In 1995, spinal radiosurgery was first applied to patients with spinal metastases, who were demonstrated radiographically recurrence or progression after treated with conventional external beam radiotherapy (12). When spinal metastases are presented with symptomatic vertebral compression fracture, mechanical instability, and acute epidural spinal cord compression, surgery is regarded as the first-line treatment (13). For patients not requiring surgery or unbearable to surgery, cEBRT is taken into consideration (low- to intermediate-dose in 1 or more fractions) (14). With imaging and treatment technology developing, SBRT has increasingly established its role in the treatment for spinal metastases. Selecting patients treated with spinal SBRT is of great significance, which can avoid the catastrophic consequences of failure. For carefully selected patients, SBRT could be a standard treatment modality.
There were few patients with radiographic follow-up in our study. Therefore, we cannot evaluate the LC rate of all patients. Of patients with radiographic follow-up, the 1-year LC rate was 92.0%. The result was consistent with several previous analysis (15–19). In addition, 6- and 9-month LC rates were 92.8% and 92.5%, respectively. Another study (20) about a median follow-up of 6 months (range, 3–12 months), 6- and 9-month LC rates were 86% and 86%, respectively. The rates were consistent with our result. The 2-year LC rate ranged from 73%-83.9% (15, 16, 19). In our study, for most patients, there was a lack of long-term radiographic follow-up. Therefore, the 2-year LC rate was not reported. Furthermore, for different treating aims, LC rates were 90% and 88% in patients as a primary treatment modality and treated for radiographic tumor progression (21). With regard to different histologies, LC rate varied from 80% (breast cancer with one local failure at 57 months) to 100% (cervical cancer and hepatobiliary cancer), while no statistically significant difference was found (8). According to above studies, we can think that SBRT could provide durable local tumor control.
Chang et al. (22) reported that LC was observed in 75 of 83 lesions. Of those 8 lesions regarded as local failure, they were hepatocellular carcinoma (5 cases), lung cancer (1 case), breast cancer (1 case) and RCC (1 case). For our study, 8 patients experienced local failure with a 1-month follow-up. Among these, there were breast cancer (1 patient), liver cancer (2 patients), melanoma (2 patients), small cell lung cancer (SCLC) (1 patient), esophagus cancer (1 patient), and uninary tract tumors (1 patient). No significant difference was observed in primary cancer with LC (P = 0.247).
As for 1-month LC, we reported that paraspinal extension (P = 0.046) was the only statistically significant factor. In the study (23), on univariate and multivariate analysis, the presence of epidural mass was also identified as a significant prognostic factor for LC (P = 0.026, 0.002, respectively). The significant prognostic factors correlated with LC rate included colorectal cancer (P < 0.01), spinal metastases from colorectal cancer (P < 0.01), radiation histology (P = 0.02), dosimetric data of delivered maximum dose (P < 0.01) (17). Moreover, an interval between primary diagnosis of cancer and SBRT of ≤ 30 months (P = 0.01; HR = 0.27) and histology of primary disease (NSCLC, RCC, melanoma, other) (P = 0.01; HR = 0.21) (16), a rapidly growing primary tumor (P = 0.047), and poor performance status (P = 0.035) were found to be significant predictors of worse LC (24). Nevertheless, there was no statistically significant difference correlated with LC in our findings. In some degree, it might be due to that there were fewer patients experienced radiographic follow-up and analyzed on the univariate and multivariate analysis eventually.
We also pay attention to the survival outcomes. We reported that the OS rates at 1- and 2-year were 57% and 50%, respectively. These results are consistent with prior reports in the literature. The 1- and 2-year OS rates were 64.9% and 43.7%, respectively (16). The 1-year OS rate was 65.0% (17). The 1- and 2-year OS estimates were 80% and 57%, respectively (19). The 1- and 2-year overall survival rates were 77.2 and 49.4 %, respectively (25). We reported a better overall survival than previous studies. Compared with previous results (8, 16, 17, 25, 26), there were the favorable median and mean survival periods demonstrated in our study, 35.63 and 35.98 months (95% CI, 30.61–41.35 months), respectively. In some degree, it suggested appropriate patient selection via definite inclusion and exclusion criteria.
On univariate analysis, the factors that significantly affected OS were KPS score at consult (P = 0.020) and baseline pain assessed by the BPI (P = 0.038). KPS score was used to evaluate general condition of patients. Obviously, higher KPS score, and better general condition. With better general condition, patients with spinal metastases would accomplish the treatment and gain the survival benefit from SBRT. On multivariate analysis, baseline pain was the significant factor for worse OS (P = 0.031). As is known to us, for bone metastases, including spinal metastases, the most common symptom was pain. Therefore, with regard to patients with baseline pain, optimal analgesia treatment modality was critical before SBRT. Controlling pain well might predict longer overall survival. Another study (16) about the multivariate analysis for overall survival, performance status < 90 (P < 0.001; HR = 0.46) and > 1 vertebra treated with SBRT (P = 0.04; HR = 0.62) were significant predictors for worse OS. Chao et al. (27) reported that there was no statistical difference in histologies with OS (P = 0.54). This was consistent with our result (P = 0.28).
Furthermore, median OS intervals for favorable, radioresistant, and other histologies were 14, 11.2, and 7.3 months (P = 0.02), respectively (27). However, in our study, we didn’t note a significant difference in the radiosensitivity associated with OS (P = 0.54). Through the statistical analysis, there was no significant difference found in histologies with LC and overall survival. It could be predicted that spinal SBRT provides a satisfying LC and overall survival, regardless of histologies.
The most common symptom is pain for patients with spinal metastases. For these patients, SBRT aims to achieve the pain palliation and delay or even prevent the retreatment. In our study, no pain intensity score was applied to evaluate the pain intensity. We just assess the degree of pain relief depending on the subjective feeling. Of these 143 patients with baseline pain, 135 patients were assessable. We reported 76.30% (103/135 patients) of pain relief rate. According to previous studies (15, 17, 22, 28), the range of pain relief rate was 79.5%-92.3%. Among these studies, for rate of 92.3% (15), there were 48 of 51 patients experienced complete pain relief after SBRT, and 3 had partial pain relief. Moreover, in the malignant epidural compression (MEC) and without MEC group, complete pain relief rates were 90% and 93.75%, respectively. However, no statistically significant difference was noted (P = NS) in the study. Thus, the presence of MEC might not show an adverse influence on the outcomes of lesions treated with SBRT. In these patients with MEC, spinal SBRT could be a choice.
In addition, the pain-free rates of mild, moderate and severe pain were 76.8%, 56.3% and 43.8%, respectively (16). After single-dose radiosurgery (10–16 Gy), the median duration of pain relief was 13.3 months (29). The 1-year pain progression-free rate was 61.7% (17). During a follow-up ranging from 3 to 53 months (median, 21 months), long-term pain improvement occurred after SBRT (21). Univariate analysis identified age (P = 0.037) to be a prognostic factor for pain relief. In the multivariate analysis, age retained its significance in terms of pain relief (P = 0.042). Another study reported that there was no factor correlated with improved pain relief (16). Younger age could achieve better pain relief. When selecting patients to be treated with SBRT, age might be taken into consideration.
Of the study with reliable and valid measures of pain intensity, compared with three-dimensional conformal radiation therapy (3DCRT) group, SBRT patients illustrated shorter decreased time (P = 0.01) and lower value (P = 0.002) (30). As a traditional treatment paradigm, conventional external beam radiotherapy played a critical role in treating spinal metastases. With respect to the treatment of cancer pain, it is critical to administrate a drug coordinated with three-step analgesia ladder principle. In most of cases, pain flare was due to localized issue edema, which usually didn’t last so long. In general, it could be controlled by use analgesic. Pain flare was reported in 2 patients, which was successfully controlled by increasing doses of analgesic without interrupting the radiotherapy. Our result was consistent with the study, pain flare controlled well (20).
To our knowledge, there are no uniformly accepted indications in patient selection for spinal SBRT. The above factors might provide instructions in selecting patients. Moreover, the neurologic, oncologic, mechanical, and systemic (NOMS) framework (31) and the location of disease in the spine, mechanical instability, neurology, oncology, and patient fitness, prognosis and response to prior therapy framework (LMNOP) (32) might play an important role in patient selection.
As for the toxicity of patients treated with SBRT, we demonstrated a risk of VCF of 9.41% (19/202), which is consistent with previous spinal SBRT literatures reporting rates ranging from 5–42% (33). As for time to VCF, a multi-institutional study on renal cell carcinoma spinal metastases reported that the median time to VCF was 2.35 months (range, 0.03–43.01 months) (26). The median time to VCF was 2.26 months (range, 0.87–14.39 months) in our study. Therefore, it is necessary to take some protective measures to avoid the occurrence of VCF after SBRT. In the meanwhile, factors associated with VCF should be taken into consideration, before or after SBRT.
With respect to predictors of VCF post-SBRT, baseline fracture (P < 0.001), dose per fraction of ≥ 20 Gy (P = 0.005), and spinal misalignment (P = 0.002) (26), age ≥ 65 years (P = 0.008), ESCC grade 1a and 1b (P = 0.006), dose per fraction (P = 0.05), tumor progression (P = 0.045), and a Spinal Instability Neoplastic Score (SINS) of ≥ 7 (P < 0.001) (25) were confirmed as significant predictors. Prior conventional radiation was found to be significant and protective (P = 0.029) (26) and the primary tumor site of the breast (P < 0.001) (34) were found to be significant and protective of VCF. We identified time to spinal metastases as the only significant predictor for VCF (P = 0.049). A study about (25) predicting vertebral body compression following spinal SRS, 32 of 79 patients developed VCF, 20 (62.5%) of de novo fractures and 12 (37.5%) of progression. On univariate and multivariate analysis, 2-year fracture-free rates were 78.7% and 33.7% between low and high SINS group.
The most common toxicity for spinal metastases treated with SBRT was the occurrence of vertebral compression fracture. For patients, VCF would have an influence on the quality of life, such as intolerable bone pain. Hence, fracture prevention is of great importance. Up to date, to our knowledge, there was no case of radiculopathy or myelopathy during the follow-up.