Our study shows that focused radiotherapy may be associated with improved fusion rates following resection and instrumentation in patients with spinal tumors when compared to conventional radiotherapy delivery modalities. Two prior studies attempted to answer this question, however they were both inadequately powered, highlighting the difficulty of answering this question for patients with spinal tumors such as metastasis, as these patients historically do not survive long enough to collect meaningful fusion data. [23][24] Improved survival outcomes due to recent advances in targeted therapies have allowed assessment of fusion status to be a feasible outcome. Our study also reveals that intraoperative use of autograft is associated with higher 12-month fusion rates for spinal tumor patients who receive peri-operative radiotherapy in conjunction with resection and instrumentation.
The theoretical benefit of focused radiotherapy lies in the delivering a higher treatment dose to a more precise location to maximize treatment effect at the surgical bed while limiting toxicity to the spinal cord, abdominal viscera, surrounding bone, and instrumentation hardware. [25][26] Our study found a significantly higher rate of fusion for patients with focused radiotherapy at 6-months (64.0% versus 30.0%, OR: 4.15, p=0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p=0.022) compared to those who received radiation via a conventional delivery modality, indicating that the decreased radiation spillover into the surrounding bone is beneficial for fusion. A potential confounder was local spread of tumor into the fusion bed, as there was a near significant difference in the incidence of local recurrence at the time of fusion assessment (8.3 versus 35%, p=0.057). While local recurrence was not an endpoint of this study, this appears to be an additional benefit of focused radiotherapy over conventional. While this may possibly play a small role in fusion, review of the imaging showed most cases of tumor progression to be ventral to the posterior elements, where fusion was assessed. Other factors such as the number of levels fused and chest wall resection have been found to play a role in hardware failure, but our study was well match with groups having similar numbers of levels fused. [27] A higher dose of radiation should theoretically have a more pronounced deleterious effect on bone growth and therefore a higher risk of non-union. A previous study indicated that more than 40Gy delivered to the surgical bed of an anterior reconstruction appeared to increase the risk of pseudoarthrosis. [28] We compared patients with a higher radiobiological dose of radiotherapy to those with a lower radiobiological dose, but there was no significant difference in fusion among the groups (p=0.160). We found a higher incidence of clinically significant pseudoarthrosis in patients who received conventional radiotherapy when compared to those with conventional radiotherapy (19.1% versus 0%, p=0.037). Although only one patient required re-operation, there is significant pain, disability, and loss of work associated with post-operative pseudoarthrosis. [29, 30]
Expert opinion recommends at least one week between surgery and radiation to minimize the risk of wound healing complications, but there was insufficient literature to make recommendations for the timing of surgery as it relates to fusion. [12] Our study revealed no significant difference in the rate of fusion for those treated with radiotherapy within 1-month of surgery and those treated more than 1-month from their surgery at 6-months (≤ 1 month: 42.9%, > 1 month: 48.4%, OR: 0.80, p=0.781) and 12-months (≤ 1 month: 64.5%, > 1 month: 42.9%, OR: 2.42, p=0.160). Interestingly, the fusion rate at 6-months was nearly identical for the group treated within 1-month, but the fusion rate at 12-months was slightly higher for the patients treated within 1-month of surgery. This indicates that receiving radiotherapy within 1-month of surgery does not appear to have a deleterious effect on fusion rates. Some studies have found no significant benefit of protons over photons for tumor control when the treatment dose is identical. [31] However, protons allow for delivery of a higher dose of radiation with a more rapid drop-off at the treatment field margins, causing less damage to unintended surrounding structures and therefore improved outcomes. [32],[33] Our study did not note any difference in fusion outcomes for patients treated with photons compared to those treated with protons.
There is a wide array of bone graft products, with varying osteo-inductive, osteo-conductive, and osteo-genic properties which may help increase the likelihood for achieving a solid fusion. However, there is a contraindication for use of products like rhBMP in cancer patients because of a possible association between rhBMP and cancer, effectively eliminating its use in spine tumor patients. [34][35][36] Inability to use these types of products compounded with the use of peri-operative radiation explains the difficulty with obtaining a bony fusion in this patient population. Our study found a higher 12-month fusion rate when autografts such as iliac crest and femoral bone grafts were used compared to patients who received allograft and synthetic bone products (66.7% versus 37.5%, OR: 3.33, p=0.043). This finding appears to be consistent with the available evidence for non-neoplastic cases, as some studies found a better fusion rate when using autograft compared to synthetic allograft bone. [37–39][40][41]
Limitations
The question of fusion outcomes after spinal tumor resection and radiotherapy has historically been challenging to answer due to many inherent limitations of this patient population. Secondary tumors of the spinal column are the most common, and these patients often succumb to their systemic disease burden within a year of surgery. This limited the available data, as most of the patients who received radiation after resection of their spinal tumors died prior to the typical time frame one would expect to see fusion. This limited the ability to assess long term fusion, which would be most ideal. Our study started with over 1,200 potential patients, but after exclusion, there were 60 patients remaining. Another limitation of this study was our inability to factor in how much of the area of intended arthrodesis was included in the radiation treatment field. For multi-level posterior constructs, most of the instrumentation field will likely be out of the treatment field, but we were unable to account for this. We would ideally use CT imaging to assess fusion in all patients, but only x-ray imaging was available for 12% (n=7) of patients. There was also a fair amount of heterogeneity for the patients included. Patients with resection of a primary bone tumor such as chordoma may have a large bony gap making fusion much more challenging. Many of the chordoma patients received proton radiotherapy, and therefore were not included in the primary analysis. Also, there was no difference between the groups for the incidence of primary tumors (p=>0.999). Despite these limitations, this appears to be the best available data to support one method of peri-operative radiotherapy over another. A strength of this study is the external validity, being comprised of patients from tertiary care institutions in three different geographical regions of the United States.