Stereotactic Body Radiotherapy for Osseous Low Alpha-Beta Resistant Metastases for Pain Relief
Phase: NA
Conditions: Bone Metastases, Prostate Cancer, Breast Cancer, Renal Cell Carcinoma, Melanoma
Sponsor: Hamilton Health Sciences Corporation

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Stereotactic Body Radiotherapy for Osseous Low Alpha-Beta Resistant Metastases for Pain 
Relief - SOLAR-P 
Resident Investigator: Dr. Eric Nguyen 
Principal Investigator: Dr. Anand Swaminath 
Background 
The use of stereotactic body radiotherapy (SBRT) has been a topic of interest in palliative 
approaches for managing metastatic disease. Advances in radiation planning and delivery allows 
clinicians to target lesions with higher, ablative doses to tumors, while minimizing dose to organs 
and tissues at risk. SBRT has been demonstrated to be effective in controlling local metastatic 
lesions, while delaying distant progression of disease within the context of several retrospective, 
and small prospective randomized trials (1,2).  
The use of SBRT is appealing, in particular, for tumors with low alpha-beta ratios such as 
prostate cancer, breast cancer, renal cell carcinoma (RCC), melanoma, and sarcoma. Such tumors 
have inherent radioresistance to standard fractionation regimens, and benefit from dose 
escalation in order to yield more potent biological efficacy. Theoretically, this may lead to 
amplification of vascular damage, increased endothelial cell apoptosis, and enhanced antitumor 
immunity (3).  Low alpha-beta tumors classically respond to higher doses per fraction, as 
demonstrated in pre-clinical studies for instance using renal cell cancer cell lines (4), and in clinical 
studies suggesting equivalent or improved local control using more hypofractionated radiation 
regimens (5,6). The higher doses in fewer fractions theoretically may overcome innate tumor 
radioresistance resulting in improved local control and symptom resolution. 
Palliative radiotherapy (RT) has been common practice in managing painful bone 
metastases, and classically this has been administered in conventional fractionation schedules 
such as 20 Gray (Gy) in 5 fractions or 8 Gy in a single fraction. RT has been established an effective, 
low-risk approach for uncomplicated symptomatic bone metastases, and a meta-analysis showed 
overall response rate of 60% and complete response rate of 23-24% (7). Following RT, median 
time to onset of pain relief was 1-4 weeks, and median duration of response was 3-6 months. 
Multiple studies have shown no significant differences in outcomes between single fraction and 
multiple fraction regimens, though following single fraction there was a higher chance of 
retreatment (8-11).  
Retreatment with palliative RT has also been shown to be effective following no response 
or symptomatic relapse after initial treatment. In the per-protocol analysis, the SC20 trial 
reported that patients retreated with 8 Gy/1 fraction and 20 Gy/5 fractions had pain response 
rates of 45% and 51%, respectively at 2 months post-treatment (12). Overall, 48% of patients 
who received their assigned treatment had reduced pain at the site of repeat radiation, 
regardless of whether or not they responded to their initial treatment. In addition, 68% had 
improved quality of life pain scores. 

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SBRT has shown promising early results in the management of bone metastases. In 
addition to its utility in spinal lesions, SBRT has been reported to improve local control in prostate 
cancer bone metastases with reductions of in-field failure in comparison to hypofractionated 
schedules (13), but it was unclear whether this translated into long term pain relief. Also, there 
has been some research in the use of SBRT in RCC bone metastases, given its resistance to 
conventional fractionation. One study showed that SBRT improved symptom control rates at 10, 
12 and 24 months in comparison to standard external beam RT, with a median time to control of 
2 weeks (14), but documentation of pain control was variably captured, and largely extrapolated 
from clinical notes. Other retrospective data in RCC, melanoma and sarcoma suggested a high 
degree of pain relief in patients treated with SBRT for spine metastases, however pain scores 
were not prospectively captured (15), and the study was likely to be underpowered to determine 
a significant effect. In addition, a recent phase II randomized trial that included patients with 
bone metastases from all disease sites (majority lung), showed that single fraction SBRT had 
higher rates of pain response at 2 weeks and 3 months compared to conventional fractionation 
(16). However, the degree of pain response in the control group was less than expected, the 
majority of the patients on this study did not have low alpha-beta tumors, and the radiation dose 
schedule in the conventional arm was not typical of standard practice (30 Gy in 10 fractions as 
compared to 8 Gy/1 fraction or 20 Gy/ 5 fractions).  
Currently, there is a paucity of prospective data studying the use of SBRT for bone 
metastases originating from low alpha-beta tumors, with systematic reporting of changes in pain 
scores and analgesia use over time. The vast majority data looking at SBRT in bone lesions focuses 
on local control and survival, rather than more tangible outcomes in a palliative population 
including symptomatic control, durability of response (and need for retreatment), and patient 
reported quality of life; a component that is understudied in this group despite its tremendous 
value. Furthermore, SBRT for bone metastases has yet to become common practice given the 
limited evidence for its efficacy and uncertainty in regards to toxicity.  
We propose an investigation of the potential benefits of SBRT for symptomatic bone 
metastases in patients with prostate cancer, breast cancer, RCC, melanoma, and sarcoma. We 
look to conduct a prospective cohort study (SOLAR-P) that is adequately powered to analyse 
efficacy in alleviating pain from bone lesions and compare this to well-established rates in 
literature for conventionally fractionated palliative RT. We will also assess the tolerability of this 
modality, toxicity rates, and effect on quality of life. If our results show that SBRT has a significant 
benefit on this population, the goal would be to pursue a larger randomized trial to confirm the 
findings. 
 
Methods 
Patient Population: 
Patients will be accrued from the Juravinski Cancer Centre. Eligibility will be determined based 
on the criteria listed below, and informed consent will be established. 

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• Inclusion 
o Diagnosis of prostate cancer, breast cancer, renal cell carcinoma, or melanoma 
o Radiographic evidence of bone metastases requiring treatment for pain 
o BPI score of ≥ 2 
• Exclusion 
o Spinal lesions 
o Severe or progressive neurological deficit 
o Impending (Mirels’ score ≥9) or existing pathological fracture 
o Bone metastasis in a previously irradiated site 
o Active concurrent systemic therapy 
o > 5 lesions requiring treatment 
o Lesions > 5 cm in largest diameter 
o Life expectancy < 3 months 
o Age < 18 
o KPS < 50 
o Unable to provide informed consent 
Primary Outcome: 
• Overall Pain Response at 3 months: Assessed using the Brief Pain Inventory (BPI; 
Appendix A) and converting daily analgesic use to oral morphine equivalent (OME) 
o Complete response defined as BPI pain score of 0 with no increase in OME. 
o Partial response defined as BPI pain score of >0, and either a reduction of 2 or 
more with no increase in OME, or no increase in BPI with a reduction in OME or at 
least 25%. 
o Treatment failure defined as worsening pain on BPI by 2 or more, >50% increase 
in OME, re-irradiation for pain/progression, or development of pathologic 
fracture. 
Secondary Outcomes: 
• Overall Pain Response at 1 month and 6 months post SBRT: Assessed using the BPI and 
response as described above. 
• Toxicity: Acute (3 months or less), and late (greater than 3 months) adverse effects from 
RT will be recorded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) 5.0 (17). 
• Patient-reported QoL: QoL assessed by European Organization of Research and 
Treatment of Cancer Quality of Life -Questionnaire-Core-15-Palliative (EORTC QLQ-C15-
PAL) and EORTC QLQ-Bone Metastasis 22 (EORTC QLQ-BM22), measured at 1, 3, and 6 
months post SBRT (18,19). 
• Rate of Re-irradiation and Salvage Surgery due to symptomatic progression: Patients 
requiring re-irradiation will not undergo treatment for at least 4 weeks following the 
study radiation course. Patients requiring salvage surgery for disease progression, 
instability, or pathologic fractures will be reported. 

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• Local Control of Treated Lesions: To be assessed retrospectively using standard of care 
follow-up imaging. Radiographic control evaluated based on Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 (20). 
Intervention and Evaluation 
 
Pre-Treatment Evaluation: 
Patient eligibility will be determined during the initial assessment which includes a 
physical examination and review of radiographic evidence of metastases. Fracture risk will be 
assessed based on Mirels’ Staging System taking into account the clinical evaluation and imaging 
available. For patients with high clinical suspicion of impending fracture, further evaluation may 
be taken with plain film radiographs as per standard of care. 
An initial BPI will be completed prior to treatment during a clinic visit, or over the phone. 
Use of analgesic medications will be recorded. 
 
Treatment Plan: 
Enrolled patients will receive the study dose of 15 to 20 Gy in 1 fraction to all painful bony 
lesions with SBRT. Planning and delivery will be conducted using a volumetric modulated arc 
therapy (VMAT) approach on our Varian Truebeam platform. Patients will be CT simulated, with 
a vac-lock immobilization. Use of 4DCT will be dependent on the area being treated. The gross 
tumor volume (GTV) will be defined as the visible abnormality based on CT imaging. The planning 
target volume (PTV) will be an additional 5 mm in all directions. The SBRT prescription will ensure 
that at least 95% of the PTV will be covered with the prescribed dose, and that at least 99% of 
the PTV will be covered by 95% of the prescription dose. Dose to organs at risk will based on 
institutional guidelines for single fraction SBRT. Daily image guidance will be performed using 
cone beam CT aligning to relevant bony anatomy +/- PTV if visible. 
 
Evaluation During Study: 
The primary outcome will be overall pain response, measured using the BPI. Patients will 
be assessed using the BPI at baseline, and then at 1 month, 3 months, and 6 months following 
the completion of the SBRT treatment course. Responses will be obtained by patient self-
reported questionnaires in clinic or by telephone follow-up. The sum of responses will dictate the 
overall response to treatment. Patients will be seen once for treatment review during their SBRT 
course to document acute toxicity. They will also be assessed at the 1 month, 3 month, and 6 
month intervals to record acute and late toxicity using CTCAE version 5.0.  Quality of life will be 
measured using the EORTC QLQ-C15-PAL and BM22 questionnaires at the same timepoints. 
 

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Sample Size and Statistical Analysis 
 
Sample size:  
The estimated pain response at 3 months using cRT is approximately 60% (null hypothesis 
is that SBRT will have a response of 60% as well). However, we postulate that the pain response 
at 3 months using SBRT will be 80% (alternative hypothesis). Given 80% power, two-sided alpha 
of 0.05, we will require 41 patients to test this hypothesis using a one sample binomial test. We 
plan to recruit 45 patients to account for any losses to follow-up. 
 
Statistical Analysis:  
The observed proportion of pain response at 3 months with SBRT will be compared to the 
null value of 0.6 using a one sample binomial test. The corresponding 95% confidence interval 
(CI) around the observed proportion will be calculated using the Wilson score method. 
 
Study Timeline 
0-12 Months: Patient accrual, consent, RT planning and delivery. 
12-18 Months: Ongoing follow-up of study patients, planned assessments at designated 
intervals for pain, toxicity and quality of life parameters. 
18-24 Months: Data analysis, reporting and publication phase.  
 
 

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Appendix A. Brief Pain Inventory
 

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