Impact of recent clinical trials on meta-analysis of stereotactic body radiation therapy for spine metastases and urgent call for consistent study endpoints
Brief Report | Palliative Medicine and Palliative Care for Incurable Cancer

Impact of recent clinical trials on meta-analysis of stereotactic body radiation therapy for spine metastases and urgent call for consistent study endpoints

Henry C. Y. Wong1#, Shing Fung Lee2#, Samuel Ryu3, Adrian Wai Chan4, Saverio Caini5, Peter Johnstone6, Yvette van der Linden7,8, Joanne M. van der Velden9, Emily Martin10, Sara Alcorn11, Candice Johnstone12, J. Isabelle Choi13,14, Gustavo Nader Marta15,16, Eva Oldenburger17, Srinivas Raman18, Agata Rembielak19,20, Vassilios Vassiliou21, Pierluigi Bonomo22, Quynh-Nhu Nguyen23, Shirley Tse24, Peter J. Hoskin19,25*, Charles B. Simone II13,14*

1Department of Oncology, Princess Margaret Hospital, Hong Kong, China; 2Department of Radiation Oncology, National University Cancer Institute, National University Hospital, Singapore, Singapore; 3Department of Radiation Oncology, Stony Brook University Hospital, New York, NY, USA; 4Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, China; 5Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy; 6Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 7Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands; 8Centre of Expertise in Palliative Care, Leiden University Medical Centre, Leiden, The Netherlands; 9Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; 10Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, LA, USA; 11Department of Radiation Oncology, University of Minnesota Medical Center, Minneapolis, MN, USA; 12Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 13New York Proton Center, New York, NY, USA; 14Memorial Sloan Kettering Cancer Center, New York, NY, USA; 15Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil; 16Latin America Cooperative Oncology Group (LACOG), Brazil; 17Department of Radiation Oncology, University Hospital Leuven, Leuven, Belgium; 18Radiation Medicine Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada; 19Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; 20Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; 21Bank of Cyprus Oncology Centre, Department of Radiation Oncology, Nicosia, Cyprus; 22Department of Radiation Oncology, Azienda, Ospedaliero-Universitaria Careggi, Florence, Italy; 23Department of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; 24Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China; 25Mount Vernon Cancer Centre, Northwood, UK

#These authors contributed equally to this work as co-first authors.

*These authors contributed equally for the senior authorship.

Correspondence to: Dr. Henry C. Y. Wong, MBBS. Department of Oncology, Princess Margaret Hospital, 2-10 Princess Margaret Hospital Road, Lai Chi Kok, Kowloon, Hong Kong, China. Email: henrywong3011@gmail.com.

Abstract: Pain from spinal metastases can result in significant impact to patients’ quality of life. Conventional external beam radiation therapy (cEBRT) has long been shown to be effective in the pain control of patients with spinal metastases. With the advancement in radiation therapy, stereotactic body radiation therapy (SBRT) has been increasingly adopted for the treatment of spinal metastases. Multiple randomised controlled trials (RCT) have been performed to evaluate whether SBRT provides better pain relief compared to cEBRT. Previous meta-analyses showed that SBRT have significantly better complete pain response at 3 months compared to cEBRT. This report updates meta-analyses by incorporating the complete pain response data obtained from personal communication with the NRG Oncology Radiation Therapy Oncology Group (RTOG) 0631 principal investigator and the recently published RCT by Guckenberger et al. The results demonstrate that the results for complete pain response at 3 months have now changed and no longer favour SBRT. It is postulated that inconsistent definitions and reporting of study endpoints, specifically regarding vertebral compression fractures induced by radiation therapy, could be possible reasons for the difference in meta-analyses results. A consensus for standardizing study endpoints for future clinical trials in SBRT for painful bone metastases is needed to allow for better interpretation of study results.

Keywords: Spine metastases; stereotactic body radiation therapy (SBRT); palliative radiotherapy

Submitted Sep 29, 2024. Accepted for publication Feb 17, 2025. Published online Mar 25, 2025.

doi: 10.21037/apm-24-145

We demonstrated in our previous meta-analysis that stereotactic body radiation therapy (SBRT) can achieve better complete pain response at 3 and 6 months compared to conventional external beam radiation therapy (cEBRT) in patients with spine metastases (1). We are now presenting results from our updated meta-analysis with regard to complete pain response, incorporating recent data that became available after our publication in September 2023. In the NRG Oncology Radiation Therapy Oncology Group (RTOG) 0631 randomised controlled trial (RCT), complete pain response from the evaluable patients were 38.4% vs. 46.1% at 3 months and 51.5% vs. 56.4% at 6 months in the SBRT and cEBRT arms respectively, showing no statistically significant differences (personal communication with Dr. Ryu, the Principal Investigator of the RTOG 0631 trial). Recent findings by Guckenberger et al. also indicated no significant differences between SBRT and cEBRT in complete pain response at 3 months (19.4% vs. 16.1%, P=0.73) and 6 months (22.2% vs. 29.0%; P=0.53) (2).

After integrating data from these two studies into our meta-analysis, complete pain responses at 3 and 6 months were statistically non-different between SBRT and cERBT arms (Figure 1A,1B). These results diverge from our initial meta-analysis, which only included studies by Sahgal et al. and Sprave et al. (3,4), where we concluded that SBRT was associated with a statistically significant improvement in complete pain response at 3 months. A significant heterogeneity was observed in the newly updated meta-analyses (3 months: I2=72%, P=0.01; 6 months: I2=68%, P=0.02), likely due to different baseline patient characteristics and SBRT dose fractionations employed across studies.

Figure 1 Complete pain response according to intention to treat analysis. (A) Meta-analysis of complete pain response at 3 months, (B) meta-analysis of complete pain response at 6 months, (C) network meta-analysis of complete pain response at 3 months with cEBRT as reference, (D) network meta-analysis of complete pain response at 3 months with 24 Gy in 2 fractions as reference. cEBRT, conventional external beam radiation therapy; CI, confidence interval; RR, risk ratio; SBRT, stereotactic body radiation therapy.

A network meta-analysis was further conducted to evaluate the relative efficacy of various SBRT radiation schedules for achieving complete pain response in 3 months. Amongst the regimens analysed, the regimen of 24 Gy in 2 fractions, as reported by Sahgal et al. (3), was the only one demonstrating a significantly superior complete pain response at 3 months when compared to cEBRT (Figure 1C). This regimen also showed a statistically significant advantage over the 16 or 18 Gy single-fraction regimens used in RTOG 0631 trial (5), although it did not achieve significant differences when compared to the 24 Gy single-fraction schedule used by Sprave et al. (4) or the 48.5 Gy in 10 fractions or 40 Gy in 5 fractions reported by Guckenberger et al. (2) (Figure 1D).

The similar overall pain response between SBRT and cEBRT in RTOG 0631 is postulated to be due, at least in part, to a lower biologically effective dose (BED) of SBRT relative to other studies (6). Interestingly, despite higher BED10 doses used in Guckenberger et al. (72 Gy10) and Sprave et al. (81.6 Gy10) compared to Sahgal et al. (52.8 Gy10), no superior complete pain response was observed in our network meta-analysis with these higher doses. These data highlight the complexity of dose-response relationships in spine metastases pain control, which warrants further investigation. One hypothesis is that differences in pain response may not be primarily dependent on radiation dose, as similar results have been observed in multiple RTOG trials since the 1980s (7,8).

It is suggested that the pain relief from tumour control with higher SBRT doses may be offset by pain from vertebral fractures. Although long-term vertebral compression fracture rates were the same between SBRT and cEBRT in the RTOG 0631 trial, Zeng et al. reported increased local control with SBRT but at the cost of higher toxicity in a secondary analysis of 66 patients from the RCT by Sahgal et al. Eight iatrogenic vertebral compression fractures were observed post-SBRT versus four fractures post-cEBRT (9). Notably, all grade 3 adverse fracture events were in the SBRT cohort (9). Although based on small numbers, this underscores that SBRT might carry a higher risk of symptomatic vertebral fractures compared to cEBRT, with the risk of iatrogenic vertebral compression fracture generally increasing when radiation doses exceeding a single 20 Gy fraction (10).

The variability in complete pain response among published RCTs can also be attributed to the heterogeneous assessment methods and the reporting of iatrogenic vertebral fractures. Unlike the secondary analysis by Zeng et al., the RTOG 0631 trial and the RCTs by Guckenberger et al. and Sprave et al. did not clearly document whether observed vertebral compression fractures were purely iatrogenic or concurrent with local tumour progression (2,4,5,9). The timing and imaging modalities used to diagnose these fractures, such as X-ray, computed tomography or magnetic resonance imaging, were also not standardised (2,4,5,9). Assessing the pain response specifically at the treated spine is also crucial for accurate evaluation and documentation of therapeutic outcomes.

A key limitation of our meta-analyses that needs to acknowledged is the heterogeneity of the definition of pain response and study inclusion criteria of the included RCTs. Unlike other RCTs, the RTOG 0631 trial did not use the International Consensus Pain Response Endpoints (ICPRE) for the assessment of pain response (5). Specifically, the RTOG 0631 trial used a score of 3 or more to define partial pain response, instead of the improvement of 2 or more in the ICPRE (11,12), and it did not provide clear definitions regarding how changes in narcotic analgesic requirements affect the evaluation of pain response or progression (5). Moreover, the RTOG 0631 trial included patients with a higher baseline pain score compared to the other RCTs, which may have made it more difficult for the SBRT arm to demonstrate relative benefit to the cEBRT arm (5,6). The variability of the efficacy outcome measures of the included RCTs may limit the interpretation of our pooled result in the meta-analyses.

The historical RTOG 7402 RCT resulted in contrasting conclusions when employing different study endpoints (13,14). This led to the development of the ICPRE for future clinical trials on bone metastases (11,12). This group is currently updating the third version of that consensus and establishing endpoints specifically for SBRT clinical trials. This initiative is crucial to standardise endpoints, allowing for more valid comparison across studies and incorporation into future meta-analyses. We propose that iatrogenic compression fracture should be a mandatory endpoint to report, along with pain response, in SBRT clinical trials for spine metastases. This would help delineate if residual pain post-SBRT is due to iatrogenic vertebral compression fracture rather than uncontrolled disease progression. We eagerly anticipate the results of this consensus study. When offering SBRT for palliation of metastatic bone pain, it is essential to inform patients that symptomatic iatrogenic vertebral compression fractures could be a trade-off for potentially better disease control at 3 and 6 months, as suggested by previous studies that reported on these outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine for the series “Palliative Radiotherapy Column”. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-145/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-145/coif). The series “Palliative Radiotherapy Column” was commissioned by the editorial office without any funding sponsorship. S.F.L. serves as the unpaid co-chair for the Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from October 2023 to September 2025 and served as the unpaid co-Guest Editor of the series. C.J. serves as the unpaid co-chair for the Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from February 2024 to January 2026 and served as the unpaid co-Guest Editor of the series. E.O. serves as an unpaid member of Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from December 2022 to December 2026. Q.N.N. serves as an unpaid member of Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from February 2024 to January 2026. C.B.S. serves as the co-Editor-in-Chief of Annals of Palliative Medicine from April 2014 to April 2027. C.J. reports that she serves as the Current Secretary/Treasurer in the Board of Trustees of the American Registry of Radiologic Technologists (ARRT), the Councilor to American College of Radiology (ACR) in the Board of Trustees of the Wisconsin Radiological Society, and as the Past President in the Board of Trustees of the American Association for Women in Radiology (AAWR). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Wong HCY, Lee SF, Ryu S, Chan AW, Caini S, Johnstone P, van der Linden Y, van der Velden JM, Martin E, Alcorn S, Johnstone C, Choi JI, Marta GN, Oldenburger E, Raman S, Rembielak A, Vassiliou V, Bonomo P, Nguyen QN, Tse S, Hoskin PJ, Simone CB 2nd. Impact of recent clinical trials on meta-analysis of stereotactic body radiation therapy for spine metastases and urgent call for consistent study endpoints. Ann Palliat Med 2025;14(2):155-159. doi: 10.21037/apm-24-145

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