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Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy
University Hospital of Heidelberg, Department of Radiation Oncology, GermanyHeidelberg Institute of Radiation Oncology (HIRO), GermanyUniversity Hospital Zurich, Department of Radiation Oncology, Switzerland
University Hospital of Heidelberg, Department of Radiation Oncology, GermanyHeidelberg Institute of Radiation Oncology (HIRO), GermanyHeidelberg Institute of Radiation Oncology (HIRO), German Cancer Research Center (DKFZ), Germany
To report the primary endpoint of a randomized trial comparing pain response following palliative stereotactic body radiation therapy (SBRT) versus conventionally-fractionated 3D-conformal radiotherapy (3DCRT) for previously untreated spinal metastases.
Methods
Fifty-five patients with histologically/radiologically confirmed painful spinal metastases were analyzed in this single-institutional, non-blinded, randomized explorative trial. Participants were randomly assigned (1:1) to receive single-fraction SBRT (24 Gy) or 3DCRT (30 Gy in 10 fractions). The primary endpoint was pain relief of >2 points on the visual analog scale (VAS) measured within the irradiated region at 3 months following radiotherapy completion. Other recorded parameters included pain response (per International Bone Consensus response definitions), use of concurrent medications and opioid usage (oral morphine equivalent dose, OMED). All parameters were assessed at baseline and at three and six months after RT. Intention-to-treat analysis was applied. This trial is registered with ClinicalTrials.gov, number NCT02358720.
Findings
Despite no significant differences for VAS at 3 months between groups (p = 0.13), pain values decreased faster within this time period in the SBRT arm (p = 0.01). At 6 months following RT, significantly lower VAS values were reported in the SBRT group (p = 0.002). There were no differences in OMED consumption at 3 (p = 0.761) and 6 months (p = 0.174). There was a trend toward improved pain response in the SBRT arm at 3 months (p = 0.057), but significantly so after 6 months (p = 0.003). No patient in the SBRT group experienced grade ≥3 toxicities according to the Common Terminology Criteria for Adverse Events v.4.03.
Conclusions
This randomized trial demonstrates the utility of palliative SBRT for spinal metastases, which was associated with a quicker and improved pain response. Larger ongoing randomized studies will assist in further addressing these endpoints.
Approximately one third of cancer patients will develop bone metastases, approximately two thirds of which involve the vertebral column, most commonly at the thoracic and lumbar levels [
Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction.
Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases.
]. Comprehensive meta-analyses by Sze et al. and Wu et al. have provided consistent data regarding pain response after conventional external beam radiotherapy [
It has long been questioned whether an increase in radiation dose may lead to increased pain control while maintaining few toxicities. Although 3DCRT is limited in its capacity to dose-escalate owing to spinal cord dose constraints, stereotactic body radiation therapy (SBRT) is a highly conformal technique that does allow for safe dose-escalation [
]. These notions have been supported by phase I–II data demonstrating a clinical benefit of SBRT in the primary or salvage treatment of stable spinal lesions [
]. The latter is the basis for the currently ongoing RTOG 0631 phase III assessment, which aims to compare pain response and quality of life (QoL) between SBRT (single dose of 16 Gy) and EBRT (external beam radiotherapy) (single dose of 8 Gy).
To date, no randomized trials are available comparing SBRT with conventional 3DCRT in terms of pain relief. Furthermore, the interaction between ablative doses and pain response remains unclear. The aim of this randomized trial was to analyze pain response after high-dose SBRT versus conventional 3DCRT for this patient population.
Materials and methods
Subjects, recruitment strategy, and eligibility for enrollment
From November 2014 to March 2017, 60 patients with histologically confirmed cancer and painful bone metastases of the thoracic or lumbar vertebral column were randomized in both arms: high-dose single-fraction SBRT (24 Gy) versus standard fractioned 3DRT (10 × 3 Gy).
Inclusion criteria were ages 18–80, a Karnofsky performance score [
] ≥70, ability to provide written informed consent, a maximum of two irradiated vertebral bodies per region, a maximum of two different vertebral regions affected, and tumor distance >3 mm to the spinal cord. Exclusion criteria were subjects with significant neurological or psychiatric disorders precluding informed consent, previous RT to the given irradiation site, contraindications for MRI, multiple myeloma or lymphoma histology, or involvement of the cervical spine.
In total, five patients were duly excluded. Four patients in the SBRT arm had an insufficient distance between tumor and spinal cord. One participant from the control arm was excluded because of the confirmed diagnosis of multiple myeloma after randomization. 55 patients met the inclusion/exclusion criteria and were enrolled into the trial (Fig. 1).
The randomized trial, registered on clinicaltrials.gov (NCT02358720), was approved by the Heidelberg University Independent Ethics Committee (Nr. S-431/2013). Additionally, approval was given from the German Federal Office of Radiation Protection (BfS).
Design, randomized allocation, and procedures
This was a randomized, single-institutional, explorative study with the intention to compare pain response after high-dose single fraction SBRT versus conventional 3DCRT in patients with painful untreated spinal bone metastases. Details of the study design have been published previously [
High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial.
]. A block randomization approach (block size of 6) was used to ensure that the two groups were balanced.
Two different techniques were evaluated on a 1:1 basis according to the randomization list: high-dose, single-fraction (24 Gy to the 80% isodose line) SBRT versus 30 Gy in 10 fractions of conventional radiotherapy.
The randomization procedure was carried out by a central office. Prior to their enrollment into the study, patients underwent staging of the vertebral column in connection with planning computed tomography (CT) and MRI to measure the spinal cord dimension. The prerequisite for participation in the study was the exclusion of spinal cord compression, along with a sufficient distance (>3 mm) between the metastasized vertebral body and spinal cord on MRI.
The primary endpoint-related parameters were measured at the start of RT (t0), at the end of RT (t1), 3 months post-RT (t2), and 6 months post-RT (t3). These parameters included the following: documentation of pain according to the Visual Analog Scale (VAS), neuropathic pain, OMED [
], and as well as individual patient-specific data such as use of concurrent medications.
During therapy, treating physicians documented each of these parameters; subsequently, patients continued complete documentation by means of pain diaries. VAS (collated as weekly mean values) and concurrent medication usage were documented daily for 3 months, and once after 6 months. In addition, use of basic pain medications and other concurrent medications (or medication changes) were continuously recorded from the start of RT to 6 months. In addition to patient-reported neuropathic pain use, opioid analgesic usage was converted into an oral morphine equivalent dose (OMED), and any non-opioid analgesics were also recorded.
Patient records were collected by the authors. The evaluation included all recorded data up to the 6-month follow-up interval. The baseline data of the patient characteristics are presented in summary (Table 1).
The primary endpoint of this randomized, single-institutional, phase II trial was pain response after high-dose single-fraction SBRT versus conventional 3DCRT in patients with painful, previously untreated spinal metastases. The primary endpoint was defined as pain relief >2 points according to the visual analog scale (VAS) measured at the irradiated region three months after RT (t2). The pain response was assessed according to the International Bone Consensus response categories by Chow et al. [
] as complete response (CR), partial response (PR), pain progression (PP), and intermediate pain (IP) at 3 and 6 months after RT. Complete response (CR) was defined as VAS = 0 after 3 months and partial response (PR) as an improvement by at least two score points after 3 and 6 months. CR was defined as VAS = 0 at the treated site with no concurrent increase in analgesic intake (stable or reducing analgesics in daily OMED). PR was defined as pain reduction of 2 or more at the treated site without analgesic increase, or analgesic reduction of 25% or more from baseline without an increase in pain. PP was defined as increase in pain score of 2 or more above baseline at the treated site with stable OMED, or an increase of 25% or more in OMED compared with baseline with the pain score stable or 1 point above baseline. Any response not covered by the complete response, partial response, or pain progression definitions was called “intermediate pain”. Responders were defined as having CR or PR, non-responders as having PP or IP.
Radiotherapy
CT simulation was carried out with custom immobilization using Aquaplast® head masks, vacuum mattresses, and/or Wingstep® arm abduction framework. Regarding target delineation (performed with MRI co-registration), each vertebral body was divided into 3 sectors. Sectors I and III represent the lateral area of the vertebral body with the respective ipsilateral left or right pedicle, lamina, and transverse process. Sector II represents the middle third of the vertebral body with the spinous process. The gross tumor volume (GTV) was defined as the visible lesion with a 3 mm safety margin. The CTV included the affected vertebral body sector/s plus any unaffected sector. The PTV was defined by adding a 5 mm safety margin to the CTV. The volume (PRV) of the planning organ at risk (OAR), in this case the spinal cord, was a 3 mm expansion of this structure. The margin to the spinal cord was never less than 3 mm. The PTV never overlapped with the spinal cord or cauda equina.
In the SBRT cohort, the planning target volume (PTV) was to be covered by the 80% isodose line, and a single fraction of 24 Gy was prescribed to this isodose line. OAR tolerance doses were per the RTOG 0631 trial [
]. SBRT was delivered by an Elekta Versa HD linac employing MLC Agility leafs and a width of 5 mm at isocenter distance, with full dual VMAT arcs (178°–182° ccw, 182°–178° cw). Treatment was delivered using one of three possible techniques. VMAT with 6 MV flattering filter free (FFF) beams was delivered at a dose rate of 1400 MU/min. TomoTherapy (Accuray Inc., Madison, WI) was another technique; image guidance thereof comprised of pre-treatment megavoltage CT, followed by delivery of 12 Gy, followed by repeat megavoltage CT, and delivery of the remaining 12 Gy. The third technique was step-and-shoot IMRT with flattened 6 MV photons. Dose delivery and dosimetric accuracy of each plan were assessed by patient specific quality assurance (QA) using 3D-reconstucted dose measurement with the OD1500 2D-detector array inside the OCTAVIUS 4D rotational phantom.
For the 3DCRT arm, treatment was performed as irradiation of the involved vertebral body as well those immediately above and below to a total dose of 30 Gy in 10 fractions, most commonly delivered with 3 or 4 anteroposterior/posteroanterior beams. The same tolerance doses of the organs at risk as in the RTOG 0631 study are used [
]. Position verification was carried out weekly before radiotherapy by kilovoltage cone-beam CT (kV-CBCT) and before each fraction by orthogonal portal images being compared with digitally reconstructed radiographs (DRR) from the planning CT.
Statistical analysis
Owing to the exploratory nature of this study, a complete power calculation was not possible; however, with 30 patients in each group, it was possible to detect a standardized mean-value effect of 0.8 with 80% power at a significance level of 0.05.
All variables were analyzed descriptively by tabulation of the measures of the empirical distributions. According to the scale level of the variables, means and standard deviations or absolute and relative frequencies, respectively, were reported. Additionally, for variables with longitudinal measurements, the time courses of individual patients and are summarized by treatment groups. Descriptive p-values of the corresponding statistical tests comparing the treatment groups were given. The VAS was adjusted for concurrent medication. Analysis of covariance (ANOVA) with repeated measurements, with treatment group as a factor, and pain medication as a covariate, were done. The Wilcoxon signed-rank test was used to detect possible differences between groups after 3 and 6 months. Graphical visualization includes boxplots and mean course over time. Finally, we compared the groups for overall and bone survival, using Kaplan–Meier estimates and log-rank tests. Overall survival (OS) was defined as time from randomization until death, or censored at last contact.
All statistical analyses were done using SAS software Version 9.4 or higher (SAS Institute, Cary, NC, USA).
Results
Baseline characteristics were balanced between the two treatment arms (Table 1). The mean follow-up was 8.1 months for both groups. At baseline, NSAIDs were taken by 55.6% (n = 15) in the SBRT group, and opioid analgesics by 40.7% (n = 7). Corresponding numbers in the 3DCRT group were 53.6% (n = 15) and 35.7% (n = 10), respectively.
All surviving patients completed every required questionnaire. Four patients (14.8%) in the SBRT group died within 12 weeks of RT, and another 4 patients (14.8%) died of disease between 12 and 24 weeks. In the 3DCRT arm, 5 patients (17.9%) died within 3 months, and another 3 patients (10.7%) died between 3 and 6 months of RT (Fig. 1). No differences were present between groups in terms of OS (p = 0.659) and bone survival (BS) (p = 0.660) (Fig. 2, Fig. 3). The mean OS was 7.9 months for both groups.
There were no significant differences in the pattern of recorded OMED consumption between treatment arms within 3 months (t2) (p = 0.761) and 6 months (t3) after RT (p = 0.174) (Fig. 4).
Fig. 4VAS-value in both groups during 12 weeks after end of the radiotherapy.
Twenty-three (85%) participants in the SBRT group and 23 (82%) in the 3DCRT group were assessable for pain response at 3 months. Nineteen (70%) patients in the SBRT arm and 20 (71%) in the 3DCRT arm were assessable for pain relief response at 6 months. The measurement repetition for variance analysis showed no significant difference in final VAS at 3 months (t2) (p = 0.13). However, a difference in time to subjective pain relief between both groups during the first 3 months was noted (p < 0.001, Fig. 5). The VAS value decreased faster in the SBRT arm (p = 0.01, Fig. 6). At 6 months (t3) following RT, significantly lower VAS values were reported in the SBRT group (p = 0.002). No differences were discerned between groups in terms of neuropathic pain at baseline, as well as 3 and 6 months following RT (Table 2).
Fig. 5OMED consumption in both groups during 12 weeks after end of the radiotherapy.
Pain response is given in Table 3. At 3 months, there was a trend (p = 0.057) toward improved pain response in the SBRT group, as 43.5% therein experienced a CR, as compared to 17.4% in the 3DCRT group. IP was present in 21.7% of the SBRT cohort, as compared to 52.2% in the 3DCRT arm. At 6 months, 52.6% of the SBRT arm achieved CR (10.0% for 3DCRT), with IP figures of 15.8% versus 65.0%, respectively (p = 0.003). At this time period, 73.7% of the SBRT patients were categorized as responders, as compared to just 35.0% of those undergoing 3DCRT (p = 0.015).
Table 3Response according to Brief Pain Inventory score at 3 and 6 months in the per-protocol cohort.
RT was altogether tolerated well. No patient in the SBRT group experienced grade ≥3 acute or late toxicities according to the Common Terminology Criteria for Adverse Events (v.4.03). In the SBRT group, the most common acute side effect was fatigue (two cases of grade 2, three cases of grade 1). One patient developed grade 1 dermatitis and another developed grade 1 dysphagia; two patients reported in-field pain flares for the initial 1–2 days. In the 3DCRT group, the most common acute side effect was fatigue (two cases of grade 2, five cases of grade 1). Five participants had grade 1 dermatitis, three patients had dysphagia (one of which was grade 2), and one patient reported grade 2 emesis (Table 4). No cases of radiation-related myelopathy or cauda equina injury occurred (Table 5).
It is imperative to provide randomized evidence supporting the utility of advanced technologies in the palliative setting. This study compared pain responses between high-dose SBRT versus standard 3DCRT in the palliative setting for untreated spinal metastases without spinal cord compression. It was demonstrated that single-fraction SBRT reduced pain levels faster during the 3 months following RT (p < 0.001) and led to improved pain scores.
The hypothesis that ablative dosing leads to improved tumor control is not new. The application of higher biological doses was preferred for radioresistant tumors, those previously irradiated, and oligometastatic disease [
]. Experiences with single-fraction SBRT (24 Gy) is limited to a few datasets. Gerszten et al. illustrated its safety and efficiency using the CyberKnife technique in patients with advanced melanoma [
]. In this study, 23 of 28 consecutive patients had been previously irradiated at the involved spine level. The median follow-up was 13 months, and long-term improvement in pain relief was reported in 96% of patients (n = 27). The initial and post-treatment pain value was measured on a ten-point scale. Changes in analgesic dosages were not specified in detail [
The prospective non-randomized study by Nguyen and colleagues reported CRs after 3 and 6 months in 48.7% and 52.8% of 48 evaluable renal carcinoma patients [
]. The median follow up was 13.1 months, although only 8 metastases were treated with 24 Gy. Nevertheless, these results are comparable to our CR rates at 3 and 6 months with 43.5% and 52.6%. Another prospective non-randomized study demonstrated actuarial local control rates of 91.2% at 1 year in patients without prior radiation [
]. Nevertheless, these numbers line up well with another investigation displaying 90% actuarial local control in 93 patients with 103 spinal lesions. Although most patients in that study received the same dosage as this trial, no information about the pain palliation was given [
]. Lastly, as this and most studies cannot completely address late toxicities, Moussazadeh et al. reported excellent toxicity profiles in highly selected survivors with a median follow up of 6.1 years [
The retrospective study by Jhaveri et al. investigated a dose–response relationship for time to pain relief in 18 renal cancer patients with 24 various bone lesions [
A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases.
]. Two hypofractionated schedules were used 5 × 8 Gy and 3 × 8 Gy. The median follow up was 38 weeks. Pain relief was recorded in 78% of all participants. Whereby the pain relief was quicker and more durable in patient cohort treated with BED >/= 85 Gy. Only 14 patients were treated with spine lesions [
]. Nevertheless these results are in many respects comparable to ours. We achieved a similar responder rate of 73.7% after 6 months. In contrast, our study included patients with radiosensitive and radioresistant primary site. A different pain response of the various cancer could distort the results. Similar with our results, SBRT had no effect on changes in concomitant analgesic consumption [
A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases.
The preexisting pathological fracture rate in our study was 29%. The incidence of new pathological fractures at 3 and 6 months following SBRT in our trial was 8.7% (n = 2) and 27.8% (n = 5) respectively. A systematic review by Faruqi et al. discerned risk factors for VCF after high dose SBRT, such as lytic lesions, preexisting VCF, and higher dose per fraction [
Frequency of symptomatic vertebral body compression fractures requiring intervention following single-fraction stereotactic radiosurgery for spinal metastases.
Risk of vertebral compression fracture specific to osteolytic renal cell carcinoma spinal metastases after stereotactic body radiotherapy: a multi-institutional study.
]. Our study showed a moderate pathological fracture rate in the SBRT arm, although the small sample sizes may have influenced this figure. No pathological fractures in either group required salvage surgical intervention.
There are a few limitations of this study worth mentioning, in addition to the aforementioned small sample sizes, the single-center nature, and shorter follow-up. First, studies of palliation encompass inherently heterogeneous patients, and the effect on subgroups cannot be analyzed. This also makes the results difficult to extrapolate to other work, along with the fact that the particular assessment methods (e.g., VAS) and frequencies thereof may differ from other work, thus also limiting generalizability.
Second, the Chow criteria recommend that patients with a pain level of minimum 2 (or rather 50/100) VAS be included in clinical trials. We included a total of 11 patients with a VAS <20/100, which is a constraint. This criteria also endorse utilization of the worst pain score over the previous 3 days, rather than the weekly mean values measured herein; these may also limit applicability. Third, steroid doses were not accounted for, which may be associated with pain levels and whether patients experienced “pain flares”. Lastly, particular reasons for opioid utilization as well as subjective response of pain relief are inherently difficult to evaluate and are known limitations of any palliative study despite the prospective nature.
Salient points from our results indicate that ablative dosing to vertebral metastases may offer clear advantages in terms of durable pain response and rapidity of such. Although 3DCRT remains the standard of care, and economic considerations of advanced technologies for palliation remain a concern. The currently closed phase III RTOG 0631 study and the Canadian Cancer Trial Group SC24 phase II/III study (NCT02512965) have implications on the standard treatment well as its perceived cost-effectiveness.
Funding source
The sponsors of the study had no role in study design, data analysis, data interpretation and wording of the report. The corresponding author (HR) had full access to the entire data of the study and had the final responsibility regarding the decision to submit for publication.
Conflicts of interest
The authors declare that they have no competing interests.
Authors’ contributions
HR and JD developed and planned this trial. TB is responsible for statistical considerations. TS, VV, RF, IS, NHN, TB, SEW and HR performed the examinations and RT supervisions. ET performed the treatment planning. HR and TS made the data collection. All authors read and approved the final manuscript.
Research in context
Evidence before this study
Narrative literature overview using the terms “SBRT”, “spinal metastases” resulted in various single-arm prospective and retrospective work, which are summarized in the study protocol.
Added value of this study
This study compared the pain response between high-dose single-fraction SBRT (24 Gy) versus conventionally fractionated 3DCRT (30 Gy in 10 fractions) for palliative management in untreated spinal metastases without cord compression. SBRT reduced pain levels faster during the initial 3 months after RT. Durable pain relief was achieved to a greater degree at 6 months in the SBRT group. There was no significant difference in the pattern of recorded OMED consumption between treatment arms at 3 and 6 months after RT.
Implications of available evidence
SBRT may offer quicker and more durable pain relief over a 6-month time period following therapy. SBRT has clear potential as a novel treatment approach in these patients.
Acknowledgements
We thank the Tschira Foundation for funding the implementation of this study. The authors thank all study participants for their great effort.
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Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction.
Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases.
High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial.
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