Local response and pathologic fractures following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy for spinal metastases - a randomized controlled trial

Up to 40% of patients with advanced-stage cancer develop osseous spinal metastases [1]. The associated pain, immobility, pathological fractures, and neurological deficits may considerably reduce quality of life. Conventionally fractionated three-dimensional conformal radiotherapy (3DCRT) is the treatment of choice for painful osseous metastases [2, 3]. However, spinal stereotactic body radiotherapy (SBRT) is a promising alternative owing to the ability to deliver high, ablative doses for durable local control while protecting adjacent organs-at-risk (OARs) [4‐10].

Spinal SBRT has heretofore been primarily utilized for oligometastatic osseous disease and for re-irradiation of osseous metastases [11]. Prospective trials using SBRT for bone metastases have reported excellent tumor control, appropriate pain response, and low toxicity rates [12, 13].

However, there are known serious adverse events associated with spinal SBRT, such as vertebral compression fractures (VCFs) [14]. Hence, changes in bone density following ablative procedures such as SBRT are important to characterize. No randomized trials comparing bone density changes with SBRT versus conventional 3DCRT exist to date. This was a prespecified secondary analysis of a randomized trial, which evaluated bone density following SBRT versus conventional 3DCRT as part of palliative management of painful spinal metastases.

Baseline characteristics were balanced between the two treatment arms (Table 1, as previously published [17]).

Although all surviving patients completed all assessments, not all patients survived at the three and 6 month time periods. Within the first 3 months, 4 patients (14.8%) in the SBRT group had died, along with 5 patients (17.9%) in the 3DCRT arm. Between 3 and 6 months, another 4 patients (14.8%) died due to tumor progression in the SBRT cohort, along with a further 3 patients (10.7%) in the 3DCRT arm (Fig. 1). Mortality did not differ between groups. One participant in the intervention arm did not receive a CT examination at 6 months after RT. The mean follow-up was 8.1 months (95% CI 6.87–8.97) for both groups.

As compared to baseline, bone density became significantly higher at 3 and 6 months following SBRT by a median percentage of 33.8% (IQR 12.0–69.6) and 72.1% (IQR 15.2–95.7) (p < 0.01 for both), respectively (Table 2). These figures in the 3DCRT cohort were 32.9% (IQR 5.3–48.1) and 41.2% (18.9–55.0) (p < 0.01 for both), respectively. There were no statistical differences in bone density between SBRT and 3DCRT at 3 (p = 0.629) or 6 months (p = 0.327).

Subgroup evaluation of solely osteolytic lesions in the SBRT arm at 3 and 6 months confirmed a significant improvement in bone density as compared to baseline (p = 0.031 for both), corresponding to 53.9% (IQR 33.8–86.7) and 85.8% (IQR 59.9–95.7), respectively. In contrast, there were no differences between these values in the 3DCRT group (p = 0.125 and p = 0.250, respectively). There were no differences between bone density changes in the SBRT and 3DCRT groups at 3 (p = 0.594) or 6 (p = 0.519) months (Table 2).

Bone density in unaffected vertebrae did not show substantial changes within groups at 3 and 6 months following RT (SBRT: p = 0.334 and p = 0.932, 3DCRT: p = 0.956 and p = 0.616). There were also no significant differences between the SBRT and 3DCRT arms at 3 (p = 0.410) or 6 months (p = 0.661).

Preexisting pathological fractures existed in 40.7% patients in the SBRT arm vs. 17.9% in the 3DCRT group (p = 0.062) (Table 3). By 3 and 6 months, these numbers rose to 47.8% vs. 21.7% (p = 0.063) and 61.1% vs. 30.0% (p = 0.054), respectively. The incidence of new pathological fractures at 3 months was 8.7% (n = 2) in the SBRT arm vs. 4.3% (n = 1) in the 3DCRT arm. In the SBRT group, new pathological fractures at 6 months after SBRT were detected in 5 patients, (27.8%), of which 2 (40%) fractures were de novo and 3 (60%) were a progression of preexisting VCFs. These new pathological fractures initially occurred in osteolytic metastases and only in mixed metastases after 6 months (Table 3). Only 1 (5%) new pathological fracture was identified at 6 months after 3DCRT. No pathological fractures in either group required salvage surgical intervention.

This prespecified secondary evaluation of a prospective randomized trial is the first to investigate the impact of high-dose single-fraction SBRT on bone density as compared to 3DCRT. Despite the high ablative doses in the SBRT arm, the significant increase in bone density after 3 and 6 months was similar to that of 3DCRT. There was a trend towards higher baseline pathologic fractures in the SBRT cohort. Additionally a moderate rate of new fractures occurred in SBRT cohort. These findings suggest the safety of spinal SBRT from a novel perspective heretofore unaddressed in the literature.

In general, rim sclerosis, “filling in”, and an increase in bone density is regarded as a radiological response for osseous lesions [18, 19]. Particularly in the case of stability-reducing osteolysis, recalcification and structural remodelling of the bone is essential.

The subgroup analysis of osteolytic lesions in our study at 3 and 6 months after SBRT revealed a significant improvement in bone density, but without a significant difference in comparison to the 3DCRT group. Wachenfeld et al. reported an increase in CT density in osteolytic metastases to approximately 150% of the initial value at 3 months after multi-fraction irradiation [18]. Koswig and Budach showed improvement of bone density in osteolytic metastases by 173% at 6 months after multi-fraction irradiation [19]. In this trial, similar results regarding bone density were achieved. The bone density of osteolytic spinal lesions at 3 months after SBRT and 3DCRT increased by 53.9% and 46.9%, respectively. It is unclear why SBRT outperformed 3DCRT within in osteolytic lesions, but could be related to short-course dosing.

However, potential imbalances in anti-osteoresoptive therapies are unlikely, as densities of unaffected vertebrae yielded no differences between groups. Rief et al. investigated the impact of resistance training concomitantly with conventional multi-fraction 3DCRT on bone density in a randomized controlled study and found no significant differences in the uninvolved spine [20]. Therefore, it has been suggested that bisphosphonates may not exert decisive effects in this setting.

The preexisting pathological fracture rate in our study was 29%. Similar rates of preexisting VCFs (24%) were detected in a large retrospective study of 594 treated spinal tumors by Jaward et al. [21]. VCF rates in relevant studies varies between 7 and 39% [22‐26]. The retrospective analysis by Virk and colleagues of 323 spinal lesions treated with single-fraction SBRT (24 Gy) demonstrated a cumulative incidence of symptomatic VCF in the irradiated level of 7.2% [22]. The cumulative incidence of VCF at 3 and 6 months after SBRT was 0.3% and 1.9%, respectively. In our trial, the incidence of new pathological fractures at 3 and 6 months following SBRT was higher by 8.7% (n = 2) and 27.8% (n = 5) respectively. All fractured vertebral bodies in the SBRT group were initially classified as potentially at risk according to the SINS score [27], which confirms that the SINS score is a useful instrument in predicting SBRT induced pathological fractures. Rose et al. reported substantially higher rates of fracture progression after single-fraction SBRT (18–24 Gy) by 39% [23]. Another study detected VCF in 20% of 123 treated spinal segments with a median of 3 months up to the occurrence of VCF [24]. Cunha et al. documented only 11% (n = 19) of VCFs after SBRT [25], whereas another publication observed 18% (n = 34) of 187 osteolytic spinal metastasis with median follow up of 8 months [26]. Notably the highest VCF rate 43% (n = 10) occurred after SBRT (24 Gy in 1 fraction).

Symptomatic painful VCF following RT often requires spinal stabilizing intervention. Minimally invasive methods such as kyphoplasty and vertebroplasty are very effective for these purposes [28‐31]. Boehling et al. found that preexisting fractures led to earlier fracture progression, with a median progression-free survival time from initial fracture of 14 months, as compared with 25 months without preexisting fractures [24]. In contrast, Sahgal et al. reported the median time to VCF of 2.5 months (range 0.03–43.01 months), with the majority (65%) occurring within the first 4 months following SBRT [32]. Half of those patients underwent salvage surgery [32]. These findings may similarly justify early prophylactic augmentation after SBRT to avoid the sequelae mentioned above [24]. Gerszten et al. showed that fixation procedure is safe and effective even before single-fraction SBRT in patients with preexisting pathological fractures [29]. Initial apparent improvement in pain after kyphoplasty and prior SBRT was reported in 96%, and long-term improvement in spinal pain occurred in 92%. Performing SBRT subsequently may thus allow for immediate stabilization of the fracture and delivery of ablative doses for local tumor control [29].

Another approach involving simultaneous kyphoplasty and intraoperative radiotherapy is safe as well; Bludau et al. observed immediate and sustained pain relief with excellent local control (reduction of ≥3 points on the first postoperative day) [33].

However, although kyphoplasty may alleviate pain from pathological fractures, it may still fail. This may especially be true for delayed kyphoplasty failure, from which retropulsed cement and neural compression are serious complications requiring more extensive operations. Rajah et al. observed delayed kyphoplasty failure in 5%, of which 2 (50%) patients received radiotherapy [34]. The mean time to kyphoplasty failure was 2.9 ± 1.2 months [34]. Rajah et al. also identified possible predictors such as wall integrity, competency of the posterior tension band, and junctional spinal level [34].

However, the use of kyphoplasty is anatomically limited to vertebral bodies; SBRT continues to be a reliable alternative for metastases in posterolateral structures. Nevertheless, both kyphoplasty and SBRT are intended to help relieve pain and thereby improve quality of life. The optimal timing (pre−/intra−/post) of prophylactic surgical intervention with SBRT for carefully selected vulnerable patients remains difficult to ascertain.

Although strengths of our investigation include the randomized design and standardized evaluation of bone density and recording of all pathological structures, several limitations must be acknowledged. In addition to a lower sample size and shorter follow-up, robust conclusions based on statistical comparisons cannot be made, along with the concession that pathologic fractures can indeed occur after 6 months. Additionally, few studies can entirely account for other factors influencing bone density such as diet, vitamin supplementation, or particular medications. There may also be heterogeneity in these patients given the specific location of vertebral metastases (e.g. laminar/pedicle lesions versus those in the vertebral body) as well as degree of soft tissue extension. Although these may limit applicability to other studies, larger randomized data are recommended to corroborate these results.

This prespecified secondary evaluation of a prospective randomized trial is the first to investigate the impact of high-dose single-fraction SBRT on bone density as compared to 3DCRT. Despite the high ablative doses in the SBRT arm, the significant increase in bone density after 3 and 6 months was similar to that of 3DCRT. There was a trend towards higher baseline pathologic fractures in the SBRT cohort. Additionally a moderate rate of new fractures occurred in SBRT cohort. These findings suggest the safety of spinal SBRT from a novel perspective heretofore unaddressed in the literature. Future randomized investigations with larger sample sizes are recommended.