Introduction
Stereotactic body radiotherapy (SBRT) for spinal metastasis is performed under strict fixation and image guidance. This technique is also combined with intensity-modulated radiotherapy to reduce the dose received by the spinal cord while irradiating tumors with a high radiation dose [1, 2]. Randomized controlled trials (RCTs) for painful spinal metastases have reported about the superiority of SBRT over conventional irradiation [3–7]. Thus, SBRT is expected to become the standard treatment for painful spinal metastases in the future [8, 9].
Conventionally, the spinal canal is the organ at risk (OAR) during the delivery of SBRT, and radiation plans are therefore designed to minimize the dose delivered to this region. At the lumbar spine level, the cauda equina is the nerve in the spinal canal [6, 7, 10–12]. The cauda equina bundle location on the dorsal side of the spinal canal can be recognized easily using the T2-weighted magnetic resonance imaging (MRI) and computed tomographic (CT) myelography [13–20]. The cauda equina nerve is located on the dorsal side of the spinal canal, even when an image is taken in the prone position. The nerve roots on both sides are also present in the same position.
The range of movement of the cauda equina nerve in the spinal canal is within 1 mm during the interaction and intrafraction of treatment. Therefore, for tumors that are in contact with the spinal canal, if only the cauda equina nerve is recognized as the OAR, it is expected that the treatment plan will change compared to cases in which the conventional spinal canal is used as the OAR. In this study, we investigated how the tumor coverage increased when only the cauda equina nerve was used as the OAR compared to when the entire spinal canal was used.
Materials and methods
Patients
A medical physicist created a simulation plan for 10 patients with isolated lumbar metastasis. The simulation test was not reported on the hospital’s website, and individual patient consent was not obtained because the test used archived images from patients’ medical records.
Data from five men and five women were included; their average age of was 77.9 years. Prostate (four patients), lung (three patients), breast (two patients), and rectal (one patient) cancer were the primary lesions. The targeted vertebral bones were L1 (two cases), L2 (two cases), L3 (three cases), and L5 (three cases). The lesions were at one (three cases), two (two cases), three (four cases), and six sites (one case) [6], according to the classification by Cox et al. (Fig. 1A).
The positional relationship between the spinal cord (the cauda equina in the lumbar vertebra) and tumor following the Epidural Spinal Cord Compression (ESCC) scale was 0 (three cases), 1a (two cases), 1b (two cases), 1c (two cases), and 3 (one case; Figure 1B) [21]. Compression fracture cases were not included.
Radiotherapy setting
A radiation oncologist contoured the gross target volume (GTV), added a 1-mm margin, and used it as the clinical target volume (CTV). The part between the CTV and cauda equina that overlapped was cut off. The planning target volume (PTV) was set in the same range as the CTV.
The entire spinal canal, cauda equina with bilateral nerve roots, or cauda equina alone were contoured. The cauda equina is smaller than the spinal canal and is located on the dorsal side, which is distant from the vertebral body (Fig. 1C).
The treatment plan used a 6 MV without a flattering filter-free X-ray beam, the volumetric modulated arc therapy technique, and Monte Carlo dose-to-medium calculations. Moreover, we used a clinical method with high PTV coverage.
For tumors, GTV was obtained via the fusion of MRI and CT. CTV had a 1-mm margin from GTV, and PTV had a 0-mm margin from CTV. OAR (+1 mm) had a margin of 1 mm from the OAR. For sites where the tumor GTV overlaps the OAR (+1 mm), the OAR was set at a 0 -mm margin so that the tumor GTV could achieve D95. Thus, the tumor GTV and OAR were in contact.
In our simulation study, the internal margin (ITV) was not considered. Because we were targeting only the lumbar spine, we believed that the effects of, for example, respiratory movements would be small. Alignment was performed using cone-beam CT. However, in clinical practice, ITV may be necessary for areas that, for example, may be affected by respiration (e.g., thoracic spine).
A medical physicist devised a radiation treatment plan, which was later approved by a radiation oncologist, with the PTV and OAR set up in this way. The prescribed dose was 30 Gy/3 fx. The constrained doses for the OAR are presented in Table 1 [22]. We examined the degree to which the PTV coverage rate diverged between the spinal canal set as the OAR versus the cauda equina only. Tumor location and coverage rate were also calculated.
|
Organs at risk |
|
Optimal [Gy] |
Mandatory [Gy] |
|
Spinal canal* (including medulla) |
Dmax (0.1 cc) |
< 20 |
< 20 |
|
D1 cc |
< 12 |
– |
|
|
Cauda equina |
Dmax (0.1 cc) |
– |
< 20 |
|
D5 cc |
– |
< 20 |
|
|
Nerve root(s) |
Dmax (0.1 cc) |
– |
< 20 |
Statistical analyses
D80, D90, and D95 were calculated as the dose covering 80%, 90%, and 95% of the PTV volume, respectively. V80, V90, and V100 are the percentages of volume of the PTV and CTV that receive 80%, 90%, and 100% of the prescribed dose, respectively. Dmean (the mean dose received by the organ) and Dmax (the maximum dose received by the organ) were calculated within the PTV. The Dmax, Dmin (minimum dose), Dmean (the volume of the organ receiving that dose), and other relevant dose–volume data were calculated for each OAR. The correlation between the PTV and Dmax was presented as scatter plots and tested with Pearson’s correlation coefficient. A p-value of <0.05 was judged to be statistically significant (BellCurve for Excel Social Survey Research Information Co. Ltd., Tokyo, Japan).
Results
Planning target volume coverage
Setting the cauda equina only resulted in better coverage than the other OAR settings (Fig. 2) for D95, D90, and D80. The difference was not significant for the D80 setting (canal, cauda equina with nerve roots, and cauda equina were 28.8, 31.0, and 32.1 Gy, respectively). However, at D90 (canal, cauda equina with nerve roots, and cauda equina were 25.2, 28.6, and 31.0 Gy, respectively) and D95 (canal, cauda equina with nerve roots, and cauda equina were 22.2, 26.9, and 29.3 Gy, respectively), the differences in OAR contouring settings were statistically significant.
The space between the cauda equina and vertebral body improved PTV coverage when the tumor was located within the vertebral body. Conversely, the coverage was poor due to the tumor proximity to the cauda equina when the tumor was located in the vertebral arch (Fig. 1C).
Comparison between the spinal canal and cauda equina only
The ASTRO guidelines state that the radiation limit of the cauda equina is ≤ 20 Gy [12]. When the Dmax of the cauda equina was set to ≤ 20 Gy, dose hotspots were observed in the medullary area as the spinal canal Dmax increased. Figure 3 shows that when the Dmax of the spinal canal was limited to 20 Gy, the PTV D95 decreased inversely (correlation coefficient [R = −0.8517]) with the decrease in the Dmax of the OAR. If the Dmax was set to ≤ 20 Gy for the cauda equina and spinal canal, the Dmax and PTV coverage were negatively correlated (correlation coefficient [R = −0.6627]).
Part of the spinal fluid also becomes the OAR when the spinal canal is considered the OAR. Thus, the PTV coverage rate was poor if the tumor was in contact with the spinal canal. However, the PTV rate increased if the cauda equina alone was considered the OAR.
Discussion
Stereotactic body radiotherapy efficacy
Spinal SBRT is not a simple treatment and can lead to serious adverse events if performed poorly [1–5]. Additionally, spinal SBRT requires more effort for treatment planning and irradiation than normal irradiation. Having an appropriately trained staff to perform accurate SBRT for patients with painful spinal metastases is also important [13–17].
Several RCTs have suggested that local therapy for oligometastasis may prolong survival [1, 2]. Additional RCTs are currently under way. While treatment can be surgical or radiation based, safely performed SBRT [8, 9] and radiation therapy may be more common in local therapy for oligometastasis in the future because surgery is highly invasive, especially for spinal metastases. Reports of SBRT are also increasing, with good results [12, 20]. However, although trial endpoints can vary, in general, the range of local control is 80−96% at 1 year. These results suggest a superior outcome for local control when compared with conventional external beam radiation therapy (EBRT), with reported control rates ranging from 61% to 86% at 1 year [23−25].
Rades et al. has evaluated patients with metastatic spinal cord compression to compare the results of short- and long-course radiotherapy. In their results, the progression-free survival (PFS) rate at 12 months was 72% after the long course and 55% after the short course (p = 0.034). Long-course EBRT significantly improved PFS [24].
For pain management, multiple systematic reviews have shown that the overall pain response rate for conventional EBRT is ~60%, with corresponding complete response rates ranging from 0% to 24% [25–28]. However, other SBRT literature has reported high complete response rates, ranging from 46% to 92% [29–32, 20].
In a Phase II/III Radiation Therapy Oncology Group (RTOG) study, patients with up to three separate spinal cord metastases were randomized to SBRT with conventional EBRT at 8 Gy in one fraction and single fractions at 16 or 18 Gy [33]. The feasibility of successfully delivering image-guided SBRT in this trial setting has been reported [34]. The primary objective of the Phase III component of the trial was to assess the pain response rate, as measured by the 11-point Numerical Pain Scale 3 months after the start of the trial. More recently, a multicenter Phase II RCT of conventional EBRT in 5 fractions versus 20 Gy in 2 fractions versus SBRT in doses of 24 Gy has been reported [34]. The study results may provide better quality outcome data for spinal SBRT in de novo metastasis. At 3 months, 40 of 114 (35%) patients in the SBRT group and 16 of 115 (14%) patients in the EBRT group had a complete pain response (risk ratio, 1.33; 95% confidence interval, 1.14–1.55; p = 0 0002) [33].
RCTs have reported that SBRT had a better pain-relieving effect than normal irradiation for spinal metastases [35]. Sahgal et al. also reported a better outcome for SBRT (24 Gy/2 fx) over normal irradiation (20 Gy/5 fx) for painful spinal metastasis treatment [22]. However, in the RTOG 0631 study, SBRT (16–18 Gy as a single dose) was not superior to normal irradiation (8 Gy as a single dose) in painful spinal metastases [20]. The dose of radiation varies depending on the facility. Schipani et al. [36] prescribed 18 Gy/1 fx and found a 92% local control rate, whereas Yamada et al. [37] prescribed 18–24 Gy/1 fx and found a 90% local control rate. According to Chang et al. [38], irradiation at 30 Gy/5 fx and 27 Gy/3 fx reduced pain from 60% to 36%. Wang et al. [39] reported a 2-yr progressive free survival rate of 72.4% after 27–30 Gy/3 fx irradiation. Amdur et al. [40] discovered 95% local control at 15 Gy/1 fx in a Phase 2 study. We simulated at 30 Gy/3 fx, but planning for 1 fx and 5 fx would be interesting. Therefore, spinal SBRT usefulness remains controversial, even in multicenter studies. However, one meta-analysis has shown that SBRT may be more effective, suggesting that it could be applied more widely to treat vertebral body metastasis in the future.
The standard treatment for spinal metastases is decompression surgery to remove as much of the tumor as possible, followed by postoperative normal irradiation at 30 Gy for 10 fractions. However, evidence of SBRT’s effectiveness has accumulated, and surgery has improved to a minimally invasive spinal cord separation followed by radical SBRT [1–5]. Spinal cord separation creates a space between the spinal cord and tumor, and curettage is a minimally invasive method [5,41]. The dose to the spinal cord and cauda equina nerve can be reduced even if the tumor is in contact with the spinal canal if this space can be provided.
Contouring
The cauda equina and intrathecal spinal nerve roots distal to the natural taper of the true meningeal sac are at risk of radiation injury when performing SBRT. The cauda equina is the major dose-limiting organ because injury can lead to paralysis and loss of bladder and bowel function. Because it is not usually possible to precisely delineate individual nerve roots, the thecal sac (TS) has been used as a surrogate contour. Several challenges exist with this approach, and overestimating the TS contour can limit dose exposure to adjacent diseased tissue [42–44].
Not all facilities can perform surgery; therefore, it is necessary to offer high-precision radiotherapy to improve patient outcomes without surgery while minimizing radiation-caused neuritis. TS contouring differs among radiation oncologists [8]. No significant difference was found between the spinal canal and cauda equina for PTV D80 (29 Gy vs. 32 Gy, respectively). Alternatively, for PTV D95, a significant difference was observed between the spinal canal and cauda equina (22 and 29 Gy, respectively). Improving the coverage of the PTV increases the Dmax of the OAR. The longer the distance between PTV and OAR, the better the PTV coverage and lower the OAR dose. If PTV and OAR are in contact, the coverage of PTV will be lowered because the OAR dose is limited.
Unless the dose actually delivered to the PTV covers 95% of that as prescribed, tumor control is impossible. Thus, if the spinal canal is restricted, the coverage of the PTV is reduced considerably. High coverage of PTV D95 is important for effective tumor control.
Recent studies on oligometastasis have shown that it is highly possible that cancer can be cured by radical treatment for bone metastasis [1, 2]. The spinal canal at the lumbar level contains the dural matter and spinal fluid in addition to the cauda equina. The spinal fluid is a liquid and not an OAR. Therefore, only the cauda equina should be the OAR. The cauda equina is located on the dorsal side in the supine and prone positions and exits from the spinal cavity as a nerve root. Using only the cauda equina can increase the coverage rate, which was ~17% better than that of the spinal cord. A 17% lower coverage rate can lead to a lower local control rate, which is insufficient to destroy tumors. Thus, OAR contouring should be considered for the cauda equina because tumors recur if they are not removed.
In clinical practice, finding a tolerable dose for using the spinal cord as the OAR can be a problem, but the dose is meaningless if the tumor cannot be controlled by protecting the OAR. For individual patients, physicians can choose a treatment with a level of radiation injury of < 5% or can allow the cauda equina to be the primary constraint of the OAR and allow a 50% chance of injury to it. Sometimes, the tumor and OAR are connected. To prevent the onset of myelitis, PTV overlaps with OAR (cauda equina), so PTV’s D95 coverage is reduced whereas OAR is prioritized. In this case, it is imperative to inform the patient that tumor compression of the spinal cord is likely because the tumor is likely to be out of control. The recommendations of ICRU62 [45] should be followed in delineating the target volume, with an additional volume, here referred to as PTV_prescribe, recommended to account for the spinal cord’s proximity. If cauda equina is present, surgery should also be considered. In our study, we observed ~17% coverage difference between the spinal cord and cauda equina for PTV D95. This difference is related to the local control rate, and future studies are needed to determine the degree of spinal cord injury. For the optimal dose fractionation schedule, spinal SBRT has been delivered via schedules ranging from a single fraction (8–24 Gy) to hypofractionated regimes, such as 30 Gy (5 fx), 24–27 Gy (2−3 fx), and 35 Gy (5 fx). However, no definite evidence to recommend one regime over another currently exists [1, 2, 4, 7].
Previously, interobserver variability in contouring the lower lumbar spine and TS has suggested a unified consensus [8]. However, no studies have examined the benefits of subdividing the OAR. In our study, using the cauda equina alone as the OAR improved PTV coverage by 17%. Thus, if PTV coverage is reduced by reducing the dose to the OAR, tumor control is also reduced. Therefore, we believe that a comparative study targeting patient safety will be necessary in the future.
Conclusions
This study design is based on a simulation that spinal fluid can withstand a dose of 30 Gy/3 fx (BED10 = 60 Gy, BED3 = 130 Gy). Spinal fluid is a circulating fluid, and no previous study has reported that a restricted dose should be used for it. Additionally, spinal fluid may be able to withstand a 30 Gy/3 fx dose as currently there are no reports of brain fluid being ruptured by brain stereotactic radiosurgery.
There is almost only cerebrospinal fluid in the spinal canal in the area where the cauda equina is present. If the entire spinal cord is set as the OAR, the vertebral body (PTV) covered by 95% of the prescribed dose cannot be achieved. An increasing number of studies have reported that SBRT can be used to rescue patients with oligometastasis. Although our study was only a simulation examination, when considering tumor control, setting only the cauda equina as the OAR is realistic because the rescue rate is higher, especially when a tumor has invaded the bone margin. Cauda equina should be given top priority as an OAR. The spinal canal is a range that includes spinal fluid and has little clinical significance.
Conflicts of interest
The authors declare that they have no competing interests.
Funding
This publication was prepared without any external source of funding.
Ethical permission
Ethical approval was not necessary for the preparation of this article.