A quantitative and comparative evaluation of stereotactic spine radiosurgery local control: proposing a consistent measurement methodology

Ran HarelDepartment of Neurosurgery, Sheba Medical Center Affiliated to Tel-Aviv University, Tel-Aviv, Israel;

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Tehila Kaisman-ElbazRose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland;
Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland;

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Todd EmchImaging Institute, Cleveland Clinic, Cleveland;

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Paul ElsonQuantitative Health Sciences, Cleveland Clinic, Cleveland; and

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Samuel T ChaoRose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland;
Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio

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John H SuhRose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland;
Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio

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Lilyana AngelovRose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland;
Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland;

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OBJECTIVE

Stereotactic body radiotherapy (SBRT) is a precise and conformal treatment modality used in the management of metastatic spine tumors. Multiple studies have demonstrated its safety and efficacy for pain and tumor control. However, no uniform quantitative imaging methodology exists to evaluate response to treatment in these patients. This study presents radiographic local control rates post-SBRT, systematically compares measurements acquired according to WHO and Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and explores the relationship to patient outcome.

METHODS

The authors performed a retrospective review of prospectively obtained data from a cohort of 59 consecutive patients (81 metastatic isocenters) treated with SBRT and followed with serial MRI scans. Measurements were performed by a neuroradiologist blinded to the patients’ clinical course. Local control status was determined according to both WHO and RECIST measurements, and agreement between the measuring methodologies was calculated and reported.

RESULTS

Eighty-one isocenters (111 vertebral bodies) were treated with SBRT. The mean treatment dose was 13.96 Gy and the median follow-up duration was 10.8 months, during which 408 MRI scans were evaluated with both WHO and RECIST criteria for each scan point. Imaging demonstrated a mean unidimensional size decrease of 0.2 cm (p = 0.14) and a mean area size decrease of 0.99 cm2 (p = 0.03). Although 88% of the case classifications were concordant and the agreement was significant, WHO criteria were found to be more sensitive to tumor size change. The local control rates according to WHO and RECIST were 95% and 98%, respectively.

CONCLUSIONS

Although WHO volumetric measurements are admittedly superior for tumor size measurement, RECIST is simpler, reproducible, and for the first time is shown here to be comparable to WHO criteria. Thus, the application of RECIST methodology appears to be a suitable standard for evaluating post-SBRT treatment response. Moreover, using comprehensive and consistent measuring approaches, this study substantiates the efficacy of SBRT in the treatment of spine metastases.

ABBREVIATIONS

OS = overall survival ; PD = progressive disease ; PR = partial response ; RECIST = Response Evaluation Criteria in Solid Tumors ; SBRT = stereotactic body radiotherapy ; SD = stable disease ; SPINO = Spine Response Assessment in Neuro-Oncology ; VB = vertebral body.

OBJECTIVE

Stereotactic body radiotherapy (SBRT) is a precise and conformal treatment modality used in the management of metastatic spine tumors. Multiple studies have demonstrated its safety and efficacy for pain and tumor control. However, no uniform quantitative imaging methodology exists to evaluate response to treatment in these patients. This study presents radiographic local control rates post-SBRT, systematically compares measurements acquired according to WHO and Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and explores the relationship to patient outcome.

METHODS

The authors performed a retrospective review of prospectively obtained data from a cohort of 59 consecutive patients (81 metastatic isocenters) treated with SBRT and followed with serial MRI scans. Measurements were performed by a neuroradiologist blinded to the patients’ clinical course. Local control status was determined according to both WHO and RECIST measurements, and agreement between the measuring methodologies was calculated and reported.

RESULTS

Eighty-one isocenters (111 vertebral bodies) were treated with SBRT. The mean treatment dose was 13.96 Gy and the median follow-up duration was 10.8 months, during which 408 MRI scans were evaluated with both WHO and RECIST criteria for each scan point. Imaging demonstrated a mean unidimensional size decrease of 0.2 cm (p = 0.14) and a mean area size decrease of 0.99 cm2 (p = 0.03). Although 88% of the case classifications were concordant and the agreement was significant, WHO criteria were found to be more sensitive to tumor size change. The local control rates according to WHO and RECIST were 95% and 98%, respectively.

CONCLUSIONS

Although WHO volumetric measurements are admittedly superior for tumor size measurement, RECIST is simpler, reproducible, and for the first time is shown here to be comparable to WHO criteria. Thus, the application of RECIST methodology appears to be a suitable standard for evaluating post-SBRT treatment response. Moreover, using comprehensive and consistent measuring approaches, this study substantiates the efficacy of SBRT in the treatment of spine metastases.

Aan aging population, enhanced imaging, diagnostic tools, and overall improvement in cancer care have all contributed to prolonged cancer patient survival1 and an increased prevalence of spine metastases requiring treatment during their disease.2 Conventional radiation therapy was the principal radiation treatment modality for spinal metastatic lesions in the past decades,3,4 until numerous studies highlighted stereotactic body radiotherapy (SBRT) as safe and more effective in terms of local control and pain alleviation.511 Nowadays, SBRT has gained widespread acceptance as a treatment modality for patients with spine metastases, especially in the setting of radioresistant pathologies and oligometastatic disease.1215

The literature suggests that following SBRT, local control of spine metastases ranges from 82% to 96%16 regardless of primary tumor radiation sensitivity,17 and its evaluation protocols are diverse and are represented using a variety of subjective and objective metrics.16 Most studies describe limited patient cohorts,18,19 and also use highly variable measurement methodologies to assess treatment response, including MRI/CT scans for clinical evaluation—or a combination of those two modalities7,2025 (Supplemental Table 1). Also, spinal metastatic lesions are known for not being a typical skeletal lesion, given that they can be associated with epidural and/or paraspinous tissue components. Therefore, the assessment of their local control rate can be challenging because tumor regression does not necessarily translate into bony volume change, posing difficulty in defining a uniform measurement criterion for them.

The Spine Response Assessment in Neuro-Oncology (SPINO) group18,26 surveyed imaging follow-up regimens in multiple centers in 2015. Imaging modalities, methods for measurements, and local control criteria varied substantially, and the evaluation of the treated tumors in these studies was neither systematic nor blinded, resulting in a recommendation for a standardized follow-up regimen.26 Two studies recently published by the Canadian Cancer Trials Group (CCTG),10,20 including the randomized multicenter phase 2/3 trial comparing local failure rates in patients with spinal metastases that were treated with SBRT versus conventional radiation, reported outcomes based on SPINO. However, these studies defined local failure by using a combination of quantitative measurements (e.g., unequivocal increase in volume or linear dimension) and/or qualitative measurements (e.g., a new or progressive tumor in the epidural space, or neurological deterioration with an equivocal increase in preexisting epidural disease). Hence, unfortunately, in 2022 a consensus regarding the radiographic determination of local tumor control is still lacking,16 and most studies do not specify the exact method or particulars used to assess it.

In terms of assessing spine tumors and their response to treatment volumetrically, Jabehdar Maralani et al.27 retrospectively assessed local control following SBRT by using detailed volumetric assessments, with all measurements being performed by a single experienced neuroradiologist. These data suggested that although there is a consensus that the volumetric assessment of spine tumors and their response to treatment is a desirable measurement methodology, multiple challenges remain, limiting its ubiquitous implementation. Issues related to lack of imaging standardization across centers, the inherently complex characteristics of spine tumors and their contouring, interrater variability in target delineation, the impact of initial tumor size on the assessment of response, the time-consuming nature of the process, and the inability of segmentation software to effectively resolve issues related to spine instrumentation all contribute to a delay in the general acceptance of this approach. Ultimately, however, as imaging modalities are continuing to evolve, a volumetric assessment may become more easily obtained and may eventually be the standard method for local control assessment of spinal metastases.

The efficacy of oncological treatments for solid tumors was typically evaluated using objective radiographic measurements with two main validated methodologies—the WHO criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The WHO criteria were first developed in 1979 to assess local control, recurrence, and progression objectively. Specifically, the largest tumor diameter measured is multiplied by its largest perpendicular measurement.28 Using this methodology, in 1981 Miller et al. defined partial response (PR) as a decrease in disease product by ≥ 50%, progressive disease (PD) as an increase in disease products by ≥ 25%, and stable disease (SD) was defined as any change not consistent with PR or PD29 (Fig. 1 and Table 1). These criteria, though, do not specify which is the preferred imaging modality to evaluate tumor size, nor do they guide how to regard multiple or different-sized lesions.30 Therefore, a need for alternative criteria arose.

FIG. 1.
FIG. 1.

Representative posttreatment local control measurement using WHO versus RECIST criteria. Axial STIR (A) and sagittal T2-weighted MR (B) images demonstrate a renal cell carcinoma metastasis involving L1 prior to SBRT treatment. The lesion measures 4.49 × 4.4 × 2.32 cm with a WHO score of 19.8, and the RECIST score is 4.49. The posttreatment response to SBRT at 3 (C and D) and 6 (E and F) months on axial (C and E) and sagittal (D and F) images. Local tumor control is evident although not sufficient to be considered a PR according to both the WHO and RECIST criteria; hence, the lesion was regarded as SD for the entire follow-up period.

TABLE 1.

Comparison of WHO and RECIST criteria

PDSDPRDefinitionCriterion
An increase in disease products by ≥25%Any change not consistent w/ PR or PDDecrease in disease product by ≥50%Bidimensional measurement—largest tumor diam measured, multiplied by its largest perpendicular measurementWHO*
An increase in disease products by ≥20%Any change not consistent w/ % PR or PDDecrease in disease product by ≥30%Unidimensional measurement—largest tumor diam in any planeRECIST

Diam = diameter.

Based on World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No. 48. World Health Organization; 1979;28 and Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47(1):207-214.29

Based on Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247;31 and Gehan EA, Tefft MC. Will there be resistance to the RECIST (Response Evaluation Criteria in Solid Tumors)? J Natl Cancer Inst. 2000;92(3):179-181.32

In 2000, the RECIST criteria were introduced; these relied on the largest measurable tumor diameter in a unidimensional plane only, and defined PR as a ≥ 30% decrease in size and PD as a ≥ 20% increase in size31,32 (Fig. 1 and Table 1). Since then, the RECIST system has been repeatedly used to evaluate different types of solid tumors within the CNS and outside it,3336 but not in studies of spinal metastases. Suzuki et al. suggested that bone lesions should be considered nonmeasurable when using these criteria.30 In 2009, those criteria were updated to RECIST 1.1 to include bone lesions with a soft-tissue component as acceptable lesions to measure. Bone metastases without soft-tissue components, though, remained nonmeasurable lesions according to the RECIST 1.1 criteria.37 Additional scores were also used throughout the years, e.g., The University of Texas MD Anderson Cancer Center score,26 but none were sufficient to be declared as a gold standard.

This paper addresses the benefits of spinal SBRT in terms of local control according to a comprehensive prospective, simple, reproducible, and standardized radiographic oncological response measurement. The cohort was selected to allow long follow-up and multiple MRI examinations. It also sets out, for the first time, to methodically examine RECIST measurements for SBRT-treated spine metastases and compare them to the WHO criteria, and potentially establish a preferred method for treatment response evaluation.

Methods

This is a retrospective review of a prospective radiographic evaluation of patients with spine metastasis treated with SBRT. The study was approved by the Cleveland Clinic Institutional Review Board. Included patients were those who had undergone SBRT between the years 2006 and 2008, whose MRI scans were evaluated at presentation, and who all had at least 1 follow-up MRI after treatment that was subsequently evaluated by a neuroradiologist.

Eighty-five patients were consecutively treated for their 125 spinal isocenters between the years 2006 and 2008. Patients with primary spinal tumors (n = 19) as well as patients without follow-up MRI scans (n = 7) were excluded from this study. Ultimately, 59 patients with spinal metastatic disease with 81 isocenters representing 111 vertebral bodies (VBs) were treated with SBRT and their 408 follow-up MRI scans were evaluated in this study (Fig. 2).

FIG. 2.
FIG. 2.

A flowchart describing the patients included in this study. f/u = follow-up.

The SBRT procedure was previously described and is beyond the scope of the current paper.12,38,39 The prescription dose was typically 12–14 Gy in earlier years and 14–16 Gy in later years (to cover ≥ 90% of the identified clinical target volume), delivered in a single fraction. No margins were used to generate the planning target volume (i.e., planning target volume = clinical target volume). Cord constraint was set at no more than 10% of the volume to receive 10 Gy or more, with a maximum point dose of 14 Gy (≤ 0.03 cm3). Treatment was delivered using the 6-MV linear accelerator with micromultileaf collimators for beam shaping (Novalis). The patients were monitored during treatment using ExacTrac.

The following data were obtained from the medical records and are presented in Table 2: patient demographics, clinical presentation, underlying primary pathology, isocenter location, and the number of levels treated. Radiosurgical parameters including prescribed dose, isodose line, cord dose, number of fractions, and maximum dose were noted and are presented in Table 3. Spine tumor targets were evaluated using sagittal and axial T1-weighted MR images (with and without contrast when applicable), and T2-weighted images were used with consistent pulse sequences and measurement planes for each patient’s initial and follow-up post-SBRT examinations by a neuroradiologist blinded to the patients’ clinical condition. All tumors were measured in three orthogonal planes: anterior-posterior, cranial-caudal, and transverse. The largest dimension in each case was used to evaluate the RECIST criteria, whereas the two largest dimensions were used for area calculations and WHO criteria determination as demonstrated in Fig. 1. Once the initial two diameters were chosen for tumor evaluation on the pretreatment MRI, these same two diameters were consistently measured for each follow-up post-SBRT study for a given patient, maintaining internal consistency. The size and area change in percentage was calculated, and logistic formulas were used to determine the WHO and RECIST measurement correspondence.

TABLE 2.

Main patient characteristics

ParameterValue
No. of pts, no. of isocenters59,* 81
Mean age, yrs (range)59 (28–88)
Male sex, no. (%)41 (62)
Median FU, mos (range) 10.8 (1–38.9)
Mortality rate during FU, no. (%)40 (59)
1-yr survival rate (%), mean ± standard deviation67 ± 6
Median OS, mos (95% CI)16.6 (12.9–20.6)
Primary tumor types, no. (%)
 Kidney19 (29)
 Lung 17 (26)
 Breast8 (12)
 Prostate 7 (11)
 Unknown primary5 (8)
 Gastrointestinal4 (6)
 Ovarian/cervical3 (4)
 Melanoma1 (2)
 Pheochromocytoma1 (2)
 Thyroid1 (2)
Radioresistant pathology, no. (%)30 (45)
Pts w/ metachronous treatment of another isocenter (%)19.7

FU = follow-up; pts = patients.

Initially there were 66 patients; 7 were excluded for insufficient follow-up scans.

TABLE 3.

SBRT treatment-related parameters

ParameterValue
Pts treated for a single isocenter (%)90.1
Spinal levels, no. (%)
 Cervical16 (17)
 Thoracic32 (33)
 Lumbar29 (30)
 Sacral8 (8)
 Transition11 (11)
Contiguous levels treated, no. (%)
 1 level65 (67.7)
 2 levels18 (18.8)
 3 levels9 (9.3)
 4 levels4 (4.1)
Mean prescription radiation dose, Gy (range)13.96 (8–24)
Prior conventional radiation, no. (%)14 (14.6)
Prior surgery, no. (%)19 (19.8)
Mean treated vol, cm3 (range)45.3 (1.4–215.5)
Mean unidimensional pre-SBRT size, cm (range)3.6 (0.1–9.7)
Mean unidimensional size change post-SBRT, cm−0.2
Mean bidimensional (area) pre-SBRT size, cm2 (range)14.8 (0.4–57.0)
Mean bidimensional (area) size change SBRT-SRS, cm2−0.99

Percentages were calculated on 96 (the number of pre-SBRT MRI scans).

Descriptive statistics were generated; Fisher’s exact test, chi-square tests, and 2-sample t-tests were used to compare patient characteristics. Paired t-tests were used to compare pretreatment to follow-up tumor sizes, and the log-rank test was used for univariable survival comparisons. Logistic regression and the Cox proportional hazards model were used for multivariable assessment of factors associated with retreatment and overall survival (OS). The Pearson correlation was calculated between the percent change in unidimensional and bidimensional measurements. All data analyses were performed using SAS 9.4 (SAS Institute).

Results

Forty-one of the patients were male (62%) and the cohort’s mean age was 59 years (range 28–88 years). Primary tumor pathologies included the following: renal 19 (29%), lung 17 (26%), breast 8 (12%), prostate 7 (11%), unknown primary 5 (8%), gastrointestinal 4 (6%), ovarian/cervical 3 (4%), melanoma 1 (2%), pheochromocytoma 1 (2%), and thyroid 1 (2%). A total of 45% (30/66) of patients had primary tumors that were considered relatively radioresistant (Table 2). A total of 111 VBs were evaluated; 64 were single-VB target regions, 18 involved 2 contiguous VBs, 9 involved 3 contiguous VBs, and 4 involved 4 contiguous VBs at the cervicothoracic region across a total of 504 MRI scans. However, after excluding 7 patients with insufficient follow-up scans, the response to treatment was evaluated in 59 patients with metastatic disease consisting of 81 spinal isocenters.

The most involved spinal levels were the thoracic (32 isocenters, 33% of treated sites) and lumbar (29 isocenters, 30%) regions, followed by the cervical (16 isocenters, 17%) and sacral (8 isocenters, 8%) regions. There were 6 isocenters (6%) at the cervicothoracic junction, 4 isocenters (4%) at the thoracolumbar junction, and a single craniocervical junction case (1%) was treated. Four consecutive VB levels were treated only in the cervicothoracic region where the vertebrae are of smaller dimensions overall. Fourteen lesions (14.6%) were previously irradiated with conventional radiation, and surgery was performed on 19 isocenters (19.8%) prior to the SBRT treatment.

Sixty patients were initially treated for a single target isocenter, 4 patients had treatment for 2 discrete isocenters, and 2 patients underwent treatment involving 3 distinct isocenters. Thirteen patients had metachronous treatment of another isocenter; the mean interval between the first and second treatment was 8.8 months (range 2.0–27.3 months). Four patients had 3 treatment sessions, with a mean interval of 5.9 months (range 0.9–11.8 months) between the second and third treatment. The mean prescription dose was 13.96 Gy (range 8–24 Gy), with 20 isocenters (21%) receiving 12 Gy, 35 isocenters (36%) receiving 14 Gy, and 28 isocenters (29%) receiving 16 Gy. The mean percent of target receiving the prescription dose was 94.7% (range 79.4%–100%) and the mean treated volume was 45.3 cm3 (range 1.4–215.5 cm3) (Table 3).

The median number of post-SBRT follow-up scans was 3, with 26 isocenters (27%) having a single follow-up MRI scan; 19 (20%) having 2 follow-up MRI scans; 10 (10%) having 3 follow-up MRI scans; 8 (8%) having 4 follow-up MRI scans; 13 (14%) having 5 follow-up MRI scans; and 18 (19%) having more than 5 follow-up MRI scans (range 6–12 scans). Radiographic evaluation by a neuroradiologist was performed for 96 pre-SBRT MRI examinations and 408 follow-up MRI scans were obtained (with a total of 504 MRI scans evaluated). The mean unidimensional size was 3.6 cm (range 0.1–9.7 cm; n = 96), while the mean bidimensional (area) size was 14.8 cm2 (range 0.4–57.0 cm2; n = 76). Compared to the last follow-up MRI scan, the mean unidimensional size decreased by 0.2 cm and the mean bidimensional area size decreased by 0.99 cm2 (p = 0.14 and p = 0.03, respectively). Figure 3 demonstrates the correlation between the percent change in unidimensional and bidimensional measurements (Pearson correlation R2 = 0.81, p < 0.0001).

FIG. 3.
FIG. 3.

Graph showing maximum tumor shrinkage—WHO versus RECIST (n = 75). The correlation between the percent change in unidimensional and bidimensional measurements (Pearson correlation R2 = 0.81, p < 0.0001) is shown.

In our series, SBRT resulted in excellent local control rates of 95% according to WHO criteria and 98% according to RECIST measurement criteria within a median follow-up of 10.8 months. Table 4 demonstrates good agreement in response evaluation between the WHO and the RECIST measurement schemes, with 88% of the lesions demonstrating a concordant response to treatment using either system. However, WHO tends to classify lesions as PR or PD more frequently than RECIST. That is, 7/18 (39%) cases that were PR according to WHO were classified as SD (n = 6) or PD (n = 1) according to RECIST, and 3/4 (75%) PD cases according to WHO were stable according to RECIST. Figure 4 demonstrates the tumor size change in percent relative to the interval from treatment. The median tumor size change remained relatively stable throughout follow-up, generally varying from a 6.5% decrease to a 1.4% increase. Figure 1 demonstrates posttreatment response over time measurement using the WHO versus RECIST criteria.

TABLE 4.

Agreement of the WHO and the RECIST criteria

WHORECISTTotal
PRSDPD
 PR11*6118 (22%)
 SD059*059 (73%)
 PD031*4 (5%)
 Total11 (14%)68 (84%)2 (2%)81 (100%)

Values show exact concordance between response classifications.

FIG. 4.
FIG. 4.

Box plot showing relative change from baseline in unidimensional response. The median tumor size change is shown in percent relative to the interval from treatment, which remained relatively stable throughout follow-up, generally varying from a 6.5% decrease to a 1.4% increase.

Multiple factors including tumor histology, radioresistance, number of isocenters, target volume, and target size were evaluated as risk factors for recurrent treatment; younger age and treatment at doses ≤ 14 Gy were found to be statistically significant (p = 0.001 and p = 0.05, respectively), with no patient treated at > 14 Gy requiring additional treatment compared to 25% (13/52) of patients treated with ≤ 14 Gy. Multivariate analysis was used to determine the significant risk factors for retreatment, and identified age as the only independent predictor (p = 0.003). The median follow-up was 10.8 months (range 1–38.9 months), the mortality rate during follow-up was 59% (40 patients), the 1-year survival was 67% ± 6% (mean ± standard deviation), and the median OS was estimated to be 16.6 months (95% CI 12.9–20.6 months).

Discussion

With the rising incidence of cancer in the population and the increasing need for better treatment options for cancer patients, more patients are developing spinal metastases.2,40 Patchell et al.41 demonstrated the superiority of surgery combined with radiation over radiation alone for metastatic epidural spinal cord compression, and initiated a trend toward a more aggressive and localized treatment of spinal tumors.42,43 Furthermore, spinal metastases can cause significant morbidity, with pain or neurological deficit adversely affecting the patient’s quality of life.40,44,45 Hence, high rates of local control are an important treatment goal that should be considered regardless of the expected length of OS. To this end, SBRT was introduced in 1995 as a novel treatment modality for the management of spine tumors,46 and in the subsequent decades, with advancements in technologies and provider experience, has been demonstrated to be safe and effective in terms of pain relief in several published papers.6,4749

Beyond pain control/alleviation, from an oncological perspective, local tumor control is another important consideration that is being regularly addressed in papers describing SBRT treatment efficiency for spinal lesions, although its evaluation is inconsistently determined. Amdur et al.19 demonstrated a 95% local control rate in a prospective cohort of 25 patients followed by MRI, PET, or CT scans, but did not define the criteria for local control. Yamada et al.18 reported a 90% local control rate of spinal metastatic lesions in 35 patients whose disease progression was either defined using clinical parameters or verified on MRI. Another example is the paper by Gerszten et al.,7 which followed 500 SBRT-treated lesions with serial CT/MRI scans and reported 86% pain control for tumors treated for pain indications, and an overall 88% tumor control rate. The method used for tumor size evaluation in that study was not specifically described. More recent studies follow a similar pattern of local control rate descriptions without using uniform criteria.17,50 A standardized measurement system is therefore needed for the assessment of treatment outcomes that can reflect post-SBRT tumor control rate and both provide reliability to evaluate the impact of therapy in terms of the individual patient and allow for comparisons of interventions or outcomes among large patient cohorts.

In 2015, the SPINO group surveyed imaging follow-up regimens in multiple centers and further confirmed the existing nonuniformity. Imaging modalities described include CT, MRI, and PET/CT scans, with most centers using MRI as the prevailing evaluation modality. Time intervals for follow-up were also found to differ widely between centers. The commonly used metrics for local control were extremely variable, and at times were reported using either RECIST criteria, radiologist clinical determination, author evaluation, or—as in most SBRT studies—no formal evaluation method.26 An updated standardization by the SPINO group has not been provided thus far, nor is there a clear determination regarding which is the preferred imaging sequence to assess tumor response.51

Recently, the role of advanced imaging modalities, such as dynamic contrast-enhanced perfusion MRI scans and FDG-PET, has been the subject of studies evaluating response to SBRT treatment for spine metastatic disease.5255 However, this modality is not currently consistently applied as a method of evaluating or monitoring tumor progression at most centers. Machine learning and artificial intelligence are additionally being explored in spine research and diagnostic imaging,56 including in the field of spinal metastatic lesions, and are likely to enhance our knowledge in the coming decades.57,58 However, because no formal benchmark currently exists, in this paper we have worked to use the sequences most commonly acquired to evaluate spine tumors, i.e., T1-weighted and STIR MRI studies, and we apply a standardized measuring approach to allow some uniformity in terms of post-SBRT measurements of spine metastases.

Various criteria were previously described to radiographically follow and evaluate the response of solid tumors, but none have been validated for spine tumors, nor were they validated for post-SBRT spine interventions. Axial and sagittal T1-weighted images without and with contrast as well as axial and sagittal T2-weighted images are the preferred pulse sequences for quantifying metastatic disease and are typically part of a routine spine MR examination.59 When quantifying disease, care must be taken to maintain consistency between the examinations and to mitigate limitations such as the following: artifact from instrumented fusion, differing scan planes on axial images or even field of view/coverage between the follow-up examinations, and incomplete examinations when the patient is unable to tolerate the entire MR examination.

In 1979, the WHO criteria for tumor response based on size measurement were first described.28 Those criteria demonstrated low reproducibility and were not adequate to evaluate tumor size on newer imaging technologies such as CT and MRI. In 2000, therefore, the RECIST criteria were introduced, followed by their revision in 2009,37 using the largest measurable tumor unidimensional diameter for evaluation.31,32 Park et al.60 and Choi et al.33 compared the WHO and RECIST methodologies and found the WHO criteria to be more sensitive than RECIST. Harel et al.61 evaluated both WHO and RECIST criteria in a small cohort of patients who had undergone spine surgery followed by SBRT and concluded that both measuring methods could be applied, with good agreement for that study population.

In the current paper, an evaluation and comprehensive comparison of both methods applied for SBRT-treated spinal metastatic lesions were conducted, and a statistically significant agreement between both methods was demonstrated (Pearson correlation R2 = 0.81, p < 0.0001). Importantly, 95% and 98% of lesions were controlled. Eighty-eight percent of cases had the same classification according to both the WHO and the RECIST criteria, and 9 cases (11%) were classified as SD according to RECIST, but PD (3 cases) or PR (6 cases) according to WHO, suggesting that the WHO criteria are more sensitive to tumor progression. Notably, this study cohort consisted of 14.6% previously irradiated lesions and 45% radioresistant tumors that did not demonstrate different survival patterns as a result of SBRT treatment, which correlates with the notion presented recently in the literature that radioresistant or previously irradiated tumors respond equally well to SBRT as do radiosensitive tumors.17 Moreover, even though other works have reported pseudoprogression following SBRT to spinal metastases,62 in this study no pseudoprogression was demonstrated. In contrast, however, 2 very recent studies by Abugharib et al.63 and Zeng et al.64 demonstrated a beneficial OS in large patient cohorts with hormone-sensitive, radiosensitive, spinal prostate metastases. Therefore, the impact of SBRT depending on tumor histology is still debatable and should be further explored in future studies.

Moreover, the 96 lesions that were prospectively followed with serial MRI scans to a mean follow-up of 10.8 months showed a mean unidimensional tumor size measured by the RECIST to nonsignificantly decrease by 0.2 cm at the last follow-up MRI scan, whereas the mean bidimensional tumor area size, measured according to the WHO criteria, was significantly decreased by 0.99 cm2. Although this favors the precision of the WHO, both methods have a high agreement rate. Given this high concordance, the simplicity of the RECIST methodology, and the likelihood of more consistent reproducibility when using unidimensional measurements, we consider RECIST to be a suitable measurement strategy to evaluate response to SBRT treatment for spine metastasis. This holds true as long as internal consistency in the direction of measurement is applied relative to the largest diameter on the pretreatment MRI scan.

The lack of standardization impairs data integration from different studies or across centers, impairs the assessment of SBRT treatment paradigms’ efficacy, and may decrease clinical trial enrollment for these patients due to the inability to objectively assess local tumor progression. This paper examined RECIST and compared it to the WHO criteria for evaluating metastatic spinal lesions on MRI scans. The selected cohort was treated during 2006–2008 to allow for long follow-up and multiple MRI scans for evaluation. Since then, the SBRT protocol was not changed in our institution. Even though each method has some associated shortcomings and is more optimally applied for soft tissues and/or organs invaded by cancer cells, our study confirms that both the WHO and RECIST measuring criteria are convenient and consistent with each other. Hence, in light of the increasing need to advance the field of spine radiosurgery with reliable and objective measuring approaches to evaluate treatment outcomes, we recommend that a uniform measuring strategy should be pursued by centers performing spine radiosurgery.

Limitations

This study has some limitations that should be noted as well. Although the database is prospectively maintained, the study is a retrospective review of patients, and those with long-term follow-up are likely to contribute an inherent selection bias toward patients with favorable outcome. In addition, several parameters could potentially impact this study’s presented outcomes, such as the fact that the cohort is composed of mixed primary pathologies and the fact that systemic oncological treatments were not recorded. Finally, novel therapeutic options with targeted therapies and immuno-oncology may impact treatment outcomes; however, systemic oncological treatments were not specifically or reliably documented in our patient series.

Future Directions

Current imaging modalities available for monitoring local control in metastatic bone lesions demonstrate anatomical features but are currently limited in terms of correlation of outcomes at the cellular/pathological level. The use of perfusion MRI or FDG-PET uptake studies can add an important level of resolution but tend to be subjective to interpretation to some extent. Machine learning and artificial intelligence can also contribute greatly to this effort of local control imaging assessment in the future. Nonetheless, until tumor imaging and response evaluation begin to incorporate novel measuring modalities such as those mentioned above, there is a critical need to standardize our measurement approach in SBRT-treated spine metastasis to compare outcomes, not only for the individual patient but also across different treatment paradigms, and to enable multiinstitutional study outcome evaluation.

Conclusions

This study uniformly measured SBRT-treated spine metastases by systematically comparing measurements according to the WHO and RECIST criteria, reporting a ≥ 95% local control rate during a long follow-up period, demonstrating this to be an effective and durable treatment. By robustly comparing the two separate measurement strategies, the RECIST criteria were found to be accurate, reliable, simpler, and therefore favorable to use. We suggest that a standardized methodology for post-SBRT treatment evaluation and follow-up should be endorsed accordingly, thus improving the care and quality of evidence in post-SBRT treatment outcomes in patients with spine metastases.

Acknowledgments

We thank the Kerscher Family Foundation for their support of this publication.

Disclosures

Dr. Chao: research support, travel, and honorarium from Blue Earth Diagnostics; honorarium from Varian Medical Systems. Dr. Suh: scientific advisory board for Neutron Therapeutics, EmpNia, Philips, and Novocure; honoraria from Philips and Novocure. Dr. Angelov: speaker’s bureau for Brainlab.

Author Contributions

Conception and design: all authors. Acquisition of data: Angelov, Harel, Kaisman-Elbaz, Emch. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Angelov. Statistical analysis: Angelov, Harel, Emch, Elson, Chao, Suh. Administrative/technical/material support: all authors. Study supervision: Angelov, Harel.

Supplemental Information

Online-Only Content

Supplemental material is available online.

Previous Presentations

Presented as posters at the 14th Annual International Symposium on Stereotactic Body Radiation Therapy and Stereotactic Radiosurgery, Lake Buena Vista, Florida, February 2022; and at the ISRS Meeting, Milan, Italy, June 2022.

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Supplementary Materials

  • Collapse
  • Expand
  • View in gallery
    FIG. 1.

    Representative posttreatment local control measurement using WHO versus RECIST criteria. Axial STIR (A) and sagittal T2-weighted MR (B) images demonstrate a renal cell carcinoma metastasis involving L1 prior to SBRT treatment. The lesion measures 4.49 × 4.4 × 2.32 cm with a WHO score of 19.8, and the RECIST score is 4.49. The posttreatment response to SBRT at 3 (C and D) and 6 (E and F) months on axial (C and E) and sagittal (D and F) images. Local tumor control is evident although not sufficient to be considered a PR according to both the WHO and RECIST criteria; hence, the lesion was regarded as SD for the entire follow-up period.

  • View in gallery
    FIG. 2.

    A flowchart describing the patients included in this study. f/u = follow-up.

  • View in gallery
    FIG. 3.

    Graph showing maximum tumor shrinkage—WHO versus RECIST (n = 75). The correlation between the percent change in unidimensional and bidimensional measurements (Pearson correlation R2 = 0.81, p < 0.0001) is shown.

  • View in gallery
    FIG. 4.

    Box plot showing relative change from baseline in unidimensional response. The median tumor size change is shown in percent relative to the interval from treatment, which remained relatively stable throughout follow-up, generally varying from a 6.5% decrease to a 1.4% increase.

  • 1

    Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):733.

  • 2

    Sciubba DM, Pennington Z, Colman MW, et al. Spinal metastases 2021: a review of the current state of the art and future directions. Spine J. 2021;21(9):14141429.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys. 1995;32(4):959967.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Rades D, Stalpers LJ, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol. 2005;23(15):33663375.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Zeng KL, Tseng CL, Soliman H, Weiss Y, Sahgal A, Myrehaug S. Stereotactic body radiotherapy (SBRT) for oligometastatic spine metastases: an overview. Front Oncol. 2019;9:337.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Angelov L, Chao S, Heng D, Djemil T, Kolar M, Suh JH. Stereotactic spine radiosurgery (SRS) for pain and tumor control in patients with spinal metastases from renal cell carcinoma: a prospective study. Int J Radiat Oncol Biol Phys. 2008;72(1):S489.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193199.

    • Search Google Scholar
    • Export Citation
  • 8

    Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976). 2009;34(22 suppl):S78S92.

    • Search Google Scholar
    • Export Citation
  • 9

    Gerszten PC, Ozhasoglu C, Burton SA, et al. CyberKnife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery. 2004;55(1):8999.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Sahgal A, Myrehaug SD, Siva S, et al. Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2021;22(7):10231033.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Sahgal A, Myrehaug SD, Siva S, et al. CCTG SC.24/TROG 17.06: A randomized phase II/III study comparing 24Gy in 2 stereotactic body radiotherapy (SBRT) fractions versus 20Gy in 5 conventional palliative radiotherapy (CRT) fractions for patients with painful spinal metastases. Int J Radiat Oncol Biol Phys. 2020;108(5):13971398.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Balagamwala EH, Angelov L, Koyfman SA, et al. Single-fraction stereotactic body radiotherapy for spinal metastases from renal cell carcinoma. J Neurosurg Spine. 2012;17(6):556564.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Ghia AJ, Chang EL, Bishop AJ, et al. Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials. J Neurosurg Spine. 2016;24(5):829836.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Yamada Y, Laufer I, Cox BW, et al. Preliminary results of high-dose single-fraction radiotherapy for the management of chordomas of the spine and sacrum. Neurosurgery. 2013;73(4):673680.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):28302838.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Soltys SG, Grimm J, Milano MT, et al. Stereotactic body radiation therapy for spinal metastases: tumor control probability analyses and recommended reporting standards. Int J Radiat Oncol Biol Phys. 2021;110(1):112123.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Yamada Y, Katsoulakis E, Laufer I, et al. The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery. Neurosurg Focus. 2017;42(1):E6.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Yamada Y, Lovelock DM, Yenice KM, et al. Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys. 2005;62(1):5361.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Amdur RJ, Bennett J, Olivier K, et al. A prospective, phase II study demonstrating the potential value and limitation of radiosurgery for spine metastases. Am J Clin Oncol. 2009;32(5):515520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Zeng KL, Myrehaug S, Soliman H, et al. Mature local control and reirradiation rates comparing spine stereotactic body radiation therapy with conventional palliative external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2022;114(2):293300.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007;7(2):151160.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Garg AK, Shiu AS, Yang J, et al. Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer. 2012;118(20):50695077.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Bernstein MB, Chang EL, Amini B, et al. Spine stereotactic radiosurgery for patients with metastatic thyroid cancer: secondary analysis of phase I/II trials. Thyroid. 2016;26(9):12691275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Ning MS, Deegan BJ, Ho JC, et al. Low incidence of late failure and toxicity after spine stereotactic radiosurgery: secondary analysis of phase I/II trials with long-term follow-up. Radiother Oncol. 2019;138:8085.

    • Search Google Scholar
    • Export Citation
  • 25

    Redmond KJ, Sciubba D, Khan M, et al. A phase 2 study of post-operative stereotactic body radiation therapy (SBRT) for solid tumor spine metastases. Int J Radiat Oncol Biol Phys. 2020;106(2):261268.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Thibault I, Chang EL, Sheehan J, et al. Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group. Lancet Oncol. 2015;16(16):e595e603.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Jabehdar Maralani P, Tseng CL, Baharjoo H, et al. The initial step towards establishing a quantitative, magnetic resonance imaging-based framework for response assessment of spinal metastases after stereotactic body radiation therapy. Neurosurgery. 2021;89(5):884891.

    • Crossref
    • Search Google Scholar
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