Specific Pathologic Types
Given that none of these trials contain only one tumor type, a logical question concerns whether there are any significant differences in results for different tumor types. Some of the more common primary site tumors from which metastases in the spine are treated include breast, lung, and prostate cancers, melanoma, and renal cell carcinoma. Currently, the published literature evaluating the above question is still emerging. However, the University of Pittsburgh stereotactic radiotherapy group has published three prospective trials, and one retrospective review evaluating the use of SBRT in treating vertebral metastases from renal cell, breast, lung, and melanoma primaries.[23,24,35,36]
The outcomes were similar among all four groups. Melanoma and renal cell carcinoma, two pathologies that are traditionally deemed radioresistant, responded well to a single-fraction mean dose of 21.7 and 16 Gy, respectively. The melanoma lesions had a response rate of 96% and renal cell lesions had an 89% response rate, in terms of patients experiencing some pain relief. The lung and breast cancer groups both received a mean dose of 19 Gy, with the lung cancer patients having an 89% symptom response rate (65/73 lesions) and the breast cancer patients having a 96% symptom response rate (55/57 lesions).
Similar results were reported by Teh et al, who retrospectively reported on 23 extracranial RCC lesions treated with hypofractionated SBRT.[18,19] Fourteen patients received 24 to 40 Gy in three to six fractions. At a mean follow-up of 9 months, 93% of patients experienced some pain relief, with an overall local control rate of 87%. While these results are encouraging and suggest that similar outcomes can be obtained with hypofractionated or single-fraction therapy, it is unclear which dosing regimen is the best to use. There is a need for larger prospective, randomized trials to evaluate this clinical question.
Nonvertebral Bony Sites
The majority of SBRT data reported in the literature involve its use for bony disease in the spinal column. Two studies have reported on the use of SBRT for metastases to the sacrum.[37,38] Gibbs et al reported retrospectively on their experience with three sacral lesions treated with single-fraction stereotactic radiosurgery. All three received 18 Gy in a single fraction. No long-term side effects from the radiotherapy were reported; two of the three had undergone conventional radiotherapy prior to the stereotactic treatment. The University of Pittsburgh group gave an average dose of 15 Gy in one fraction to the target with 13 of 13 patients reporting pain relief after SBRT. No neurologic toxicity was reported in the follow-up period of 6 months.
Our clinical experience on the topic (unpublished) shows that SBRT can be successfully used to treat painful metastases in sites such as the ribs, pelvis, sternum, scapulae, and elsewhere. Approximately 33% of our bony disease sites have been outside of the spinal column. Overall, a 93% pain relief rate has been achieved.
Patterns of Symptomatic Failure
Because of the tight treatment margin and rapid dose fall-off involved in SBRT, recurrence adjacent to the treated segment can be a concern. Ryu et al retrospectively examined failure after single-fraction radiotherapy (10–16 Gy) to the spine for pain control. At the actual treated site, pain relapse was 7%. At adjacent sites, the symptomatic relapse rate was 5%. In their 500-patient prospective trial, Gerszten et al found that no patients experienced relapse at adjacent sites.
Toxicity to the Spinal Cord
Toxicity to the spinal cord is a major concern in the treatment of vertebral metastases with SBRT. This is especially important in patients with solitary or oligometastases, who will survive long after treatment.
Ryu et al examined post-SBRT toxicity retrospectively in 230 lesions treated with single-fraction SBRT (8–18 Gy, mean = 14.3 Gy). None of the patients had been treated with spinal radiotherapy prior to SBRT. Among those who were treated at a dose of 18 Gy, the highest point dose to the spinal cord was 19.2 Gy (in one patient). The average dose to 10% of the spinal cord volume in this 18-Gy cohort was 9.8 ± 1.5 Gy. None of these patients developed spinal cord toxicity. From the cumulated dose-volume histogram of all 230 lesions, the average dose to the 10% spinal cord volume was 9.2 ± 2.3 Gy. One patient developed a radiation-induced myelopathy 13 months after a single fraction of 16-Gy radiotherapy. In this patient, the highest spinal cord point dose was 14.6 Gy.
Given these results, the study concluded that the partial-volume tolerance of the spinal cord is at least 10 Gy to 10% of the spinal cord volume 5 mm above and below the target. This suggestion of 10% of the restricted cord volume receiving 10 Gy or less has been followed in both the University of Pittsburgh and Henry Ford Hospital groups’ prospective trials, with minimal to no spinal cord toxicity being reported.[17,23-26,35,36]
Patient survival outcome was not reported in the majority of studies reviewed here. The major endpoints were pain or symptom relief as well as side effects. One retrospective study found that 4 of 14 patients eventually died from disease, at an average follow-up of 6 months. Three of those patients died of systemic disease, and one died of local progression. One prospective study reported that 2 of 15 patients died at an average follow-up of 9 months, but no specific cause of death was given.
With such a heterogeneous group of studies, it is difficult to make a definitive claim about the survival benefit of SBRT. Patient-, disease- , and treatment-related factors (including performance status, tumor type and radioresistance, tumor burden and number of metastatic lesions, treatment response, and many others) will have an effect on survival in patients receiving SBRT. Additionally, to the best of our knowledge, no studies have compared SBRT and conventional radiotherapy head-to-head for the treatment of bony metastases with survival as a primary endpoint. The need for a well-organized study to examine the potential survival benefit of this technology and how it compares to conventional radiotherapy in this patient setting is warranted.
A cost-effectiveness analysis is very important in the evaluation of a new treatment approach such as SBRT. This can be performed by collecting and comparing cost and outcome data (symptom or pain relief, use of medications, survival, side effects, symptom-free duration, frequency of retreatment, and many others) for patients undergoing SBRT or conventional radiotherapy in randomized trials. Various randomized trials have compared a conventional single-fraction regimen with a conventional multifraction regimen.[1-5] To date, no reported randomized trial has compared SBRT and conventional radiotherapy in patients with painful bone metastases. SBRT may benefit most patients with isolated or oligometastases and more radioresistant tumors. However, SBRT is more expensive than conventional radiotherapy. A cost-benefit analysis is needed in future studies.
Summary and Conclusions
The use of SBRT has been shown to be safe and effective in relieving bone pain from metastatic disease. Current published results suggest that we can use single-fraction stereotactic radiosurgery at up to 20 Gy for relief of acute bone pain. Importantly, this is true even for radioresistant tumor types such as melanoma and renal cell carcinoma. However, the optimal dose schedule for specific tumor types is not known. Spinal cord toxicity is minimal when 10% of the restricted spinal cord volume (encompassing 5 mm above and below the target) receives 10 Gy or less.
Overall pain relief with this technique is around 90%. Symptomatic relapse rates can range from 5% to 12% (unpublished data), depending on treatment dose and tumor pathology. It is difficult to draw specific conclusions concerning what factors may necessitate a higher dose per fraction or what other factors influence outcomes.
Additionally, no trials have investigated hypofractionation, as opposed to single fractionation, in the treatment of bony metastases. Such evaluations have been performed in the conventional radiotherapy literature, and it would make sense for the SBRT literature to follow suit. Furthermore, the reporting of degree of pain relief would further elucidate the usefulness of this therapy.
Large well-designed prospective trials of SBRT with long-term follow-up are warranted. In addition, various tumor pathologies and their respective outcomes need to be evaluated in separate studies. Level 1 evidence can then be used to make specific conclusions regarding SBRT and its clinical utility.