Jacob A. Miller, Ehsan H. Balagamwala, Camille A. Berriochoa, Lilyana Angelov, John H. Suh, Edward C. Benzel, Alireza M. Mohammadi, Todd Emch, Anthony Magnelli, Andrew Godley, Peng Qi and Samuel T. Chao
Spine stereotactic radiosurgery (SRS) is a safe and effective treatment for spinal metastases. However, it is unknown whether this highly conformal radiation technique is suitable at instrumented sites given the potential for microscopic disease seeding. The authors hypothesized that spinal decompression with instrumentation is not associated with increased local failure (LF) following SRS.
A 2:1 propensity-matched retrospective cohort study of patients undergoing SRS for spinal metastasis was conducted. Patients with less than 1 month of radiographic follow-up were excluded. Each SRS treatment with spinal decompression and instrumentation was propensity matched to 2 controls without decompression or instrumentation on the basis of demographic, disease-related, dosimetric, and treatment-site characteristics. Standardized differences were used to assess for balance between matched cohorts.
The primary outcome was the 12-month cumulative incidence of LF, with death as a competing risk. Lesions demonstrating any in-field progression were considered LFs. Secondary outcomes of interest were post-SRS pain flare, vertebral compression fracture, instrumentation failure, and any Grade ≥ 3 toxicity. Cumulative incidences analysis was used to estimate LF in each cohort, which were compared via Gray’s test. Multivariate competing-risks regression was then used to adjust for prespecified covariates.
Of 650 candidates for the control group, 166 were propensity matched to 83 patients with instrumentation. Baseline characteristics were well balanced. The median prescription dose was 16 Gy in each cohort. The 12-month cumulative incidence of LF was not statistically significantly different between cohorts (22.8% [instrumentation] vs 15.8% [control], p = 0.25). After adjusting for the prespecified covariates in a multivariate competing-risks model, decompression with instrumentation did not contribute to a greater risk of LF (HR 1.21, 95% CI 0.74–1.98, p = 0.45). The incidences of post-SRS pain flare (11% vs 14%, p = 0.55), vertebral compression fracture (12% vs 22%, p = 0.04), and Grade ≥ 3 toxicity (1% vs 1%, p = 1.00) were not increased at instrumented sites. No instrumentation failures were observed.
In this propensity-matched analysis, LF and toxicity were similar among cohorts, suggesting that decompression with instrumentation does not significantly impact the efficacy or safety of spine SRS. Accordingly, spinal instrumentation may not be a contraindication to SRS. Future studies comparing SRS to conventional radiotherapy at instrumented sites in matched populations are warranted.
Jacob A. Miller, Ehsan H. Balagamwala, Samuel T. Chao, Todd Emch, John H. Suh, Toufik Djemil and Lilyana Angelov
The objective of this study was to define symptomatic and radiographic outcomes following spine stereotactic radiosurgery (SRS) for the treatment of multiple myeloma.
All patients with pathological diagnoses of myeloma undergoing spine SRS at a single institution were included. Patients with less than 1 month of follow-up were excluded. The primary outcome measure was the cumulative incidence of pain relief after spine SRS, while secondary outcomes included the cumulative incidences of radiographic failure and vertebral fracture. Pain scores before and after treatment were prospectively collected using the Brief Pain Inventory (BPI), a validated questionnaire used to assess severity and impact of pain upon daily functions.
Fifty-six treatments (in 38 patients) were eligible for inclusion. Epidural disease was present in nearly all treatment sites (77%). Moreover, preexisting vertebral fracture (63%), thecal sac compression (55%), and neural foraminal involvement (48%) were common. Many treatment sites had undergone prior local therapy, including external beam radiation therapy (EBRT; 30%), surgery (23%), and kyphoplasty (21%). At the time of consultation for SRS, the worst, current, and average BPI pain scores at these treatment sites were 6, 4, and 4, respectively. The median prescription dose was 16 Gy in a single fraction. The median clinical follow-up duration after SRS was 26 months. The 6- and 12-month cumulative incidences of radiographic failure were 6% and 9%, respectively. Among painful treatment sites, 41% achieved pain relief adjusted for narcotic usage, with a median time to relief of 1.6 months. The 6- and 12-month cumulative incidences of adjusted pain progression were 13% and 15%, respectively. After SRS, 1-month and 3-month worst, current, and average BPI scores all significantly decreased (p < 0.01). Vertebral fracture occurred following 12 treatments (21%), with an 18% cumulative incidence of fracture at 6 and 12 months. Two patients (4%) developed pain flare following spine SRS.
This study reports the largest series of myeloma lesions treated with spine SRS. A rapid and durable symptomatic response was observed, with a median time to pain relief of 1.6 months. This response was durable among 85% of patients at 12 months following treatment, with 91% local control. The efficacy and minimal toxicity of spine SRS is likely related to the delivery of ablative and conformal radiation doses to the target. SRS should be considered with doses of 14–16 Gy in a single fraction for patients with multiple myeloma and limited spinal disease, myelosuppression requiring “marrow-sparing” radiation therapy, or recurrent disease after EBRT.
Jacob A. Miller, Ehsan H. Balagamwala, Lilyana Angelov, John H. Suh, Brian Rini, Jorge A. Garcia, Manmeet Ahluwalia and Samuel T. Chao
Systemic control of metastatic renal cell carcinoma (mRCC) has substantially improved with the development of VEGF, mTOR, and checkpoint inhibitors. The current first-line standard of care is a VEGF tyrosine kinase inhibitor (TKI). In preclinical models, TKIs potentiate the response to radiotherapy. Such improved efficacy may prolong the time to salvage therapies, including whole-brain radiotherapy or second-line systemic therapy.
As the prevalence of mRCC has increased, the utilization of spine stereotactic radiosurgery (SRS) has also increased. However, clinical outcomes following concurrent treatment with SRS and TKIs remain largely undefined. The purpose of this investigation was to determine the safety and efficacy of TKIs when delivered concurrently with SRS. The authors hypothesized that first-line TKIs delivered concurrently with SRS significantly increase local control compared with SRS alone or TKIs alone, without increased toxicity.
A retrospective cohort study of patients undergoing spine SRS for mRCC was conducted. Patients undergoing SRS were divided into 4 cohorts: those receiving concurrent first-line TKI therapy (A), systemic therapy–naïve patients (B), and patients who were undergoing SRS with (C) or without (D) concurrent TKI treatment after failure of first-line therapy. A negative control cohort (E) was also included, consisting of patients with spinal metastases managed with TKIs alone. The primary outcome was 12-month local failure, defined as any in-field radiographic progression. Multivariate competing risks regression was used to determine the independent effect of concurrent first-line TKI therapy upon local failure.
One hundred patients who underwent 151 spine SRS treatments (232 vertebral levels) were included. At the time of SRS, 46% were receiving concurrent TKI therapy. In each SRS cohort, the median prescription dose was 16 Gy in 1 fraction. Patients in Cohort A had the highest burden of epidural disease (96%, p < 0.01).
At 12 months, the cumulative incidence of local failure was 4% in Cohort A, compared with 19%–27% in Cohorts B–D and 57% in Cohort E (p < 0.01). Multivariate competing risks regression demonstrated that concurrent first-line TKI treatment (Cohort A) was independently associated with a local control benefit (HR 0.21, p = 0.04). In contrast, patients treated with TKIs alone (Cohort E) experienced an increased rate of local failure (HR 2.43, p = 0.03). No toxicities of Grade 3 or greater occurred following SRS with concurrent TKI treatment, and the incidence of post-SRS vertebral fracture (overall 21%) and pain flare (overall 17%) were similar across cohorts.
The prognosis for patients with mRCC has significantly improved with TKIs. The present investigation suggests a local control benefit with the addition of concurrent first-line TKI therapy to spine SRS. These results have implications in the oligometastatic setting and support a body of preclinical radiobiological research.
Ehsan H. Balagamwala, Lilyana Angelov, Shlomo A. Koyfman, John H. Suh, Chandana A. Reddy, Toufik Djemil, Grant K. Hunter, Ping Xia and Samuel T. Chao
Stereotactic body radiotherapy (SBRT) has emerged as an important treatment option for spinal metastases from renal cell carcinoma (RCC) as a means to overcome RCC's inherent radioresistance. The authors reviewed the outcomes of SBRT for the treatment of RCC metastases to the spine at their institution, and they identified factors associated with treatment failure.
Fifty-seven patients (88 treatment sites) with RCC metastases to the spine received single-fraction SBRT. Pain relief was based on the Brief Pain Inventory and was adjusted for narcotic use according to the Radiation Therapy Oncology Group protocol 0631. Toxicity was scored according to Common Toxicity Criteria for Adverse Events version 4.0. Radiographic failure was defined as infield or adjacent (within 1 vertebral body [VB]) failure on follow-up MRI. Multivariate analyses were performed to correlate outcomes with the following variables: epidural, paraspinal, single-level, or multilevel disease (2–5 sites); neural foramen involvement; and VB fracture prior to SBRT. Kaplan-Meier analysis and Cox proportional hazards modeling were used for statistical analysis.
The median follow-up and survival periods were 5.4 months (range 0.3–38 months) and 8.3 months (range 1.5–38 months), respectively. The median time to radiographic failure and unadjusted pain progression were 26.5 and 26.0 months, respectively. The median time to pain relief (from date of simulation) and duration of pain relief (from date of treatment) were 0.9 months (range 0.1–4.4 months) and 5.4 months (range 0.1–37.4 months), respectively. Multivariate analyses demonstrated that multilevel disease (hazard ratio [HR] 3.5, p = 0.02) and neural foramen involvement (HR 3.4, p = 0.02) were correlated with radiographic failure; multilevel disease (HR 2.3, p = 0.056) and VB fracture (HR 2.4, p = 0.046) were correlated with unadjusted pain progression. One patient experienced Grade 3 nausea and vomiting; no other Grade 3 or 4 toxicities were observed. Twelve treatment sites (14%) were complicated by subsequent vertebral fractures.
Stereotactic body radiotherapy for RCC metastases to the spine offers fast and durable pain relief with minimal toxicity. Stereotactic body radiotherapy seems optimal for patients who have solitary or few spinal metastases. Patients with neural foramen involvement are at an increased risk for failure.