Results of the current retrospective study present SBRT as an effective treatment for bone metastases. SBRT has been increasingly accepted as a valuable option for selective patients with metastatic disease. Using the appropriate imaging modality for treatment planning, SBRT offers an excellent local control with acceptable toxicity profile21. However, response assessment after SBRT is a challenging topic, which is not only limited to the bone, as we confront difficulties to interpret the changes in imaging modalities after stereotactic radiotherapy in other organs, like brain, liver and lung22–24. Appropriate evaluating of diagnostic images is a critical point in the process of the disease and can prevent the risks of unnecessary interventions. Besides that, pain response should be considered after RT for bone metastases, as pain relief is the most important goal in such patients. In this retrospective study, we report our institutional results regarding imaging-based local control and pain response after SBRT for bone metastases.
The SPINO-group published a report in 2015, focusing on response assessment after SBRT for spinal metastases13. The consensus is based on an international survey and not yet evaluated in clinical trials. We considered the recommendations from SPINO group for image-based tumor- and pain response, although we analyzed both spine and non-spine bone metastases in our study. The MRI is the preferred modality for response assessment after SBRT; however, we should be aware of some unique aspects such as pseudo-progression (PP) and vertebral compression fracture (VCF) when interpreting the post-SBRT images.
PP is a well-known phenomenon after SBRT in different organs. It was first reported for spine metastasis in a case report from 2015 and the authors described PP as subacute, post-radiotherapy reaction that mimics progressive disease (PD) with increased contrast enhancement and ultimate stabilization and regression25. Time is an important factor evaluating post-SBRT radiological changes, as PP present few weeks up to 6 months after radiation, in contrast to radio-necrosis (RN) which is a late effect and can occur even years after therapy25. Amini et al. did an analysis of osseous pseudo-progression in vertebral body following SBRT in patients from two prospective phase I/II clinical trials26. They defined the osseous pseudo-progression as “transient growth in signal abnormality centered at the lesion with a sustained decline on FU MRI that was not attributable to chemotherapy”. They reported the rates of PP and PD of 14% and 24% respectively. Furthermore, there was a significant association between single-fraction SBRT and development of PP26. The so far published randomized trials comparing SBRT versus conventional RT have not reported the rates of PP12,27,28. SPINO group defined any new or progressive tumor within the epidural space as local progression13, but we have recently published a case report showing clear epidural involvement on radiological images after spine SBRT, however, the histological analysis revealed no tumor cells in epidural space29. Therefore, it is critical to distinguish between PP, PD and RN to avoid false patient management. In our study, we observed PP as a common finding after SBRT, however not all patients had MRI shortly after the therapy and therefore it was not possible to report the exact rate of PP.
VCF is a well-known and most common complication after spine SBRT. The rate of VCF after single fraction SBRT (SF-SBRT) with 18-24Gy was reported around 39%, and lytic lesions and location below T10 confer a high risk of fracture30. The median time to fracture was 25 months and VCF was seen earlier in patients with lytic lesions compared to sclerotic lesions30. Sahgal et al. reported 14% of new or progressing VCF after spine SBRT, using different fractionation and considering SINS-score to determine its predictive value31. They defined the high dose per fraction, lytic lesion and baseline fracture as significant predictors of VCF31. A review from 2017 reported a crude VCF rate of 13.9%32. Jawad et al. demonstrated low rates of VCF for 5.7% in their multi-institutional study, using 1-5 fractions for spine SBRT33. We report here the rates of new/progressive fractures for spine and non-spine metastases as 4.5% and 4.7% respectively. As half of our cohort had metastatic prostate cancer, one reason for our low rates of fractures could be the sclerotic nature of the metastases. Another reason might be related to our moderate SBRT schema with median total dose of 24Gy in three fractions.
As mentioned above, MRI is the most recommended imaging modality for radiological assessment of bone metastasis after SBRT. Hwang et al. reported the MRI changes after SBRT for osteoblastic spinal lesions, as these metastases usually show no obvious radiological volumetric alterations17. They classified signal intensity (SI) alterations on T2-MRI sequences as following: 1) no changes in SI; 2) increased SI; 3) increased SI intermixed with dark SI; 4) changed to complete dark SI. Most of our patients had prostate cancer as primary diagnosis; therefore, we assessed the T2 weighted MRI sequences for radiological response evaluation after SBRT for both spine and non-spine bone metastases as described above. According to recommendations from SPINO group, the routine use of contrast-enhanced T1-MRI sequences to visualize spinal metastases is controversial as both normal bone marrow and tumor are enhanced13. The interpretation becomes even more difficult after SBRT and therefore we considered the T1-MRI with gadolinium only for delineating the epidural and para-spinal tumor components. Although the patient population was heterogeneous in our cohort, SBRT achieved 80% of LC at almost 2 years. More than 40% of our patients survived and among the population who died in FU time, 40% had still SD at the irradiated sites. These results are in line with data from other studies, showing an excellent rate of LC after SBRT for osseous metastases21.
Considering pain response, the randomized phase 2 trial from Germany reported significant improved pain values in SBRT group 6 months after the therapy in patients with spinal metastases12. However, as they chose the SF-SBRT with 24Gy, the rates of new pathological fracture were high in that study, with 8.7% and 27.8% at 3 and 6 months respectively12. Another randomized phase 2 trial from Netherlands compared SBRT versus conventional RT for bone metastases using different fractionations28. SBRT group did not show significant pain improve, but because of selective dropout, this trial was underpowered to detect the difference in pain response28. The NRG Oncology/RTOG 0631 trial initial results were presented at ASTRO annual meeting in 201934. Randomizing patients with spinal metastases into SBRT and conventional RT groups, this study showed negative results for SBRT arm, as pain control was similar at 3 months between two groups. Finally, the Canadian randomized phase 3 trial compared spine SBRT with 24Gy in two daily fractions with conventional RT at a dose of 20Gy in five fractions27. The SBRT was superior to conventional RT and improved the complete pain response at 3 months. Interestingly, the incidence of VCF was equal between two groups, showing the safety of SBRT regimen27. In our retrospective study, the majority of patients (62.9%) had no pain prior to SBRT and the indication was mostly local ablation in oligo-metastatic/progressive disease. This group of patients remained asymptomatic after SBRT. In symptomatic group, only two patients experienced pain exacerbation following SBRT with only one of them required analgesic medication.