissue.  However, new technologies now allow delivery of radical 
ablative doses of radiation within 1-5 fractions and has made aggressive treatment of lesions close 
to sensible organs, such as the spinal cord and oesophagus possible, without violating dose 
constraints to these organs.  
The American Society of Radiation Oncology defines stereotactic ablative radiotherapy (SABR) as 
external beam radiotherapy used to deliver a high dose of radiation very precisely to an 
extracranial target within the body, as a single dose or a small number of fractions [10].  SABR is 
also referred to as stereotactic body radiotherapy (SBRT). With new advances in radiotherapy we 
may be able to improve outcome for patients with oligometastatic disease. 
A randomized, phase II study (OLIGOMEZ), presented at ASTRO 2018, have shown prolonged 
progression-free survival (PFS) when adding local consolidative treatment (SABR and/or surgery) 
to maintenance treatment after induction therapy for patients with lung cancer (Gomez et al., Oral 
Scientific Session, ASTRO 2018, data not yet published, see reference for protocol information 
[11]). 
Palma, D.A has recently published data on the randomized, phase II, open-label study called SABR-
COMET. The study recruited patients with a broad spectrum of different cancer subtypes and 
found improved PFS and overall survival (OS) when offering SABR to patients with OMD vs 

3 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
palliative standard of care (SOC). Median OS was 28 months in the SOC group vs. 41 months in 
group offered SABR [12]. 
Ost et al. published in 2018 data on a multicenter phase II trial documenting the beneficial 
outcome of metastasis-directed therapy (MDT) (SABR and/or surgery) vs. surveillance alone for 
patients with oligo-recurrent prostate cancer. At a median follow-up time of 3 years, the median 
androgen deprivation therapy-free survival was 13 months for the surveillance group and 21 
months for the MDT group [13].  
Overall, these data suggest that local ablative therapy of metastases could improve the systemic 
control of disease. 
 Bone metastases and SABR 
1.3.1 Bone metastases 
Bone metastases are common in advanced cancer, with 70−85% of patients diagnosed with bone 
metastases at the time of autopsy [14]. Spine metastases occur in up to 70% of all involved osseous 
sites, leading to significant morbidity [15]. Bone metastases are complicated by skeletal-related 
events (SREs), which are local irreversible changes and include pathologic fracture, bone surgery, 
and spinal cord compression. Lage et al. showed that half of all patients with prostate cancer and 
bone metastases experienced 1 or more SREs [16]. Recently, a new endpoint termed symptomatic 
skeletal events (SSEs), defined as radiation to bone, symptomatic pathologic fracture, surgery to 
bone, or symptomatic spinal cord compression have been introduced in the literature [17-19]. In 
contrast with SREs, ascertainment of SSEs does not necessary include scheduled radiographic 
assessments and rate the symptomatology higher.  
1.3.2 Local control rate 
When SABR is used for treating spine bone metastases, the results are encouraging. Local control 
rates generally exceed 80% at 1 year, while high rates of pain control have been attained. Low rates 
of toxicity have been reported, assuming strict dose constraints are respected [20]. Most studies 
examining SABR of bone metastases have looked exclusively at spinal bone metastases, but studies 
documenting results in non-spine bone metastases have been published [21, 22]. Publications on 

4 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
long-term follow-up following SABR are now emerging. Moussazadeh et al. reported in 2015 a 
median follow-up of 6.1 years where 91.6% of lesions remained stable [23]. These results suggest a 
durable response in long-term survivors.  
In respect to spine bone metastases, a large proportion of the local failures can be attributed to 
poor tumour coverage limited by spinal cord constraints [24]. Previous reports have suggested that 
when an epidural tumour is within 2-5 mm of the spinal cord, target coverage is difficult to obtain 
[25]. Therefore, most studies exclude patients with epidural disease. Bishop et al. found, that 
minimum dose (Dmin) to GTV ≤ 21 Gy in 3 fractions was an independent predictor for local recurrence 
[24] and argued that conservative spinal cord constraints increase the risk for marginal failures.  
There is insufficient evidence to suggest superiority of either single or multiple fraction regimens 
with respect to local control and pain control [26]. However, there have been studies documenting 
that a single fraction treatment may have an increased frequency of toxicity, especially risk of 
fracture [27]. 
1.3.1 SABR versus palliative fractionation schemes  
Palliative fractionation schemes have been proven to decrease pain and improve quality of life. 
However, no increase in overall survival has been reported [28, 29] in contrast to SABR. The crude 
local control (LC) rate is reported higher for SABR compared with palliative fractionation schemes, 
suggesting superiority of SABR [30, 31].  Approximately 8–42% of patients treated with palliative 
fractionation schemes need re-treatment due to pain progression [32], and this is more frequent 
compared to stereotactic higher doses according to Chow et al [29]. Radioresistant tumours like 
renal cell carcinoma or malignant melanoma shows LC rates after SABR, which are comparable to 
those obtained with SABR for radiosensitive tumours [33-38]. In contrast, for unfavourable 
histological types, large retrospective analyses of spinal metastases suggests, that the rate of relapse 
approaches 80% within 2 years after palliative fractionation schemes [39]. Recently, data from a 
prospective, randomized, single-institution, phase 2, non-inferiority trial have been published from 
the same author. The study assesses the relative efficacy of high-dose, single-fraction SBRT vs 
standard multifraction radiotherapy (MFRT). No differences were found in treatment-related toxic 
effects or quality-of-life scores after SABR vs MFRT. Local control rates at 1 and 2 years were higher 

5 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
in patients receiving single-fraction SBRT. The authors conclude that SABR should be considered for 
patients expected to have relatively long survival [31] (full article in print).  
1.3.2 Pain relief 
Following low-dose palliative fractionation schemes, several randomized trials and meta-analyses 
have confirmed complete and overall pain response rates ranging from ∼10% to 30% and 50% to 
70%, respectively [29, 40]. There have been various studies showing that after treatment with 
palliative fractionation schemes, pain levels stabilize anywhere from four weeks to three months 
after treatment in a variety of tumours that have metastasized to the bone [41, 42]. SABR is 
expected to achieve higher rates of pain control than palliative fractionation schemes, because 
some retrospective analyses have shown that SABR offers an overall pain relief rate of 74.3–86%, 
regardless of the setting as either upfront or retreatment [43-46]. Nugyen et al. compared single-
fraction SBRT vs MFRT for alleviation of pain in patients with mostly non-spine bone metastases. 
The author concludes that SABR has higher rates of pain response (complete response and partial 
response) than MFRT. At 2 weeks pain response was seen in 62% of patients treated with SABR 
versus 36% for patients treated with MFRT. The difference was significant, and the same tendency 
was seen at 3 and 9 months [31].  
In addition, SABR may offer a quicker resolution of symptoms when compared to palliative 
fractionation schemes, due to the ability to limit dose to critical structures while enabling 
hypofractionation with higher fraction size to the disease. 
Jhaveri et al. demonstrated that for patients treated with a BED greater than 85 Gy (α/β =7), pain 
relief was more consistent and quicker, as compared to patients treated with BED less than 85 Gy 
in patients with renal cell carcinomas (RCC).  The  average pain stabilization time was two weeks in 
the setting of RCC metastases, which are considered to be radioresistant when treated with 
palliative fractionation schemes [47]. 
 SABR – what’s left to explore 
SABR to bone metastases is rapidly emerging into standard practice, however, it is still considered 
investigational and not without risk. Serious toxicities such as pneumonitis, radiation-induced 
myelopathy, esophageal toxic effects and fracture, including vertebral compression fracture (VCF), 

6 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
have been reported. The literature is scarce in respect to the optimal dose fractionation scheme, 
and the optimal imaging work-up, is not yet clearly defined.  
Prospective studies are needed to further evaluate efficacy, the optimal dose fractionation scheme 
and toxicity risk, before we can establish its role as a standard of care.  Longer follow-up is warranted 
to accurately determine late effects. Furthermore, we need to explore the benefit of SABR over 
palliative fractionation schemes. A topic, that several studies are exploring [31, 48]. 
Besides treating OMD, SABR are being increasingly used to treat OPD with very little evidence to 
support superior outcome. A few small retrospective studies have addressed this topic and shown 
favourable survival outcome compared to historical data [38, 49-52].  
2 Bony-M 
The Bony-M trial evaluates the efficacy and safety of SABR to bone metastases in patients with OMD, 
when pragmatically introduced into a daily clinical setting. In this study all osseous oligometastases 
from all solid tumours can be treated regardless of location, if organ at risk (OAR) constraints can 
be met. The approach is pragmatic as all pre-treatment evaluations are done by the referring 
oncologist and the party that approve the SABR plan. 
3 Endpoints 
3.1      Primary endpoint 
• Rate of local control (LC) 1-year post SABR 
Aim: To evaluate the rate of LC at the radiated site 1- year post SABR 
Hypothesis: The rate of LC is more than 75 % at 1-year post treatment. 
How: Patients will have CT and clinical evaluation every 3-4 month after SABR according to the 
 standard clinical follow-up program.  
 Secondary endpoints 
• Rate of Symptomatic Skeletal Event (SSE) at the irradiated site(s) 
• Progression-free survival (PFS)  

7 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
• The rate of NCI CTCAE ≥ grade 3 toxicity  
• Overall survival (OS) 
• Time to progression (TTP) outside the radiation field 
• LC rate two years post-SABR 
• Pain reduction from baseline evaluated by “Numeric Pain Rating Scale (NPRS)” and 
analgesic consumption.  
• 
Quality of life (QoL) measured with EQ-5D-5L.  
Toxicity, NPRS, analgesic consumption /antineoplastic treatment and EQ-5D-5L will be registered 
at baseline and at each follow-up (see table 1). 
 Exploratory studies 
• Delineation study (Difference in target volume definition of bone metastases: Dual energy 
CT versus conventional CT, MR versus CT, PET-MR versus CT and in intra/inter delineation). 
• Subgroup analysis (outcome according to histological profile). 
• Subgroup analysis (toxicity according to location of metastasis - spine metastasis versus non-
spine metastasis). 
• Description of the use of online treatment adaption to keep minimal doses to OAR. 
• Frequency and extent of compromise in prescription dose and/or to target coverage 
(GTV/CTV/PTV) due to OAR constraints (6.2). 
 Definition of endpoint-related concepts 
Only patients who receive the treatment are included for analysis. 
• Local control rate is defined as the absence of progression within the treated area on imaging 
with CT -, MR -, or PET-CT - scan (radiologist interpretation, see section 5.5). Analysis is done 
at a lesion level, lesion by lesion.  Patients are not censored from analysis in case of a new 
lesion outside the treated volume. Within the treated area is defined as, within or adjacent 
to the PTV.  
• Symptomatic Skeletal Event (SSE) of the irradiated site is defined as a radiographically 
verification of fracture (vertebral or non-vertebral, pathological or non-pathological), within 
or adjacent to the PTV of the irradiated site. The fracture must co-exist with one of the 

8 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
following symptoms/interventions: progression in pain (according to definition in section 
3.5), development of neurological symptoms/ symptomatic spinal cord compression or a 
need for surgical intervention/ reirradiation. It should be concluded from the treating 
physician that the symptom/intervention is a result of the fracture. Vertebral fractures 
include end plate–only fractures. Analysis is done at a lesion level, lesion by lesion. Patients 
with a pathological fracture before the radiation therapy, will not be included for analysis. 
• Progressive disease (PD) is noted if the radiologist has deemed clear progression, otherwise 
one or more consecutive imaging studies is needed (see section 5.5).  
• Progression-free survival is defined as time from inclusion until disease progression or 
death.   
• OS is defined as time from inclusion until death from any cause. 
• Time to progression outside the radiation field is defined, as the time from inclusion until 
progression outside the radiation field, determined by a CT -, MR -, or PET-CT – scan (see 
section 5.5).  Outside the radiation field is defined as outside and not adjacent to the PTV. 
• Early toxicity is defined as toxicity occurring within three months of radiotherapy 
completion.  
• Late toxicity is defined as toxicity occurring three months or longer after radiotherapy 
completion.  
• Metastases are considered non-spine if they are located outside of the vertebral column or 
sacrum.  
• Contiguous lesions treated within one volume represents one target. 
 Pain assessment and the Numeric pain rating scale (NPRS)  
In the conventional radiation setting, the International Consensus Pain Response Endpoints (ICPRE) 
has been developed for clinical endpoints as pain for bone metastases  [28]. There are currently no 
corresponding definitions for the use of SABR. A few studies have reported good pain control by 
SABR both in the upfront- and the retreatment setting, using the ICPRE guideline [46, 53, 54].  
In this protocol, we will likewise use the ICPRE to evaluate pain response.  Response categories is 
based on patient reported pain scores (NPRS) and analgesic consumption (convert to oral morphine-
equivalent dose). The NPRS is a valid and reliable scale to measure pain intensity [59] [60]. The 11-

9 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
point NPRS ranges from '0' representing one pain extreme (e.g. “no pain”) to '10' representing the 
other pain extreme (e.g. “pain as bad as you can imagine” or “worst pain imaginable”).  See 
Appendix F.  
Registration of NPRS will be registered at baseline and each follow-up for all included patients. The 
patient will complete the baseline NPRS within one week prior the first day of treatment. Analysis 
of pain reduction will only include patients with NPRS ≥ 1 registered at baseline. We intend to report 
the best response during follow-up. If more than one lesion is treated with SABR, the index lesion 
will be used to assess the pain response. The index lesion is defined as the lesion with the highest 
pretreatment pain score. If a patient has two or more lesions with the same maximum pain score, 
the index lesion is defined as the most cranial located lesion.   
 
• A complete pain response is defined as a pain score of 0 out of 10 at the treated site with no 
concomitant increase in analgesic intake 
• A partial pain response is defined as a pain reduction of 2 or more at the treated site without 
analgesic increase, or an analgesic reduction of 25% with no increase in pain score or 1 point 
above baseline.  
• Pain progression is defined as an increase in pain score of 2 or more above baseline with 
stable analgesic intake or an analgesic increase of 25% with stable pain score.  
• An indeterminate response is any response not captured in the above definitions. 
4 Study design, sample size calculation and timeframe 
 Study design  
This is a prospective, investigator-initiated, phase II, multicentre-study, investigating the efficacy 
and toxicity of definitive SABR of osseous oligometastases, when pragmatically introduced into a 
daily clinical setting.  
 Sample size 
At least 67 patients will be included in this study. Patients with de novo- and induced OMD, as well 
as patients with oligo-recurrence or oligo-progression disease can be included. 

10 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Following study closure, 12 months of follow-up after radiotherapy completion will be allowed for 
all patients, at which point data will be collected for primary end-point analysis. Further analysis will 
be performed 2 and 5 years after the last patient has completed radiotherapy. Analysis of data in 
respect to secondary endpoints and exploratory studies might be analysed at any point of time, at 
the discretion of the study group. Data will be kept in databases 10 years after the last patient is 
included. 
Data will be filed and stored using electronical ’case report forms’ (CRFs) in REDCap (Research 
Electronic Data).  
 Sample size calculation for primary endpoint 
Simons two stage design is used for sample size calculation [55, 56]. Simons two stage design is used 
for sample size calculation [55, 56]. The null hypothesis that the true 1- year local control rate is 60% 
and will be tested against a one-sided alternative. The interim analysis will be performed after one-
year follow up of the first 27 patients. Recruitment will continue after inclusion of these 27 patients 
and will not wait the results of the interim analysis. If there are 17 patients or fewer with local 
control at one year in these 27 patients at the interim analysis after one-year follow up, the study 
will be paused, and the trial committee will discuss cessation of the study or dose adjustment (see 
section 9.3).  Otherwise, 40 additional patients will be included and treated for a total of 67 treated 
patients. The null hypothesis will be rejected if 47 or more out of 67 patients have local control, at 
the radiated site, at 1-year after treatment. This design yields a one-sided type I error rate of 5% 
and power of 80% if the true 1- year local control rate is 75%. The last reported CTCAE classification 
status and response assessment will be registered in cases where the patient is lost for follow-up 
(e.g. succumbs from a “not treatment related” grade 5 event) prior to the 1-year assessment. In 
other words, such patients will be recorded at one year according to the latest available toxicity and 
response assessment. A re-estimation of the required sample size will be made if more than 20% of 
patients fail to reach 1-year follow-up in the first stage of the trial in order to account for attrition 
and time-to-event analysis. 
 
 
 

11 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Timeframe 
At least 67 patients will be enrolled within a timeframe of a maximum of three years. The study 
will close after three years regardless if the planned number of enrolled patients is reached or not.  
5 Visits and follow-up procedure 
 Visits 
Patients will be scheduled for visits/follow-up according to Table 1.  Additional imaging or laboratory 
investigations are at the discretion of the treating oncologist. 
Final assessment will be completed 52 weeks/12 months post radiotherapy and the participants will 
hereafter be registered through chart review and routine clinical appointments. 
Registration will only be obtained from the patient's electronic records after they have signed 
informed consent. The clinical information registered will include age, sex, height, weight, smoking 
history, medical and surgery history, allergy, medicine, performance status, objective examination, 
type of disease, stage, disease localization, type of systemic treatment, details from the radiation 
treatment plan (e.g.  prescription and delivered dose to target/organs at risk, size of targets, CTV 
and PTV margins and compromises), toxicity assessment, pain assessment, quality-of-life (QOL) 
questionnaires, time to disease progression, time to death, blood test results, pathology, and scan 
results. 
The aim is to document long time follow-up in respect to local control rate, OS, PFS, rate of SSE, TTP 
outside the radiation field at 1-, 2- and 5-years and acute/ late toxicities.  
 Toxicity assessment. 
 Registration of toxicity will be assessed according to a prespecified selection of organ related 
adverse events defined by NCI-CTCAE version 5.0. See Appendix I and the following link:   
https://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The registration of the CTCAE will depend on the site of the target:   
Thorax:  Dermatitis Radiation, Esophagitis, Fistula, Fracture, Myelitis, Nausea, Pain, Perforation, 
Peripheral sensory/motor neuropathy, Pleuritis, Pneumothorax, Soft tissue necrosis, Ulcer. 

12 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Abdomen/pelvic: Acute kidney injury, Dermatitis Radiation, Diarrhoea, Fistula, Fractures, 
Gastro-intestinal obstruction, Haematuria, Haemorrhage, Myelitis, Nausea, Pain, Perforation, 
Peripheral sensory/Motor Neuropathy, Ulcer, Urinary tract obstruction. 
Extremities: Dermatitis Radiation, Fractures, Joint range of motion decrease, Pain, Peripheral 
sensory/Motor Neuropathy, Soft tissue necrosis. 
The scored toxicity is the highest toxicity in the period between the current and previous visit 
date. 
 Blood sampling 
Blood samples are collected as part of the standard follow-up program and will be analysed 
immediately according to clinical practice. The test results will be registered in the electronical CRF. 
The standard panel registered is: haemoglobin, white blood cells, platelets, liver function tests; 
(alanine transaminase (ALT) or aspartate aminotransferase (AST), alkaline phosphatase (ALP), 
albumin, bilirubin, INR, APTT), kidney function test (creatinine, e-GFR) and relevant tumour markers 
depending on the underlying cancer (e.g. CEA, CA 19.9, CA-125, PSA). 
 
 
 
 
 
 
 
 

13 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Table 1 Schedule for registrations before radiation and at follow-up. 
 
Baseline 
2 weeks post 
RT* 
12 (11-13) 
weeks post 
RT 
24 (22-26) 
weeks post RT 
36 (34-38) 
weeks post RT 
52 (50-52) 
weeks post RT 
Signed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Analgesic consumption 
/Antineoplastic treatment 
(see section 5.8) 
X 
X 
X 
X 
X 
X 
Blood sample *2 
X 
 
X 
X 
X 
X 
(EuroQol EQ-5D-5L Index)  
X 
X 
X 
X 
X 
Symptom score (CTCAE 5.0) 
(including PS) 
X 
X 
X 
X 
X 
X 
NPRS scoring  
X 
X 
X 
X 
X 
X 
CT thorax/abdomen (within 
28 days of inclusion, and 
according to standard Follow-
up program) 
X 
 
X 
X 
X 
X 
MR columna totalis *3 
(X) 
 
(X) 
(X) 
(X) 
(X) 
Renography*4 
(X) 
 
 
 
 
 
 
* 
Either consultation at the clinic or consultation by phone call. 
*2 
Haemoglobin, white blood cells, platelets, liver function tests (alanine transaminase (ALT) or aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), albumin, bilirubin, INR, APTT), kidney function test (creatinine, 
e-GFR), relevant tumour markers depending on underlying cancer (e.g. CEA, CA 19.9, CA-125, PSA). 
*3 
Only mandatory before inclusion for vertebral or paraspinal targets, if epidural/intraspinal tumour growth cannot 
be precluded. For vertebral or paraspinal targets a simulation MR scan is mandatory. 
*4 
Depending on the site of target and at the discretion of the treating physician.  

14 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Supplemental examinations i.e. test for lung function, blood sample or other examinations are 
prescribed before initiation of the SABR at the discretion of the treating physician. 
 Scanning procedure 
All imaging at follow-up is considered standard and should minimally include a CT of 
thorax/abdomen. It is important to ensure that the irradiated treatment site is included in the 
scanning field. MR scan and/or PET-CT scan (with whatever relevant tracer) is recommended, if 
standard for that malignancy/site, or if the treating physician finds it relevant in respect to 
evaluating the target area(s).  
 Response evaluation   
The application of the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) for bone 
metastases is limited, even though RECIST 1.1 was developed to include bone metastases as a 
measurable site to track [57]. It describes that lytic or mixed lesions are deemed to be measurable 
only if soft-tissue (e.g., paraspinal) extensions that are 10 mm or larger can be identified. 
Furthermore, blastic bone lesions are deemed non-measurable. There are currently no standardized 
criteria to classify bone lesions other than RECIST 1.1. The University of Texas MD Anderson Cancer 
Center (MDACC) has developed its own response criteria for bone metastases, which includes spinal 
bone metastases [58]. Conclusively, no validated criteria for response evaluation is eligible. 
Therefore, in our study we asses response evaluation based on the interpretation of a radiologist 
with oncological experienced and based on the below definitions, which are modifications from the 
MDACC response criteria’s.  
  
• A partial response (PR) is coded if there is unequivocal decrease in target lesions and/or 
development of a sclerotic rim or partial sclerotic fill for lytic lesions on CT. 
• Progressive disease (PD) is based on increase in tumor size interpreted by a radiologist.  
• A complete response (CR) is coded if there is complete disappearance of tracer activity on 
PET-CT, normalisation of signal intensity on an MR scan or bone density on CT or/and 
complete sclerotic fill for lytic lesions on CT.  
• Stable disease (SD) is coded for any response other than CR, PR or PD.  

15 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
In cases in which it is unclear whether changes within the bone is secondary to radiation or disease 
progression, one or more successive scanning evaluation showing enlarged dimensions is required, 
before the disease is classified as progressing. Due to risk of pseudo-progression and necrosis [59], 
confirmatory scans should be obtained if asymptomatic early tumor enlargement is seen. In some 
cases, biopsy might be needed to confirm diagnosis.  
 Supplemental treatment 
Proton pump inhibitors (PPI) and other supportive medicine during treatment are prescribed at the 
discretion of the treating physician. Corticosteroid premedication can be mandated, at the 
discretion of the treating physician (in which case, its use needs to be reported on the appropriate 
CRF). Analgesic medication should be noted in the CRF at all visits. Paracetamol could be 
administered at day 1 after the last radiotherapy to avoid pain flare. 
 EuroQol EQ-5D-5L Index 
To examine the participants’ quality of life (QoL) during follow up, they will be asked to fill in a QoL 
questionnaire. The QoL questionnaire that will be used, is the EuroQol EQ-5D-5L Index, which is a 
standardized and validated instrument. The EQ-5D index is a relatively simple five-item 
questionnaire 
(measuring 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression). It produces a composite score between 0 and 1 (multiplied by 100 to yield a 
result between 0-100).  
 Systemic therapy 
Antineoplastic systemic therapy will be paused before, during and after radiation at the discretion 
of the physician, depending on the interaction with radiotherapy.  
Hormonal therapy, bone antiresorptive therapy and immunotherapy are allowed throughout the 
treatment. The antineoplastic therapy (including bone antiresorptive medicine) should be noted in 
the CRF at all visits. 
 

16 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
6 Participants  
At least 67 patients will be included in the study.  
Note that pain as a symptom is not required for inclusion in this protocol. 
 Inclusion criteria 
• 
Histology or cytology proven non-haematological cancer.   
• 
At least one lesion in the bones is required. 
• 
ECOG performance status ≤ 2. 
• 
≥ 18 years old. 
• 
Life expectancy > 6 months. 
• 
GTV diameter ≤ 5 cm.  
• 
In case of de novo OMD and OMD recurrence a maximum of 5 targets (including the 
primary tumour) in a maximum of 3 organ sites are allowed.  
• 
In case of OPD * and induced OMD*2 only 3 metastases (including the primary tumour) are 
allowed.  
• 
The metastatic lesion(s) must be visible on a CT- or MR- scan and suitable for treatment 
with SABR. 
• 
All metastatic sites are treated or planned for ablative therapy (including surgery) - for OPD 
only the sites in progression is required to fulfil this criterion.  
• 
A baseline scan within 28 days of inclusion (CT or PET- CT).  
• 
For spine/paraspinal targets, an MR scan is mandatory, if epidural growth cannot be 
precluded on the baseline CT scan. 
• 
No curative intended treatment option available. 
• 
An ablative strategy should be deemed clinically relevant and is at the discretion of the 
treating physician to decide. 
• 
Ability to understand and the willingness to sign a written informed consent document. 
 

17 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Exclusion criteria 
• Patient cannot tolerate physical set up required for SABR. 
• Uncontrolled intercurrent illness. 
• Pregnancy. 
• Bilsky score ≥ 1b. If the patient is treated with surgery, a pre-operative Bilsky score ≥ 1b is 
an exclusion criterion as well. See appendix A for Bilsky score. 
• Presence of myelopathy from the target area. 
• Candidate for surgical treatment (determined by the institutions clinical oncologist, 
neurosurgeon or orthopaedic surgeon). 
• For spine/paraspinal lesions where epidural growth cannot be precluded on the baseline 
CT scan: patients for whom an MR scan is contraindicated. 
• Mechanical instability and/or fracture risk *3. 
• For spine disease, involvement of ≥ three contiguous vertebrae. 
• Uncontrolled disease in respect to malignant pleural effusion, ascites, lymphangitic 
carcinomatosis, pleural carcinomatosis or peritoneal carcinomatosis.  
• Patients with uncontrolled brain metastases.  
• If the patient has received previous radiotherapy, the combined dose at the radiation site 
must not exceed the dose constraints according to Appendix B. 
* OPD 
Progression of a limited number of metastatic lesions, while remaining metastases are controlled with systemic 
therapy. A maximum of 3 progressing metastases. This includes both progressive enlargement of a known metastasis 
and the development of a new metastasis. 
*2 Induced OMD  
widespread metastatic disease is mostly eradicated by systemic treatment, but drug resistant clones are left behind, 
or the metastasis is located at a site not accessed by systemic therapy:  Maximum 3 metastases. Only pre-existing 
metastases are allowed. The development of new metastases is not allowed 
*3 
Clinicians should consult a neurosurgeon, orthopaedic surgeon or radiologist and evaluate patients for stabilization 
prior to SABR if the following risk factors are observed: baseline VCF, significant lytic tumour burden, spinal 
malalignment, a SINS1 > 6 or if the physician, for any reason, suspect the lesion to be unstable. 
 
1 The Spine Instability Neoplastic Score (SINS) should be used in the risk assessment, but a modified SINS score, where 
evaluation of the radiographic spinal alignment in standing position is not necessarily required. (see Appendix G). 

18 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Enrolment 
Bony-M is a national, multicentre study. The treating oncologists at the relevant Oncology 
Departments will be informed, when the study is ready to include patients. Potential participants 
will be informed about the trial, while attending a routine visit at the respective Oncology 
Departments, and after oral consent from the patient, be referred to the relevant unit. The local 
investigator will after the patient’s referral, receive the relevant medical information from the 
referring physician. These information’s will be used to evaluate possible treatments options and 
includes an assessment whether the patient is a candidate for this or other trials, which is a standard 
procedure for the clinics. Information searched includes diagnosis, previous treatment, latest scan 
and comorbidities. 
If the patient is a relevant candidate for the study, he or she will be invited in for a detailed 
information by a physician of the project team. The patient should be provided with full and 
adequate verbal and written information about the objectives, the study outlines and possible risks 
and benefits of participating in the study. The information will be given under private conditions, 
and the patient will be encouraged to have a relative or friend attending.  The subjects have the 
right to ask questions about the study and should be given adequate time, at least one day to make 
the decision to participate in the study or not. The subject should be clearly informed that the data 
collected in the study will not identify any subject taking part in the study, following the Law in 
Personal Data and the General Data Protection Regulation (GDPR) (EU) 2016/679. 
The subjects should be informed that it is voluntary to participate and that they can withdraw from 
the study at any time without giving any reason. The subjects should further be informed that a 
decision not to participate in the study or to withdraw will not be questioned or effect their future 
medical care or treatment at the clinic. 
Written Informed Consent must be obtained from all participating subjects before enrolment in the 
study. The Informed Consent form should also be signed, at the same occasion, by the investigator 
who gave the written and verbal information. No trial related procedures can take place unless a 
written informed consent is obtained. 
The subjects will consent to participation in the study; regulatory authorities to gain full access to 
hospital records, to control the data collected in the study; recording, collecting and processing of 

19 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
data and storing data in a database. Contact information for the oncologist responsible of the study 
will be provided. 
If the patient chooses not to participate in the study, he or she will continue the standard treatment 
of care in the primary unit in charge of the oncology course. 
 Withdrawal from the study 
A patient may be withdrawn from the study if any of the following events occur: 
• If, in the opinion of the investigator, withdrawal is necessary for medical or technical reasons 
• Major protocol violation 
• Informed consent withdrawal 
In case of a withdrawal before first treatment day, another patient will be enrolled (with a new 
patient number). The withdrawn patient will be accounted for in the statistical analysis. The reason 
for withdrawal should be clearly described. Relevant data should be obtained when possible, and 
all relevant assessments should be completed, preferably according to the schedule for the final 
assessment. The CRF should be completed.  
7 Radiotherapy planning 
 Simulation 
A CT scan with the patient immobilised in the treatment position is required for delineation. Slice 
separation ≤2 mm is mandatory. Use of intravenous contrast is at the discretion of referring 
physician. 
A baseline MR scan (with axial T1-weighted and T2-weighted images) should preferably (but not 
mandatorily) be acquired with the patient in the treatment position. MR simulation should be used 
if available at the department. Additional requirements for spinal/paraspinal targets: 
• Acquisition of the baseline MR scan with the patient in the treatment position is mandatory.  
• MR slice separation should be ≤3 mm.  

20 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
• MR and CT images must be co-registered prior to delineation and treatment planning, with 
focus on the treatment area. 
If a PET-CT scan is available and acquired within 8 weeks prior to the current treatment it should be 
imported to the treatment planning system. 
A variety of immobilization devices may be used. For cervical spine or cervicothoracic junctional 
areas, a rigid head and neck immobilization device is mandatory. 
 Dose prescription 
Two dose fractionation schemes will be available  
 
Table 2 dose prescribed to the GTV 
Regime 
number 
Total 
dose 
GTV (Gy) 
Fractions 
Dose per fraction 
GTV (Gy /%) 
Dose per fraction 
PTV (Gy/%) 
Prescribed 
dose 
GTV (BED 10) 
1 
37.5 
3 
12.5/100 
8.375/67 
84.4 
2 
30 
3 
10/100 
6.7/67 
60 
 
Dose distribution within the target area should be non-homogenous, with steep dose gradients 
outside the gross tumour volume (GTV) according to the Nordic SABR practice [60-62]. Dose is 
prescribed to the GTV. GTV should be covered by 95% isodose (GTV D99% > 95%). Mean GTV dose 
≥ 100%. CTV should be covered by 80% isodose (CTV D99% > 80%). The planning target volume (PTV) 
should be covered by the 67% isodose (PTV D99% > 67%).  
Dose outside the GTV (Body- GTV) should preferably meet the constraint D1cc ≤ 107%. Dose outside 
the PTV (Body-PTV) should be kept as low as possible and D1cc, D2cc and D5cc for Body-PTV should be 
reported. The maximum allowed dose should fulfil D0.1cc ≤ 140%. Hotspots at the edge of the GTV 
should be avoided. 
The choice of dose regime depends on the proximity to OAR and the decision making should ideally 
follow the steps described here:  

21 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
1. Dose regime one (12.5 Gy x 3 fractions) is recommended. Optimal GTV, CTV 
and PTV coverages, as described in this section, and constraints to OAR should 
be maintained.   
2. If this is not possible due to OAR constraints, the target coverage can be 
compromised to parts of GTV, CTV and/or PTV. It is recommended that the 
mean dose to the GTV and PTV should be at least 80% of the prescribed dose, 
i.e. 30 Gy for the GTV and 20 Gy for the PTV.  
3. If this also is not possible, dose regime two (10 Gy x 3 fraction) should be 
explored.  
4. If this still is not possible due to OAR constraints, the target coverage can be 
compromised to parts of GTV, CTV and/or PTV. It is recommended that the 
mean dose to the GTV and PTV should be at least 80% of the prescribed dose, 
i.e. 24 Gy for the GTV and 16 Gy for the PTV.  
5. If none of the above-mentioned requirements can be achieved, the patient 
should be withdrawn from the study. 
 
 Treatment delivery technique and position verification 
SABR is delivered with external photon beam radiotherapy, utilizing energies in the range of 6-15 
MV. Treatment is planned using Intensity modulated radiotherapy (IMRT) or volumetric modulated 
arc therapy (VMAT). The accuracy of target localization should be ≤ 2 mm from simulation through 
all steps and duration of treatment for spine/paraspinal targets. Strict dose constraint to the spinal 
cord will be applied. Daily adaption will be performed if available. Treatment using MR-linac can be 
used if available. 
Daily image guidance is mandatory for position verification. The type and frequency of image 
guidance (e.g. Cone beam computed tomography (CBCT) or Exactrac) is at the discretion of the 
respective institutions. The anticipated setup uncertainty during treatment, the calculated 
treatment time and proximity to OAR must be considered.   
Treatment interruptions should be kept to a minimum. Treatment can be given on the same day as 
simulation when feasible, but it is not required. 

22 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Patients are treated with conformal treatment plans. Modern dose calculation algorithms (Monte 
Carlo, Acuros, AAA, Collapsed Cone or similar) must be used to account for tissue inhomogeneities.  
 Quality assurance 
To achieve similar dose planning strategies, all initially participating centres have performed dose 
planning for two representative patients and have reported set-up verification strategies. Centres 
joining the protocol will plan the same patients for comparison prior to first patient enrolment.  
8 Target and organs at risk 
  Target definition 
Target definition for bone metastases outside spine (outside C1-L5 and os sacrum): 
Gross tumour volume (GTV) will be delineated as visible tumour.  
GTV is defined as the area of disease seen on CT-scan and MR- scan. In addition, if the patient has a 
positron emission tomography (PET)/CT-scan recently done, the PET images should be fused with 
the simulation CT and PET avid areas contribute to GTV delineation.  
CTV is defined  by expanding the GTV with a margin of 5 mm and shaped to the bone (unless soft 
tissue involvement). Shaping to other anatomical boundaries is at the discretion of the treating 
oncologist and should be noted in the CRF. 
The PTV margin follows the institutional practice and is registered in the CRF.  
Target definition for bone metastases S1-S5: 
For delineations of sacral targets, the GTV are delineated according to the International consensus 
recommendations for target volume delineation specific to sacral metastases and spinal 
stereotactic body radiation therapy (SBRT) (Dunne et al. 2020). See Appendix C. The PTV margin 
follows the institutional practice and is registered in the CRF.  
 
Target definition for spinal bone metastases (from vertebrae C1-L5): 
 
The clinical target volume (CTV) and gross tumor volume (GTV) are delineated according to  
 
the International Consensus Guidelines by COX et al 2012 [63]. 

23 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
Gross tumor volume (GTV):  Visible tumour on MR scan (T1 and T2 sequences), CT and/or PET-scan. 
A paraspinal mass ≤ 5 cm in the greatest dimension contiguous with 
spine metastases is included. 
Clinical target volume (CTV):  GTV 
+ 
involved 
sector 
according 
to 
Appendix 
D.  
If the tumour is localized closer than 2 mm to a neighbouring sector, 
this sector should be included in the CTV as well. Circumferential CTVs 
encircling the cord should be used only when the vertebral body, 
bilateral pedicles or lamina and spinous process are all involved. 
Planning target volume (PTV): CTV + 2 mm.  
Instead of modifying the PTV at dural margin and adjacent critical 
structures to allow spacing, the PTV should be compromised to keep 
constraints to OAR.  
 Organ at risk (OAR) definition  
8.2.1 OAR: none-spine 
None-spine OAR are outlined as separate volumes as the outer contour of the organ, unless  
otherwise specified. For delineation we recommend following the contouring atlas at: 
https://www.rtog.org/corelab/contouringatlases.aspx 
It is for the treating physician to decide whether to contour the bowel bag or intestines.  
    
8.2.2 OAR - Spine 
Spinal cord constraints are defined according to the report of AAPM Task Group 101[66]. Spinal cord 
volume is defined as fusion with T2-weighted and T1-weighted MR scan and at contoured at least 
10 cm above/below the superior/inferior extent. For spinal cord dose constraints see appendix B.   
Spinal Cord is delineated encompassing medulla.  
An OAR is only to be delineated if the organ is expected to receive a relevant radiation dose (at the 
discretion of the treating physician). See Appendix E. 

24 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Dose constraints to OAR are listed in Appendix B. Application of stricter constraints to OAR is at the 
discretion of the treating physician but should be noted in the CRF. Normal tissue constraints will 
be prioritized over target coverage and should not be compromised – this also apply within the PTV. 
However, for soft constraints (External (Skin) and the Thoracic Wall), the dose to OAR can be 
compromised in favour of covering the target if there is a strong clinical argument. The reason for 
this compromise should be noted in the CRF. See also section 7.2. The thoracic Wall is delineated as 
a 15 mm outer margin of the lung, including costae. Skin is delineated as an inner margin of 10 mm 
of BODY. 
SpinalCord PRV is at the discretion of the respective institutions, but at least 1.5 mm margin is 
mandatory (not shaped to the bone). Dose constraints for the spinal cord also apply to the spinal 
cord PRV. For Stomach, Oesophagus, Duodenum, Small Intestines, Large Intestines, Rectum and the 
anal region a PRV margin of at least 5 mm is mandatory (shaped to the bone). Other margins are at 
the discretion of the institutional practice. Renography will be performed to evaluate kidney 
function before treatment in patients, where the kidneys can be expected to receive a relevant 
radiation dose (at the discretion of the treating physician). The renography is performed following 
the standard protocols of the individual departments.   
 Previous RT 
If the patient has received previous radiotherapy, the combined dose must be considered, when 
evaluating if the dose constraints for the OAR are met. 
9 Safety assessment 
 Adverse events (AE) 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject who has received SABR. This does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavourable and unintended symptom, (including 
an abnormal laboratory finding), or disease temporarily without any association with SABR. The AEs 
that will be reported are based upon organs at risks that most likely will be affected from SABR. This 
will depend on the site of treatment. 
 

25 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
All adverse events will be graded according to the NCI-CTCAE v5.0 scale and will be reported 
on the appropriate CRF-form. 
 Serious adverse events (SAE) 
A serious adverse event (SAE) in human trials is defined as any untoward medical occurrence that, 
at any dose, results in death or is life-threatening, is disabling, requires hospitalization (whether 
initial or prolonged and does not include planned hospitalization) or requires intervention to 
prevent permanent impairment/damage. 
All SAEs must be registered by the local investigator on the appropriate CRF and must be followed 
until they are fully settled. 
Progression or deteriorating of malignancy during the study (including new metastatic lesions or 
death due to progression), will be part of the efficacy assessment and should NOT be reported as 
an AE/SAE. 
Symptoms clearly associated with malignancy during the study should NOT be reported as AE / SAE 
unless they are: 
 
• Newly emerged (i.e. not present at baseline) and correlation with the underlying malignancy 
and old / new metastatic lesions are unclear. 
• If there is any uncertainty as to whether an exacerbation of the subject's condition is due to 
the cancer disease or due to an AE, it must be reported as an AE or an SAE depending on the 
situation. 
 
The local Investigator (together with the treating physician) must determine the relationship 
between the radiation treatment and the occurrence of a SAE as not suspected or suspected as 
defined below: 
 
 

26 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Not suspected: 
 
A causal relationship of the radiation treatment is unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions provide 
enough explanation for the observed event. 
Suspected: 
 
There is a reasonable possibility that the radiation treatment caused the 
adverse event. ‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the radiation treatment and the adverse event. 
 
Furthermore, the local investigator (together with the treating physician) must determine whether 
a suspected serious adverse event is expected, or unexpected as defined below: 
 
Expected:  
 
If the treating physician/local investigator recognize the suspected SAE as an 
event reported in the literature and/or known from the clinical experience, this 
adverse event should be considered as expected.  
Unexpected:  
 
If the treating physician/local investigator do not recognize the suspected SAE 
as an event reported in the literature and/or known from the clinical 
experience, this event should be considered as unexpected. 
 
The assessment of an SAE should be based upon organs at risks that most likely will be affected from 
the radiation. 
Any suspected, unexpected SAE must be reported by the local investigator to the sponsor within 
one working day (after being aware of the incident). The sponsor can choose to change the 
registration of a suspected unexpected SAE to a suspected expected SAE after an audit of the case. 
The Sponsor will inform the Ethical Committees of all relevant information about unexpected SAE, 
suspected to be related to the radiation treatment, that are fatal or life-threatening as soon as 
possible, and in any case no later than seven days after knowledge of such a case. Relevant follow-
up information for these cases will subsequently be submitted within an additional eight days.  

27 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Once a year throughout the clinical trial, the sponsor will provide an updated safety report 
highlighting SAE to the Ethics Committee. 
For events not reported in the CTCAE version 5.0, the investigator will use the grade or 
adjectives reported in the following:  
 
Grade 1 Mild does not interfere with patient’s usual function 
Grade 2 Moderate Interferes to some extent with patient’s usual function 
Grade 3 Severe, Interferes significantly with patient’s usual function 
Grade 4 Life-threatening, results in a threat to life or in an incapacitating disability 
Grade 5 Death 
 
 Trial management committee 
A trial management committee (TMC) is set up with the participation of representatives from the 
different centres. The TMC will meet annually after study initiation, and after 1-year follow-up of 27 
patients, conduct the interim analysis (see section 4.3 on sample size calculation for primary 
endpoint).  Recruitment will continue after inclusion of the first 27 patients and will not wait the 
interim analysis. All events (See primary endpoint), will be reviewed by the TMC and if the rate of 
local progression at one year is excessive defined by the sample size calculation, the TMC can, at its 
discretion, recommend cessation of the study or dose adjustment. Furthermore, all grade 4 and 5 
toxicity deemed caused by the radiation treatment will be reviewed by the TMC.   
10 Ethical aspects 
 Ethical considerations 
Patients with OMD will have very different outcome depending on the histological profile. If a 
patient is diagnosed with a bone metastasis, surgery is seldom a recommended solution, and the 
oncologist will most often consider the strategy as a palliative course and start chemotherapy or 
other systemic treatment. When the disease is stable, the oncologist will often continue therapy 
since the alternative (pause of treatment) may expose the patient to risk of progression and possible 
onset of symptoms in the treatment-free period. By offering an oligometastatic radiotherapy 

28 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
treatment strategy, the patient might gain a chemo-free period, without side effects from systemic 
treatment. 
However, there is a risk of progression during the RT treatment period. The protocol offers a 
stereotactic radiation plan with the maximum treating period of 6 days. This will most often mean 
a treatment-free interval from systemic treatment for about 3 weeks (depending on the type of 
systemic treatment). The risk of significant progression, during that time must, in most patients, be 
considered low for our study population. However, some patients might experience flare of the 
disease during the treatment pause. The treating oncologist must balance the pros and cons and 
involve the patient in the decision-making.   
When receiving the radiotherapy, the patient might experience toxicity (early or late) from the 
radiotherapy. If the patient experiences toxicity ≥ grade 3, this might postpone the reintroduction 
of systemic therapy and affect the QoL. 
 Toxicity 
In general, SABR to bones are well tolerated. Grade ≥ 3 toxicity is rare [21, 22, 47, 68, 69]. Toxicity 
depend on the anatomic structures proximate to the radiation sites. Frequently reported toxicities 
grade 1 and 2 are dermatitis, dyspnoea, pain flare, muscle soreness, oedema, tissue induration, 
loser stools, stomach ache, fatigue, nausea, vomiting, dysphagia and anorexia  [36, 70-75]. 
10.2.1 Risk of fracture  
The use of SABR in the non-spine bone metastasis setting has proven relatively safe with a crude 
fracture rate of approximately 3- 8.5% [29, 68].   
Data on the risk of developing vertebral compression fracture (VCF) after spine SABR are variable 
5.7%-39% [76-78].  In a recent review from Chang et al. the crude risk of VCF was 13.7% and, of 
whom 45% were surgically salvaged. The median time to VCF was within months post-SBRT (median, 
3.3 months)  [79]. A dose complication relationship has been confirmed by Sahgal et al. [27]. They 
observed a 39% risk of VCF with high dose single fraction SBRT (>24 Gy). High risk of VCF after single 
fraction regimes has been confirmed by other studies [4, 23, 76]. The following factors has been 
found to be significant predictors of VCF: dose per fraction, pre-existing fracture, lytic tumour, 
location in the thoracolumbar or lumbar region and spinal misalignment (kyphosis/scoliosis and 

29 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
subluxation/translation) [27, 76]. SINS (Appendix G) is an important tool to identify the patients at 
greater risk for SABR-induced VCF, and therefore used in this protocol to assess the risk of 
mechanical instability and fracture risk [27]  
10.2.2 Risk of joint stiffness 
Another concern when using SABR to treat bone metastases is joint stiffness, which is thought to 
result from a gradual decrease in vascularity, radiation fibrosis and atrophy of joint muscles [80]. 
Joint stiffness tends not to manifest until 2–3 years after radiation therapy and therefore this toxicity 
is often underreported both in prospective and retrospective studies [81]. Stinson et al. found that 
20% of the 145 cases in their study of limb sparing radiation therapy for soft-tissue sarcoma had 
joint contracture and it was determined that inclusion of more than 50% of the joint in the radiation 
field increased this risk [73]. 
A newly published work from Wang et al. compares  outcome and toxicity of postoperative IMRT 
with two‐dimensional radiotherapy in patients with soft tissue sarcoma of extremities and trunk 
[82]. They report a risk of joint stiffness of ≥ grade 2 to be 3.9% in the IMRT arm versus 12.3% in the 
2D-RT arm (median follow up 58.1 months). 
10.2.3 Radiation Myelopathy (RM) 
RM is a late toxicity secondary to overdosing the spinal cord and is very rare in the modern era of 3-
dimensional palliative fractionation schemes. The risk of RM has re-emerged because of the 
introduction of SABR. The diagnosis of RM is a diagnosis of exclusion and defined as: “neurologic 
signs and symptoms consistent with radiation damage in the form of necrosis to the segment of the 
spinal cord irradiated, without MR evidence of recurrent or progressive tumour affecting the spinal 
cord”. Prospective studies reveal rates of RM after SABR, between 0% and 3%  [48, 83-85]. 
Sahgal et al. reported in 2013 the first logistic regression model yielding estimates for RM specific 
to SABR [83]. Dose-volume histogram (DVH) results for 9 cases of post SABR RM were reported and 
compared with a cohort of 66 spine SABR patients without RM. They recommend limiting thecal sac 
maximum point volume (Pmax) doses to 12.4 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 
fractions, 23.0 Gy in 4 fractions, and 25 Gy in 5 fractions. 

30 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
A more recent publication from 2016 by Grimm et al [86] reviewed the literature and found only a 
single manuscript, that provided dose-volume data and outcomes for each spinal cord (102 spinal 
metastases in 74 patients treated by spinal radiosurgery) [87]. In total, 3 patients developed RM. 
Estimation from this dataset, the maximum dose limits according to QUANTEC (13 Gy in a single 
fraction and 20 Gy in 3 fractions), had less than 1% risk of RM. In this study we use the QUANTEC 
recommendations for spinal cord constraints and the constraints apply for both Spinal Cord 
(encompassing the medulla) and Spinal Cord PRV. 
10.2.4 Pain flare 
Limited data is available with respect to acute reactions. Pain flare is a common adverse event after 
radiation.  From experience with palliative fractionation schemes, there is reported up to a 33% 
chance of a pain flare [88, 89].  Data on the risk of pain flare after SABR are variable. Owen et al. 
reported 10% risk of pain flare [21].  Chiang et al observed pain flare in 68.3% of patients, most 
commonly on day 1 after SABR [90] 
In this study the toxicity according to the Common Toxicity Criteria, version 5.0 at frequent visits will 
be registered.  
 Imaging 
Patients participating in this study will follow the same control schedule every 3 months as is 
standard outside trials. Radiation dose from a standard CT-scan examination is about 3-5 millisievert 
(mSv) and corresponding to about two times the annual background radiation. In some cases, the 
treatment is delivered with CT-guidance (CBCT- guidance). Two CBCT scans equals the radiation 
dose from one standard CT- scan. A CBCT before each treatment is standard practice. Depending on 
the target area, clinical situation and positioning challenges, additional CBCT’s might be necessary 
during treatment delivery to ensure the correct position of the patient. The precise delivery of SABR 
is crucial due to the high dose gradients and small treatment margins. This is especially important 
when treating spine metastases. In some settings, the treatment is delivered with other forms of 
image-guidance (e.g. ExactTrac) and in these cases the dose corresponds to < 0.1 mSv pr. acquisition.  
Overall, the risk is not considered to be significant given the illness of the participants. 
MR images are performed without  ionizing radiation, so patients are not exposed to the harmful 
effects of ionizing radiation. But while there are no known health hazards from temporary exposure 

31 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
to the MR environment, the MR environment involves a strong,  magnetic field.  The strong magnetic 
field may displace or cause heating of magnetic objects within the body (pacemaker, artificial joints, 
cochlear implants or other medical implants). Careful screening of people and objects entering the 
MR environment is critical to ensure nothing enters the magnet area that may become a projectile. 
Some patients find the inside of the MR scanner to be uncomfortably small and may experience 
claustrophobia. The magnetic fields that change with time create loud knocking noises which may 
harm hearing if adequate ear protection is not used.   
The number of MR images/sequences performed before and during each treatment will depend on 
the biology of the primary tumor, the location of the target and the set-up challenges for the 
individual patient.    
 Contrast agents and blood tests 
Contrast agents are used to improve visualization of the inside of the body produced by CT and MR 
imaging. The use of contrast agents also carries some risk, including side effects such as allergic 
reactions to the contrast agent. Mild reactions do occur and include metallic taste in the mouth, 
nausea and vomiting, headache, itching, flushing, mild skin rash or hives. Severe reactions are very 
uncommon and include difficulty in breathing, swelling of the throat, dizziness and profound low 
blood pressure and treatment is necessary. Death due to allergic reactions to the contrast is 
extremely rare. 
 After a blood test or injection, there is a risk of a small bruised area on the skin where the needle 
went in. Rarely a larger area of bruising may appear.  
 Pregnancy 
Women of childbearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; or abstinence) during treatment. Female partners of childbearing potential 
of male subjects must also agree to use highly effective contraception during treatment. If the 
woman wishes to become pregnant in the future, this must be discussed prior to entering the study. 
 Insurance 
Patients participating in the study are covered by national regulations. 

32 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
11 Data management 
Data will be filed and stored using electronical ’case report forms’ (CRFs) in a REDCap database 
provided by The Capital Region.  The informed consent will ensure the sponsor, the 
representatives appointed by the sponsor and regulatory authorities’ access to the patient's 
electronic records and collect information (see section 5.1). The access is required in order to 
conduct and report the results from the study and to secure that all regulations are followed. This 
includes both self-regulations, quality control and monitoring, of which all are obliged to follow. 
All treatment plans will be exported to the Danish national radiotherapy plan database (DcmCollab 
database), from where doses to target and OAR will be extracted for analysis.  
The data management system ensures compliance with current legislation and regulations on data 
handling and data safety. The study will be conducted in accordance with the General Data 
Protection Regulation (GDPR). All information will be kept strictly confidential in a database affiliated 
with this research project and in accordance with the rules of the GDPR (EU) 2016/679. The trial will be 
registered at the Hospitals Knowledge Center for Data protection compliance (Region Hovedstadens 
Videnscenter for Dataanmeldelser). 
12 Protocol handling and economy 
This study will be performed according to the Helsinki Declaration (Seoul version, October 2008). 
Approval from the ethical committee will be obtained before inclusion is started. The study is 
investigator initiated and the principal investigator has the overall responsibility for the scientific 
and ethical protocols, progression of the trial and finishing of academic publications. Regardless of 
positive, negative or inconclusive results, the trial will be made publicly available through 
conferences and international, scientific journals. The study group will follow the Vancouver rules 
(http://www.icmje.org/). Every 6 month the primary investigator review with the local investigator’s 
submitted forms and treatment plans to ensure they are collected in line with the protocol. The trial 
management committee and others that have substantially contributed, will be invited for 
authorship of the final manuscript according to the Vancouver declaration. The study will be part of 
a PhD study, and is supported by Varian Medical Systems with 2.000.000 DKK and by DCCC 
Radiotherapy - The Danish National Research Centre for Radiotherapy via the Danish Cancer Society 

33 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
(grant no. R191-A11526) with 450.000 DKK. The donations will cover a Ph.D. study, and this trial is 
one of two planned trials of the Ph.D.  The donations will be deposited to a prespecified research 
account at the Department of Oncology, Herlev and Gentofte Hospital, which is subject to official 
control and audit. None of the researchers has financial interests in the investigation or the Varian 
Medical System. No remuneration will be paid to patients for participation in the trial. 
13 Feasibility 
Data from this study is the property of the investigators. Use of data or results derived from study 
population is only allowed if approved jointly by all members of the study group.  Before a decision 
is made to publish, a consensus among the investigators must have been reached on how to 
interpret study results. The TMC and others that have substantially contributed will be invited for 
authorship of the final manuscript according to the Vancouver declaration.  
14 Perspectives 
The Bony-M study will facilitate the implementation of SABR for osseous oligo metastases, including 
the very important training of physicians, physicists and technologists in the practical manoeuvres 
in the online adaptation process.  SABR represents a major undertaking for radiotherapy 
departments and is associated with risks of severe toxicity.  We will gain knowledge on the effect of 
local definitive treatment of OMD. 
We foresee that the demand for these treatments will increase significantly in near future. Exploring 
the exquisite technological solutions for precise delivery, will add to a broad catalogue of treatment 
options supporting the need for individualized treatment options.  
The trial will be performed in close collaboration between different radiotherapy centres. This will 
support future collaborations between the centres. This collaboration will facilitate improved 
professional competences and a larger patient cohort, compared to a single centre study. 
 
 

34 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 Bilsky score 
 
 
Figure of the 6-point epidural spinal cord compression (ESCC) grading scale proposed by Bilsky et al. 
[91]. Figure adapted from Tseng et al. [92] 
 
Grade 
Anatomical Involvement 
0 
Denotes bone-only disease 
1a 
Epidural impingement, without deformation of the thecal sac 
1b 
Deformation of the thecal sac, without spinal cord abutment 
1c 
Deformation of the thecal sac with spinal cord abutment, but without cord compression 
2 
Spinal cord compression, but with CSF visible around the cord 
3 
Spinal cord compression, no CSF visible around the cord. 
 
 

35 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Constraints 
 
Hard constraints (Bold type) signifies: 
Planning objectives which should not be compromised.  
Soft constraints (Italics) signifies: 
Planning objectives which can be compromised in favor of covering the 
target if there is a strong clinical argument. 
*DMax 
Defined as the near-point maximum dose, defined in this case as D0.027 cc 
 
 
OAR 
3 fractions 
Endpoint 
Hard constraints  
 
 
1 Esophagus 
D0.5cc < 25,2 Gy1 
 
Stenosis, fistula 
2 Heart 
D0.035cc < 30 Gy2  
D15cc < 24 Gy 2 
 
Pericarditis 
3 Trachea/MainBronchus (including the lobar 
bronchi) 
D0.5cc < 32 Gy1 
Stenosis, fistula, 
hemorrhage 
4 Lung_R + Lung_L 
V20Gy < 10%1 
Pneumonitis 
5 GreatVessel (Aorta and V. cava)/Pulmonary vessels 
D0.5cc < 45 Gy 1+2 
Aneurysm 
6 Bladder  
D15cc < 16.8 Gy1 
 D0.5cc < 28.2 Gy1 
 
Cystitis 
fistula 
7 Duodenum/Stomach 
D0.5cc < 22,2 Gy 1 
D 5,0cc < 16,5 Gy 1 
 
Ulceration   
fistula obstruction 
Enteritis haemorrhage  
8 SmallBowel 
D0.5cc < 25,2 Gy 1 
D 5,0cc < 17,7 Gy 1 
 
Ulceration   
fistula obstruction 
Enteritis haemorrhage 
9 LargeBowel/Rectum/AnalCanal 
D0.5cc < 28,2 Gy 1 
 
Colitis 
10 BowelCavity 
D1cc < 30Gy3 
D5cc < 21 Gy3 
 
Ulceration   
fistula obstruction 
Enteritis haemorrhage 
11 Kidney 
For each kidney: 
V10Gy ≤ 25%4 
 
For patients with one kidney or target close to 
the kidney: V8.5Gy < 10% to the residual 
healthy kidney5 
Deterioration of kidney 
function 
12 SpinalCord (encompassing medulla) + SpinalCord 
PRV 
 
Both constraints should be fulfilled for both 
objectives (SpinalCord and SpinalCord PRV) 
Dmax point * < 21.9 Gy2 
D 0.35 cc < 18 Gy2 
Myelitis 
13 FemoralHead/HumeralHead 
D 10 cc < 21,9 Gy 1 
 
Necrosis 

36 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
14 Liver (minus GTV) 
(healthy liver) 
Minimum 700 cm3 below 15 Gy 3 
Liver function 
Soft constraints 
 
 
 
15 External (Skin) 
Delineated as an inner margin of 10 mm of BODY. 
D10cc <30 Gy2 
Ulceration 
16 Rib / ThoracicWall 
ThoracicWall is delineated as 15 mm outer margin of 
the lung, including costae. 
D0.5cc<37Gy1 
D30 cc <30 Gy1 
Fracture 
Soft tissue fibrosis 
 
 
1) 
Hanna, G.G., et al., UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy. 
Clin Oncol (R Coll Radiol), 2018. 30(1): p. 5-14 (35). 
 
2) 
Benedict, S.H., et al., Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med 
Phys, 2010. 37(8): p. 4078-101 (37). 
 
3) 
DLGCG (Danish liver-gallbladder cancergroup): 
http://www.gicancer.dk/Content/Files/Dokumenter/DLGCG/Retningslinier_DLGCG%20Radioterapiudv
alg.pdf 
4) 
Personal communicater: Anna M.E.Bruynzeel, MD phD, VU University Medical Center Amsterdam. 
5) 
Institutional practice. 
 
Extra planning objectives  
At the discretion of the treating physician to decide. Factors as the estimated life expectancy of the  
patient, risk of radiculopathy because of tumor growth and risk of radiation-induced radiculopathy  
must be balanced. 
Constraints 
3 fractions 
Endpoint 
SpinalNerve_ Roots 
Dmax point* < 24 Gy6 
V5 cc <20,4 6 
 
Neuritis 
CaudaEquina 
Dmax point* < 24 Gy6 
V5 cc <21,96 
 
Neuritis 
SacralPlexus/BrachialPlexus 
Dmax point* < 24 Gy6 
V5 cc <22,56 
 
Neuritis 
PeripheryNerve 
Dmax point* ≤ 24.5 Gy5 
Neuritis 
 
*DMax 
The near-point maximum dose, defined in this case as D0.027 cc 
5) 
Institutional practice. 
6) 
Dr Luis Schiappacasse, Radiation Oncology Department UniversityHospitalLausanne (CHUV) 
Switzerland. 
 

37 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 Dunne - Target delineation in the sacrum 
International consensus recommendations for target volume delineation specific to sacral 
metastases and spinal stereotactic body radiotherapy (SBRT) (Dunne 2020). 
 
 
 Stereotactic Radiosurgery Sacral Classification System. 1. vertebral body [1* represents the 
subsequent caudal vertebral body (S2 in this illustration)]; 2. left anterior ala; 3. left posterior ala; 4. 
left lamina; 5. spinous process; 6. right lamina; 7. right posterior ala; 8. right anterior ala. 
 
 
 
 

38 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Recommendations for target volume definition of the sacrum in spinal stereotactic body radiation 
therapy/stereotactic radiosurgery (SBRT/SRS). 
 
 
 
 
 

39 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Cox - CTV delineation guidelines 
International Spine Radiosurgery Consortium anatomic classification system for consensus target 
volumes for spine radiosurgery (Cox 2012). 
 
 
Guidelines for spinal SRS bony CTV delineation (Cox 2012). 
 
 
 
 

40 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 DcmCollab export 
List of structures to be exported to the Danish national radiotherapy plan database (DcmCollab 
database) : 
GTV, CTV, PTV, Body-GTV, Body-PTV, trigger_BONYM, AnalCanal, Aorta, Bladder, BowelCavity, 
BrachialPlexus, BrachialPlexus PRV, CaudaEquina and SacralPlexus, Duodenum, Duodenum_PRV, 
Esophagus, Esophagus_PRV, External (skin), Femur_R, Femur_L, GreatVesselHumerus_R, 
Humerus_L, Heart, Ileum, Jejunum, Kidney_R, Kidney_L, LargeBowel, Liver, Lung_R, Lung_L, 
MainBronchus, PeripheryNerve, PeripheryNerve PRV, Rectum, Rib, SmallBowel, SpinalCord, 
SpinalCord_PRV, SpinalNerve_Roots, SpinalNerve_Roots PRV, Stomach, Stomach_PRV,  Trachea, 
Uterus, V_CavaInferior, Vagina, VB_Thoracic, VB_Lumbal, VB_Sacrum. 
A structure set including all the above-mentioned structures should be created for all patients. This 
will support the export to the DcmCollab  database. Only relevant structures are delineated (at the 
discretion of the treating physician). The structure nomenclature should ideally follow Santanam et 
al. 2012 [93]. The trigger (trigger_BonyM) should be left empty in order to have an easy import into 
the BonyM protocol in the DcmCollab database. However, the specific naming can be determined 
by the individual institutions, but the naming should be consistent within an institution. Name of 
the DcmCollab protocol: Bony-M 
 
 
 
 
 
 
 
 

41 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 Numeric Pain Rating Scale (NPRS) 
 
 
 
Hvis du skal beskrive den værste smerter du har haft [gennem de seneste 3 dage], hvordan har du 
da haft det?  
 
Afkryds kun ét felt. 
 
Ingen 
smerter 
Værst tænkelige  
smerter 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Forklaring: 
[område] erstattes med fx ’ryg-/ben’, ’skulder’, ’knæ’ osv. 
 
 
 
 
 
Generelle [område]-smerter 

42 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 Spine instability neoplastic score (SINS) 
Table adapted from Fisher et al. [94]. 
The Spine Instability Neoplastic Score (SINS) should be used in the risk assessment. 
However in this study a modified SINS score is used, where evaluation of the radiographic spinal 
alignment in standing position is not necessarily required. 
 
 
 
 
 

43 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 
 EQ-5D-5L 
 
 

44 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 
 
 
 

45 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
 
 
 
 
 

46 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
  CTCAE v. 5.0 
 
MedDRA SOC 
CTCAE Term 
Definition 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Grade 5    
Gastrointestinal 
disorders 
Anal ulcer 
A 
disorder 
characterized by a 
circumscribed, 
erosive lesion on the 
mucosal surface of 
the anal canal. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered GI function 
Severely altered GI 
function; 
TPN 
indicated; 
elective 
invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Colonic 
obstruction 
A 
disorder 
characterized 
by 
blockage 
of 
the 
normal flow of the 
intestinal contents in 
the colon. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered GI function 
Hospitalization 
indicated; 
invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Colonic 
perforation 
A 
disorder 
characterized by a 
rupture 
in 
the 
colonic wall. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Colonic ulcer 
A 
disorder 
characterized by a 
circumscribed, 
erosive lesion on the 
mucosal surface of 
the colon. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered GI function 
Severely altered GI 
function; 
TPN 
indicated; 
elective 
invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Diarrhea 
A 
disorder 
characterized by an 
increase 
in 
frequency 
and/or 
loose 
or 
watery 
bowel movements. 
Increase 
of 
<4 
stools per day over 
baseline; 
mild 
increase in ostomy 
output compared 
to baseline 
Increase of 4 - 6 
stools per day over 
baseline; 
moderate increase 
in ostomy output 
compared 
to 
baseline; limiting 
instrumental ADL 
Increase 
of 
>=7 
stools per day over 
baseline; 
hospitalization 
indicated; 
severe 
increase in ostomy 
output compared to 
baseline; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Esophageal 
perforation 
A 
disorder 
characterized by a 
rupture in the wall of 
the esophagus. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 

47 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Gastrointestinal 
disorders 
Esophagitis 
A 
disorder 
characterized 
by 
inflammation of the 
esophageal wall. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered 
eating/swallowing; 
oral supplements 
indicated 
Severely 
altered 
eating/swallowing; 
tube feeding, TPN, 
or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Gastric 
perforation 
A 
disorder 
characterized by a 
rupture 
in 
the 
stomach wall. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Gastric ulcer 
A 
disorder 
characterized by a 
circumscribed, 
erosive lesion on the 
mucosal surface of 
the stomach. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered 
GI 
function; medical 
intervention 
indicated; limiting 
instrumental ADL 
Severely altered GI 
function; 
TPN 
indicated; 
elective 
invasive 
intervention 
indicated; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Gastrointestinal 
fistula 
A 
disorder 
characterized by an 
abnormal 
communication 
between any part of 
the gastrointestinal 
system and another 
organ or anatomic 
site. 
Asymptomatic 
Symptomatic, 
invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Lower 
gastrointestinal 
hemorrhage 
A 
disorder 
characterized 
by 
bleeding from the 
lower 
gastrointestinal tract 
(small 
intestine, 
large intestine, and 
anus). 
Mild 
symptoms; 
intervention 
not 
indicated 
Moderate 
symptoms; 
intervention 
indicated 
Transfusion 
indicated; 
invasive 
intervention 
indicated; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Nausea 
A 
disorder 
characterized by a 
queasy 
sensation 
and/or the urge to 
vomit. 
Loss of appetite 
without alteration 
in eating habits 
Oral 
intake 
decreased without 
significant weight 
loss, dehydration 
or malnutrition 
Inadequate 
oral 
caloric 
or 
fluid 
intake; tube feeding, 
TPN, 
or 
hospitalization 
indicated 
 - 
 - 
Gastrointestinal 
disorders 
Obstruction 
gastric 
A 
disorder 
characterized 
by 
blockage 
of 
the 
normal flow of the 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
Symptomatic; 
altered 
GI 
Hospitalization 
indicated; 
invasive 
intervention 
Life-threatening 
consequences; 
urgent 
operative 
Death 

48 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
contents 
in 
the 
stomach. 
intervention 
not 
indicated 
function; limiting 
instrumental ADL 
indicated; 
limiting 
self care ADL 
intervention 
indicated 
Gastrointestinal 
disorders 
Rectal 
obstruction 
A 
disorder 
characterized 
by 
blockage 
of 
the 
normal flow of the 
intestinal contents in 
the rectum. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered 
GI 
function; limiting 
instrumental ADL 
Hospitalization 
indicated; 
invasive 
intervention 
indicated; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Rectal 
perforation 
A 
disorder 
characterized by a 
rupture in the rectal 
wall. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Rectal ulcer 
A 
disorder 
characterized by a 
circumscribed, 
erosive lesion on the 
mucosal surface of 
the rectum. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered GI function 
(e.g., 
altered 
dietary 
habits, 
vomiting, 
diarrhea) 
Severely altered GI 
function; 
TPN 
indicated; 
elective 
invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Retroperitoneal 
hemorrhage 
A 
disorder 
characterized 
by 
bleeding from the 
retroperitoneal 
area. 
 - 
Self-limited; 
intervention 
indicated 
Transfusion 
indicated; 
invasive 
intervention 
indicated; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Small intestinal 
obstruction 
A 
disorder 
characterized 
by 
blockage 
of 
the 
normal flow of the 
intestinal 
contents 
of 
the 
small 
intestine. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered 
GI 
function; limiting 
instrumental ADL 
Hospitalization 
indicated; 
invasive 
intervention 
indicated; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Small intestinal 
perforation 
A 
disorder 
characterized by a 
rupture in the small 
intestine wall. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 
Gastrointestinal 
disorders 
Small intestine 
ulcer 
A 
disorder 
characterized by a 
circumscribed, 
erosive lesion on the 
mucosal surface of 
the small intestine. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
altered 
GI 
function; limiting 
instrumental ADL 
Severely altered GI 
function; 
TPN 
indicated; 
elective 
invasive 
intervention 
indicated; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
operative 
intervention 
indicated 
Death 

49 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Gastrointestinal 
disorders 
Upper 
gastrointestinal 
hemorrhage 
A 
disorder 
characterized 
by 
bleeding from the 
upper 
gastrointestinal tract 
(oral cavity, pharynx, 
esophagus, 
and 
stomach). 
Mild 
symptoms; 
intervention 
not 
indicated 
Moderate 
symptoms; 
intervention 
indicated 
Transfusion 
indicated; 
invasive 
intervention 
indicated; 
hospitalization 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
General disorders 
and 
administration 
site conditions 
Pain 
A 
disorder 
characterized by the 
sensation of marked 
discomfort, distress 
or agony. 
Mild pain 
Moderate 
pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self care ADL 
 - 
 - 
Infections 
and 
infestations 
Myelitis 
A 
disorder 
characterized 
by 
inflammation 
involving the spinal 
cord. 
Symptoms 
include 
weakness, 
paresthesia, sensory 
loss, 
marked 
discomfort 
and 
incontinence. 
Asymptomatic; 
mild signs (e.g., 
Babinski's reflex or 
Lhermitte's sign) 
Moderate 
weakness 
or 
sensory 
loss; 
limiting 
instrumental ADL 
Severe weakness or 
sensory loss; limiting 
self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Musculoskeletal 
and 
connective 
tissue disorders 
Joint range of 
motion 
decreased 
A 
disorder 
characterized by a 
decrease 
in 
joint 
flexibility 
of 
any 
joint. 
<=25% 
loss 
of 
ROM 
(range 
of 
motion); 
decreased 
ROM 
limiting 
athletic 
activity 
>25 
- 
50% 
decrease in ROM; 
limiting 
instrumental ADL 
>50% decrease in 
ROM; limiting self 
care ADL 
 - 
 - 
Musculoskeletal 
and 
connective 
tissue disorders 
Soft 
tissue 
necrosis 
A 
disorder 
characterized by a 
necrotic 
process 
occurring in the soft 
tissues 
 
- 
Local wound care; 
medical 
intervention 
indicated 
(e.g., 
dressings 
or 
topical 
medications) 
Operative 
debridement 
or 
other 
invasive 
intervention 
indicated 
(e.g., 
tissue 
reconstruction, flap, 
or grafting) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Nervous 
system 
disorders 
Peripheral 
motor 
neuropathy 
A 
disorder 
characterized 
by 
damage 
or 
dysfunction of the 
peripheral 
motor 
nerves. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 

50 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Nervous 
system 
disorders 
Peripheral 
sensory 
neuropathy 
A 
disorder 
characterized 
by 
damage 
or 
dysfunction of the 
peripheral 
sensory 
nerves. 
Asymptomatic 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe 
symptoms; 
limiting self care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 - 
Renal and urinary 
disorders 
Acute 
kidney 
injury 
A 
disorder 
characterized by the 
acute loss of renal 
function (within 2 
weeks) 
and 
is 
traditionally 
classified 
as 
pre-
renal 
(low 
blood 
flow into kidney), 
renal 
(kidney 
damage) and post-
renal 
causes 
(ureteral or bladder 
outflow 
obstruction). 
 - 
 - 
Hospitalization 
indicated 
Life-threatening 
consequences; 
dialysis 
indicated 
Death 
Renal and urinary 
disorders 
Bladder 
perforation 
A 
disorder 
characterized by a 
rupture 
in 
the 
bladder wall. 
 - 
Invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
organ 
failure; 
urgent 
operative 
intervention 
indicated 
Death 
Renal and urinary 
disorders 
Hematuria 
A 
disorder 
characterized 
by 
laboratory 
test 
results that indicate 
blood in the urine. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
urinary catheter or 
bladder irrigation 
indicated; limiting 
instrumental ADL 
Gross 
hematuria; 
transfusion, 
IV 
medications, 
or 
hospitalization 
indicated; 
elective 
invasive 
intervention 
indicated; 
limiting 
self care ADL 
Life-threatening 
consequences; 
urgent invasive 
intervention 
indicated 
Death 
Renal and urinary 
disorders 
Urinary fistula 
A 
disorder 
characterized by an 
abnormal 
communication 
between any part of 
the urinary system 
and another organ 
or anatomic site. 
 - 
Symptomatic, 
invasive 
intervention 
not 
indicated 
Invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent invasive 
intervention 
indicated 
Death 

51 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
Renal and urinary 
disorders 
Urinary 
tract 
obstruction 
A 
disorder 
characterized 
by 
blockage 
of 
the 
normal 
flow 
of 
contents 
of 
the 
urinary tract. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic but 
no 
hydronephrosis, 
sepsis, 
or 
renal 
dysfunction; 
urethral 
dilation, 
urinary 
or 
suprapubic 
catheter indicated 
Altered 
organ 
function 
(e.g., 
hydronephrosis 
or 
renal 
dysfunction); 
invasive 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
Pleuritic pain 
A 
disorder 
characterized by a 
sensation of marked 
discomfort in the 
pleura. 
Mild pain 
Moderate 
pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self care ADL 
 - 
 - 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
Pneumothorax 
A 
disorder 
characterized 
by 
abnormal presence 
of air in the pleural 
cavity resulting in 
the collapse of the 
lung. 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic; 
intervention 
indicated 
Sclerosis 
and/or 
operative 
intervention 
indicated; 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Injury, poisoning 
and 
procedural 
complications 
Dermatitis 
radiation 
A 
finding 
of 
cutaneous 
inflammatory 
reaction occurring as 
a result of exposure 
to 
biologically 
effective levels of 
ionizing radiation. 
Faint erythema or 
dry desquamation 
Moderate to brisk 
erythema; patchy 
moist 
desquamation, 
mostly confined to 
skin 
folds 
and 
creases; moderate 
edema 
Moist desquamation 
in areas other than 
skin 
folds 
and 
creases; 
bleeding 
induced by minor 
trauma or abrasion 
Life-threatening 
consequences; 
skin necrosis or 
ulceration 
of 
full 
thickness 
dermis; 
spontaneous 
bleeding 
from 
involved 
site; 
skin 
graft 
indicated 
Death 
Injury, poisoning 
and 
procedural 
complications 
Fracture 
 
Asymptomatic; 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated 
Symptomatic but 
non-displaced; 
immobilization 
indicated 
Severe 
symptoms; 
displaced or open 
wound with bone 
exposure; 
limiting 
self 
care 
ADL; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
 

52 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
References 
1. 
Hellman, S. and R.R. Weichselbaum, Importance of local control in an era of systemic therapy. 
Nat Clin Pract Oncol, 2005. 2(2): p. 60-1. 
2. 
Withers, H.R. and S.P. Lee, Modeling growth kinetics and statistical distribution of 
oligometastases. Semin Radiat Oncol, 2006. 16(2): p. 111-9. 
3. 
Weichselbaum, R.R. and S. Hellman, Oligometastases revisited. Nat Rev Clin Oncol, 2011. 
8(6): p. 378-82. 
4. 
Thibault, I., et al., Spine stereotactic body radiotherapy for renal cell cancer spinal 
metastases: analysis of outcomes and risk of vertebral compression fracture. J Neurosurg 
Spine, 2014. 21(5): p. 711-8. 
5. 
Primrose, J.N., Surgery for colorectal liver metastases. Br J Cancer, 2010. 102(9): p. 1313-8. 
6. 
Simmonds, P.C., et al., Surgical resection of hepatic metastases from colorectal cancer: a 
systematic review of published studies. Br J Cancer, 2006. 94(7): p. 982-99. 
7. 
Pawlik, T.M. and M.A. Choti, Surgical therapy for colorectal metastases to the liver. J 
Gastrointest Surg, 2007. 11(8): p. 1057-77. 
8. 
Sardenberg, R.A., et al., Pulmonary metastasectomy from soft tissue sarcomas. Clinics (Sao 
Paulo), 2010. 65(9): p. 871-6. 
9. 
Meimarakis, G., et al., Evaluation of a new prognostic score (Munich score) to predict long-
term survival after resection of pulmonary renal cell carcinoma metastases. Am J Surg, 2011. 
202(2): p. 158-67. 
10. 
Potters, L., et al., American Society for Therapeutic Radiology and Oncology (ASTRO) and 
American College of Radiology (ACR) practice guideline for the performance of stereotactic 
body radiation therapy. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 326-32. 
11. 
Gomez, D.R., et al., Local consolidative therapy versus maintenance therapy or observation 
for patients with oligometastatic non-small-cell lung cancer without progression after first-
line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol, 
2016. 17(12): p. 1672-1682. 
12. 
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, 2019. 
13. 
Ost, P., et al., Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate 
Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol, 2018. 
36(5): p. 446-453. 
14. 
Tubiana-Hulin, M., Incidence, prevalence and distribution of bone metastases. Bone, 1991. 
12 Suppl 1: p. S9-10. 
15. 
Ecker, R.D., et al., Diagnosis and treatment of vertebral column metastases. Mayo Clin Proc, 
2005. 80(9): p. 1177-86. 

53 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
16. 
Lage, M.J., et al., The cost of treating skeletal-related events in patients with prostate cancer. 
Am J Manag Care, 2008. 14(5): p. 317-22. 
17. 
Parker, C., et al., Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl 
J Med, 2013. 369(3): p. 213-23. 
18. 
Sartor, O., et al., Effect of radium-223 dichloride on symptomatic skeletal events in patients 
with castration-resistant prostate cancer and bone metastases: results from a phase 3, 
double-blind, randomised trial. Lancet Oncol, 2014. 15(7): p. 738-46. 
19. 
Smith, M.R., et al., Denosumab for the prevention of skeletal complications in metastatic 
castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic 
skeletal events. Ann Oncol, 2015. 26(2): p. 368-74. 
20. 
Huo, M., et al., Stereotactic spine radiosurgery: Review of safety and efficacy with respect to 
dose and fractionation. Surg Neurol Int, 2017. 8: p. 30. 
21. 
Owen, D., et al., Outcomes and toxicities of stereotactic body radiation therapy for non-spine 
bone oligometastases. Pract Radiat Oncol, 2014. 4(2): p. e143-e149. 
22. 
Ito, K., et al., Patterns of Intraosseous Recurrence After Stereotactic Body Radiation Therapy 
for Coxal Bone Metastasis. Int J Radiat Oncol Biol Phys, 2018. 100(1): p. 159-161. 
23. 
Moussazadeh, N., et al., Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic 
Radiosurgery. Int J Radiat Oncol Biol Phys, 2015. 93(2): p. 361-7. 
24. 
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(5): p. 1016-1026. 
25. 
Sahgal, A., D.A. Larson, and E.L. Chang, Stereotactic body radiosurgery for spinal metastases: 
a critical review. Int J Radiat Oncol Biol Phys, 2008. 71(3): p. 652-65. 
26. 
Bedard, G., et al., Stereotactic body radiation therapy for non-spine bone metastases--a 
review of the literature. Ann Palliat Med, 2016. 5(1): p. 58-66. 
27. 
Sahgal, A., et al., Vertebral compression fracture after spine stereotactic body radiotherapy: 
a multi-institutional analysis with a focus on radiation dose and the spinal instability 
neoplastic score. J Clin Oncol, 2013. 31(27): p. 3426-31. 
28. 
Chow, E., et al., Update of the international consensus on palliative radiotherapy endpoints 
for future clinical trials in bone metastases. Int J Radiat Oncol Biol Phys, 2012. 82(5): p. 1730-
7. 
29. 
Chow, E., et al., Palliative radiotherapy trials for bone metastases: a systematic review. J Clin 
Oncol, 2007. 25(11): p. 1423-36. 
30. 
Redmond, K.J., et al., Postoperative Stereotactic Body Radiation Therapy (SBRT) for Spine 
Metastases: A Critical Review to Guide Practice. Int J Radiat Oncol Biol Phys, 2016. 95(5): p. 
1414-1428. 
31. 
Nguyen, Q.N., et al., Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy 
for Pain Relief in Patients With Predominantly Nonspine Bone Metastases: A Randomized 
Phase 2 Trial. JAMA Oncol, 2019. 

54 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
32. 
Huisman, M., et al., Effectiveness of reirradiation for painful bone metastases: a systematic 
review and meta-analysis. Int J Radiat Oncol Biol Phys, 2012. 84(1): p. 8-14. 
33. 
Kothari, G., et al., Outcomes of stereotactic radiotherapy for cranial and extracranial 
metastatic renal cell carcinoma: a systematic review. Acta Oncol, 2015. 54(2): p. 148-57. 
34. 
Youland, R.S., et al., 18F-FDG PET response and clinical outcomes after stereotactic body 
radiation therapy for metastatic melanoma. Adv Radiat Oncol, 2017. 2(2): p. 204-210. 
35. 
Gerszten, P.C., et al., Stereotactic radiosurgery for spinal metastases from renal cell 
carcinoma. J Neurosurg Spine, 2005. 3(4): p. 288-95. 
36. 
Nguyen, Q.N., et al., Management of spinal metastases from renal cell carcinoma using 
stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys, 2010. 76(4): p. 1185-92. 
37. 
Hunter, G.K., et al., The efficacy of external beam radiotherapy and stereotactic body 
radiotherapy for painful spinal metastases from renal cell carcinoma. Pract Radiat Oncol, 
2012. 2(4): p. e95-e100. 
38. 
Meyer, E., et al., Stereotactic radiation therapy in the strategy of treatment of metastatic 
renal cell carcinoma: A study of the Getug group. Eur J Cancer, 2018. 98: p. 38-47. 
39. 
Laufer, I., et al., The NOMS framework: approach to the treatment of spinal metastatic 
tumors. Oncologist, 2013. 18(6): p. 744-51. 
40. 
Sze, W.M., et al., Palliation of metastatic bone pain: single fraction versus multifraction 
radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev, 
2004(2): p. CD004721. 
41. 
Agarawal, J.P., et al., The role of external beam radiotherapy in the management of bone 
metastases. Clin Oncol (R Coll Radiol), 2006. 18(10): p. 747-60. 
42. 
Greenberg, H.S., J.H. Kim, and J.B. Posner, Epidural spinal cord compression from metastatic 
tumor: results with a new treatment protocol. Ann Neurol, 1980. 8(4): p. 361-6. 
43. 
Gerszten, P.C., et al., Radiosurgery for spinal metastases: clinical experience in 500 cases 
from a single institution. Spine (Phila Pa 1976), 2007. 32(2): p. 193-9. 
44. 
Hashmi, A., et al., Re-irradiation stereotactic body radiotherapy for spinal metastases: a 
multi-institutional outcome analysis. J Neurosurg Spine, 2016. 25(5): p. 646-653. 
45. 
Myrehaug, S., et al., Reirradiation spine stereotactic body radiation therapy for spinal 
metastases: systematic review. J Neurosurg Spine, 2017. 27(4): p. 428-435. 
46. 
Ogawa, H., et al., Re-irradiation for painful bone metastases using stereotactic body 
radiotherapy. Acta Oncol, 2018. 57(12): p. 1700-1704. 
47. 
Jhaveri, P.M., et al., A dose-response relationship for time to bone pain resolution after 
stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases. Acta 
Oncol, 2012. 51(5): p. 584-8. 
48. 
Ryu, S., et al., RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for 
localized (1-3) spine metastases: phase 2 results. Pract Radiat Oncol, 2014. 4(2): p. 76-81. 

55 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
49. 
Weickhardt, A.J., et al., Local ablative therapy of oligoprogressive disease prolongs disease 
control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J 
Thorac Oncol, 2012. 7(12): p. 1807-14. 
50. 
Gan, G.N., et al., Stereotactic radiation therapy can safely and durably control sites of extra-
central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung 
cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys, 2014. 88(4): p. 892-8. 
51. 
Straka, C., et al., Ablation of a site of progression with stereotactic body radiation therapy 
extends sunitinib treatment from 14 to 22 months. J Clin Oncol, 2013. 31(23): p. e401-3. 
52. 
Pembroke, C.A., B. Fortin, and N. Kopek, Comparison of survival and prognostic factors in 
patients 
treated 
with 
stereotactic 
body 
radiotherapy 
for 
oligometastases 
or 
oligoprogression. Radiother Oncol, 2018. 
53. 
Wang, X.S., et al., Stereotactic body radiation therapy for management of spinal metastases 
in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol, 2012. 13(4): p. 
395-402. 
54. 
Garg, A.K., et al., Prospective evaluation of spinal reirradiation by using stereotactic body 
radiation therapy: The University of Texas MD Anderson Cancer Center experience. Cancer, 
2011. 117(15): p. 3509-16. 
55. 
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 1989. 
10(1): p. 1-10. 
56. 
Jung, S.H., et al., Admissible two-stage designs for phase II cancer clinical trials. Stat Med, 
2004. 23(4): p. 561-9. 
57. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
58. 
Costelloe, C.M., et al., Cancer Response Criteria and Bone Metastases: RECIST 1.1, MDA and 
PERCIST. J Cancer, 2010. 1: p. 80-92. 
59. 
Taylor, D.R. and J.A. Weaver, Tumor pseudoprogression of spinal metastasis after 
radiosurgery: a novel concept and case reports. J Neurosurg Spine, 2015. 22(5): p. 534-9. 
60. 
Blomgren, H., et al., Stereotactic high dose fraction radiation therapy of extracranial tumors 
using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol, 1995. 
34(6): p. 861-70. 
61. 
Lax, I., et al., Stereotactic radiotherapy of malignancies in the abdomen. Methodological 
aspects. Acta Oncol, 1994. 33(6): p. 677-83. 
62. 
Craft, D., et al., The Price of Target Dose Uniformity. Int J Radiat Oncol Biol Phys, 2016. 96(4): 
p. 913-914. 
63. 
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(5): p. e597-605. 

56 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
64. 
Bentzen, S.M., et al., Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): 
an introduction to the scientific issues. Int J Radiat Oncol Biol Phys, 2010. 76(3 Suppl): p. S3-
9. 
65. 
Marks, L.B., et al., Use of normal tissue complication probability models in the clinic. Int J 
Radiat Oncol Biol Phys, 2010. 76(3 Suppl): p. S10-9. 
66. 
Benedict, S.H., et al., Stereotactic body radiation therapy: the report of AAPM Task Group 
101. Med Phys, 2010. 37(8): p. 4078-101. 
67. 
Ryu, S., et al., Partial volume tolerance of the spinal cord and complications of single-dose 
radiosurgery. Cancer, 2007. 109(3): p. 628-36. 
68. 
Erler, D., et al., Local control and fracture risk following stereotactic body radiation therapy 
for non-spine bone metastases. Radiother Oncol, 2018. 127(2): p. 304-309. 
69. 
Zelefsky, M.J., et al., Tumor control outcomes after hypofractionated and single-dose 
stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases 
from renal cell carcinoma. Int J Radiat Oncol Biol Phys, 2012. 82(5): p. 1744-8. 
70. 
Greco, C., et al., Predictors of local control after single-dose stereotactic image-guided 
intensity-modulated radiotherapy for extracranial metastases. Int J Radiat Oncol Biol Phys, 
2011. 79(4): p. 1151-7. 
71. 
Yamada, Y., et al., High-dose, single-fraction image-guided intensity-modulated radiotherapy 
for metastatic spinal lesions. Int J Radiat Oncol Biol Phys, 2008. 71(2): p. 484-90. 
72. 
Guckenberger, M., et al., Safety and efficacy of stereotactic body radiotherapy as primary 
treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol, 2014. 9: p. 
226. 
73. 
Stinson, S.F., et al., Acute and long-term effects on limb function of combined modality limb 
sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys, 1991. 21(6): 
p. 1493-9. 
74. 
Cox, B.W., et al., Esophageal toxicity from high-dose, single-fraction paraspinal stereotactic 
radiosurgery. Int J Radiat Oncol Biol Phys, 2012. 83(5): p. e661-7. 
75. 
Gomez, D.R., et al., Low rate of thoracic toxicity in palliative paraspinal single-fraction 
stereotactic body radiation therapy. Radiother Oncol, 2009. 93(3): p. 414-8. 
76. 
Rose, P.S., et al., Risk of fracture after single fraction image-guided intensity-modulated 
radiation therapy to spinal metastases. J Clin Oncol, 2009. 27(30): p. 5075-9. 
77. 
Cunha, M.V., et al., Vertebral compression fracture (VCF) after spine stereotactic body 
radiation therapy (SBRT): analysis of predictive factors. Int J Radiat Oncol Biol Phys, 2012. 
84(3): p. e343-9. 
78. 
Jawad, M.S., et al., Vertebral compression fractures after stereotactic body radiation therapy: 
a large, multi-institutional, multinational evaluation. J Neurosurg Spine, 2016. 24(6): p. 928-
36. 
79. 
Chang, J.H., et al., Stereotactic Body Radiotherapy for Spinal Metastases: What are the Risks 
and How Do We Minimize Them? Spine (Phila Pa 1976), 2016. 41 Suppl 20: p. S238-S245. 

57 
Protocol version 1.1, 01052020. Stereotactic ablative radiotherapy (SABR) of bony metastases in patients with 
oligometastatic disease - A phase II study 
80. 
Wu, V.W. and Y.N. Lam, Radiation-induced temporo-mandibular joint disorder in post-
radiotherapy nasopharyngeal carcinoma patients: assessment and treatment. J Med Radiat 
Sci, 2016. 63(2): p. 124-32. 
81. 
Davis, A.M., et al., Late radiation morbidity following randomization to preoperative versus 
postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol, 2005. 75(1): 
p. 48-53. 
82. 
Wang, J., et al., Comparison of outcome and toxicity of postoperative intensity-modulated 
radiation therapy with two-dimensional radiotherapy in patients with soft tissue sarcoma of 
extremities and trunk. Cancer Med, 2019. 
83. 
Sahgal, A., et al., Probabilities of radiation myelopathy specific to stereotactic body radiation 
therapy to guide safe practice. Int J Radiat Oncol Biol Phys, 2013. 85(2): p. 341-7. 
84. 
Amdur, R.J., et al., A prospective, phase II study demonstrating the potential value and 
limitation of radiosurgery for spine metastases. Am J Clin Oncol, 2009. 32(5): p. 515-20. 
85. 
Garg, A.K., et al., Phase 1/2 trial of single-session stereotactic body radiotherapy for 
previously unirradiated spinal metastases. Cancer, 2012. 118(20): p. 5069-77. 
86. 
Grimm, J., et al., Estimated Risk Level of Unified Stereotactic Body Radiation Therapy Dose 
Tolerance Limits for Spinal Cord. Semin Radiat Oncol, 2016. 26(2): p. 165-71. 
87. 
Gibbs, I.C., et al., Image-guided robotic radiosurgery for spinal metastases. Radiother Oncol, 
2007. 82(2): p. 185-90. 
88. 
Hird, A., et al., Dexamethasone for the prophylaxis of radiation-induced pain flare after 
palliative radiotherapy for symptomatic bone metastases: a phase II study. Clin Oncol (R Coll 
Radiol), 2009. 21(4): p. 329-35. 
89. 
Loblaw, D.A., et al., Pain flare in patients with bone metastases after palliative radiotherapy-
-a nested randomized control trial. Support Care Cancer, 2007. 15(4): p. 451-5. 
90. 
Chiang, A., et al., Pain flare is a common adverse event in steroid-naive patients after spine 
stereotactic body radiation therapy: a prospective clinical trial. Int J Radiat Oncol Biol Phys, 
2013. 86(4): p. 638-42. 
91. 
Bilsky, M.H., et al., Reliability analysis of the epidural spinal cord compression scale. J 
Neurosurg Spine, 2010. 13(3): p. 324-8. 
92. 
Tseng, C.L., et al., Spine Stereotactic Body Radiotherapy: Indications, Outcomes, and Points 
of Caution. Global Spine J, 2017. 7(2): p. 179-197. 
93. 
Santanam, L., et al., Standardizing naming conventions in radiation oncology. Int J Radiat 
Oncol Biol Phys, 2012. 83(4): p. 1344-9. 
94. 
Fisher, C.G., 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(22): p. E1221-9.