A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here^※

Introduction

Bones are one of the most common sites of distant metastasis in advanced malignancies (1). The incidence of patients with bone metastases is likely to increase with continued advances in systemic therapy (2). Bone metastases commonly present with pain, which can be debilitating and may significantly affect quality of life (QOL) (3). Conventional external beam radiotherapy (cEBRT) has been used to treat patients with painful bone metastases for decades (4). Radiation is effective in alleviating pain in patients with bone metastases because it kills off tumour cells and deactivates osteoclasts, which in turn stabilizes the bones and reduces the pressure effect on surrounding nerves (4). Many radiation doses and schedules have been used, with none of them showing superiority over another with regards to pain response (5,6).

Since the pooled overall pain response of cEBRT is around 60% (5,7), there has been interest whether dose escalation can result in a higher pain response. Highly conformal radiation techniques, such as stereotactic body radiation therapy (SBRT), allow delivery of a much higher dose per fraction to a target while sparing the critical structures nearby (8). Seven randomized controlled trials (RCTs) using SBRT have been performed to date, all with different inclusion criteria, study endpoints and radiation treatment schedules (9-15). Unfortunately, their results are somewhat conflicting. For example, the RCT by Sahgal et al. demonstrated superiority of SBRT, whereas that by Pielkenrood et al. did not (11,14).

The American Society for Radiation Oncology (ASTRO) evidence-based guideline on palliative radiation therapy for bone metastases published in 2017 suggested that SBRT should be considered only in a trial setting (16). Similarly, the 2022 European Society for Radiotherapy and Oncology (ESTRO) guidelines for patients with uncomplicated bone metastases also recommended that there is not enough evidence for routine use of SBRT in patients with painful bone metastases (17).

Four systematic reviews comparing SBRT versus cEBRT for patients with previously unirradiated painful bone metastasis were published in 2022 (18-21). Two of these reviews reported a benefit of SBRT over cEBRT in overall pain response at 3 months (18,20), whereas the other two did not (19,21).

This clinical practice review aims to discuss the conclusions of and discrepancies between the systematic reviews, how the radiation oncology community should use these results in clinical practice, and how future research should be performed to better define the role of SBRT in the treatment of bone metastases.

Study design of the systematic reviews

All four reviews used overall pain response at 3 months as their primary endpoint (18-21). Overall pain response and complete pain response at other time points were studied as co-primary endpoints by Song et al. (18), whereas they were secondary endpoints in the publications of Lee et al. and Ito et al. (19,21). Adverse events were assessed as secondary endpoints in all four studies. Lee et al. and Ito et al. also assessed local control and QOL as secondary endpoints (19,21) (Table 1).

Song et al. included RCTs, prospective cohort studies, and retrospective analyses in their systematic review. The inclusion of study designs other than RCTs could be problematic, as the documentation of pain response in these primary studies may be incomplete and could be done at varying timepoints, which cannot be directly compared. Song et al. addressed this point by performing a separate meta-analyses for all included studies and RCTs only (18). Only conclusions of the meta-analysis of RCTs by Song et al. will be discussed in this paper. The other three systematic reviews only included RCTs. Table 2 summarises RCTs that were included. It is important to highlight that the phase 3 RTOG 0631 trial by Ryu et al., which is the largest such RCT comparing SBRT and cEBRT to date with 339 patients, has only been published in abstract form to date (13). An exploratory sensitivity analysis excluding Ryu et al. was performed by Lee et al., but not by Ito et al. (19,21).

Ito et al. and Wang et al. performed meta-analyses of results using relative risk ratios (RR), whereas Lee et al. and Song et al. used odds ratio (OR) (18-21). Reporting using ORs in meta-analysis may overestimate the relative risk when the incidence of the endpoint is common (for example, more than 20%) (22). This may have affected the interpretation of the results.

Commentary on results of systematic reviews and meta-analyses

Pain response

Overall pain response at 3 months was superior for SBRT in the systematic reviews by Song et al. and Wang et al., but not in those by Ito et al. and Lee et al. (18-21). The most likely reason for this difference is the inclusion of the negative RTOG 0631 trial of Ryu et al. by Ito et al. and Lee et al., since it was heavily weighted due to its large sample size. Song et al. excluded RTOG 0631 from their analysis, on the basis that “only the abstract without primary endpoint was published” (18). The meta-analysis by Wang et al. did not give any specific reasons for excluding RTOG 0631 (20). An exploratory analysis by Lee et al. confirmed that if RTOG 0631 was excluded, SBRT would be associated with statistically significant benefit over cEBRT in overall pain response at 3 months (21).

Lee et al. noted the inclusion of patients with more severe pain in RTOG 0631 at baseline and its more stringent definition of partial pain response as possible reasons why the trial had negative findings, compared to other RCTs (21). The RTOG 0631 trial defined partial response as a reduction of worst pain score of 3 or more compared with baseline on a scale of 0 to 10. However, the other RCTs generally used the definition of the International Consensus on Palliative Radiotherapy Endpoints (ICPRE) (23,24), which characterises a partial pain response as a reduction of worst pain score of 2 points or more compared with baseline on a scale of 0 to 10 without increase in oral morphine equivalent consumption. However, it remains unclear whether the results of RTOG 0631 would be different using this more liberal definition.

Other reasons cited to explain the negative result of RTOG 0631 included the lower dose used (16 or 18 Gy single fraction; BED10: 41.6 or 50.4 Gy₁₀) compared with the dose in the RCT by Sprave et al. (24 Gy single fraction; BED10: 81.6 Gy₁₀) (10) and Sahgal et al. (24 Gy in 2 fractions; BED10: 52.8 Gy₁₀) (11). Another possible explanation is that the RTOG 0631 study allowed patients to have up to a total of three study segments in the spine, compared to only one in Sahgal et al.’s study and two in Sprave et al.’s (10,11,13,25). Treatment of non-study spine metastases was not permitted in RTOG 0631, whereas this was allowed in Sahgal et al.’s study at the discretion of the treating radiation oncologists (11,25). Coupled with patients’ higher baseline pain score compared to the other studies, there is a possibility that patients in RTOG 0631 had more severe and extensive spinal disease, possibly contributing to spinal instability (26). An unstable spine results in mechanical pain on top of the pain from the studied spinal segments, resulting in the relative benefit of SBRT over cEBRT not being as pronounced in RTOG 0631. Although RTOG 0631 attempted to control for the confounding effect of spinal instability by recruiting patients with a spinal collapse of less than 50% and excluding those with vertebral compression fracture and bony retropulsion, this was not likely as sensitive as the Spinal Instability in Neoplasia Score (SINS) employed by Sahgal et al. (11,25), which has shown reliability and validity amongst both spine surgeons and radiation oncologists (27,28).

While the benefit of overall pain response at 3 months for SBRT was inconsistent among the four meta-analyses, SBRT resulted in more frequent complete pain response at 3 and 6 months in all three reviews that included it as an endpoint (18,19,21). However, the RTOG 0631 trial results for complete pain response at any time point have not yet been reported, and therefore the meta-analyses did not include it into their calculations. It is not known whether the same conclusion will be reached once RTOG 0631 is fully published. Wang et al. and Song et al. also studied pain response at 1 month (18,20). No differences were seen in the overall and complete pain responses in both studies. Future studies need to better characterise the time to pain response for the different radiation techniques. For some patients with intractable pain and a poor prognosis, having complete pain relief at 3 months after radiation treatment may not be meaningful. A possible way to understand patients’ time to pain response is to use pain diaries or (abbreviated) patient-reported outcome measure tools.

The durability of pain relief after initial pain response is also important and arguably more clinically meaningful than assessing pain response at a specific time point. However, most existing studies that include duration of response as an endpoint considered competing events such as death and reirradiation as censored rather than events of interest and therefore may overestimate the results (29). Net Pain Relief, which is the proportion of remaining life spent with pain response, has been advocated to be an important endpoint in palliative radiotherapy for bone metastasis and could be used in future studies assessing SBRT (30).

One of the major potential advantages of systemic reviews is their greater power to perform subgroup analyses. For example, Lee et al. found that multiple-fraction SBRT regimens were more effective than single-fraction regimens and that the proportion of baseline pain scores 5 or higher had an impact on the OR of relief from SBRT (21). Song et al. showed that giving SBRT with static field intensity modulated radiation therapy (IMRT) instead of volumetric modulated arc therapy (VMAT), Novalis shaped beam therapy or Cyberknife had better analgesic effect, possibly due to more hot spots generated by the low homogeneity index of IMRT (18). However, subgroup findings between these systemic reviews also varied. Song et al. demonstrated that the analgesic advantage with SBRT was more pronounced with spinal lesions compared to non-spine lesions when all studies (including non-RCTs) were analysed. This observation was not seen when the subgroup analysis was performed in RCTs only (18). Ito et al. and Lee et al. also showed that the benefit of SBRT in patients with spine or non-spine lesions were not statistically different in their subgroup analysis (19,21). While the RCTs predominantly had patients with spine metastases, close to half (133 out of 267 patients, 49.8%) of the patients in the non-RCTs of the meta-analysis by Song et al. had non-spine bone metastases (18,31-34). The imbalance of patients between the spine and non-spine subgroups in the RCTs may be a reason why a difference was not shown.

Local progression

The secondary endpoint of local progression was included in the meta-analyse of Song et al. and Lee et al. (18,21). Lee et al. found that there was a significantly lower local progression rate in the SBRT group, based on the RCTs by Nguyen et al. and Sahgal et al. (OR =0.19; P<0.01) (11,12). Song et al. analyzed the local progression-free survival (PFS) of these two RCTs and showed that there was no statistical difference, but there was a trend towards better PFS in the SBRT group (pooled hazard ratio: 0.18, P=0.334) (18). Local progression rates may be a more appropriate endpoint than PFS for analyzing RCTs which contain patients with diverse tumour histologies, who receive many types of systemic treatments, and who have highly variable overall prognoses, as death may occur before local progression in patients with metastatic disease. The lower risk of local failure following SBRT was confirmed at longer follow-up of the cohort of patients previously enrolled in the study of Sahgal et al. (35).

Adverse events

The four meta-analyses consistently showed that the fracture rate was not increased in the SBRT group (18-21). However, the median follow-up ranged from 6 to 8.1 months among the RCTs which specified the duration of follow-up, and therefore this conclusion should be treated with caution (9-11,18-21). One hundred thirty seven patients treated with SBRT in the trial of Sahgal et al. were reviewed for long term complications (35). At a median follow up of 11.3 months, there was a trend towards an increased rate of iatrogenic vertebral compressive fracture (VCF) after SBRT compared with cEBRT (P=0.0866), with all of the five grade 3 VCF in the SBRT group (35). This suggests that the risk of VCF could become more apparent with longer follow-up and may be underestimated by the current meta-analyses.

In the meta-analysis by Lee et al., patients in the SBRT group had a higher rate of pain flare (43%) compared to the cEBRT group (33%) (21). However, the definition of pain flare was not well defined in the individual RCTs. Sahgal et al.’s study specified pain flare as any patient-reported increase in pain that required dexamethasone during and up to 1 month after radiotherapy (11). More studies are needed to investigate the severity of pain flare and how it affects the QOL of patients.

The incidence of other adverse events of grade 2 or higher, such as nausea, fatigue, radiation dermatitis, and dysphagia, were similar between the two arms in the systematic reviews. No radiation myelopathy events were seen.

QOL

Westhoff et al. demonstrated that patients who have a pain response to radiotherapy have a better QOL (36). However, other problems caused by bone metastases, such as impairments in mobility and performing activities of daily living, also affect patients’ QOL and may not necessarily correlate with their level of pain (37,38). Hence, assessing QOL with a validated patient-reported tool may be more useful than performing pain assessment alone in evaluating the efficacy of treatments for bone metastases.

The systematic reviews by Ito et al. and Lee et al. included QOL as a secondary endpoint. Although they found complete pain response was improved with SBRT at 3 months, improvement in QOL was not consistently observed (19,21). Pielkenrood et al. and Ryu et al. even showed that patients who received cEBRT had a better QOL (13,39). However, different trials used different instruments to assess QOL. This makes the results harder to interpret, especially when viewed in combination with the heterogeneity in histologies, systemic treatments used, number of metastatic sites (both in bone and non-bone), and disease prognosis amongst study participants.

An additional confounding factor in assessing the benefits of SBRT to cEBRT is that the latter were performed using 2D or 3D conformal techniques. Randomised phase II studies using conventional radiotherapy schedules but different treatment techniques in the two arms have suggested that patients treated with VMAT for bone metastases had a better QOL than those treated with cEBRT, possibly because of its ability to give less radiation dose to normal tissues and hence result in fewer side effects (40,41). The results of an ongoing multi-centre phase III study are eagerly awaited to confirm the improvement in QOL with these advanced techniques (42). Future studies that study QOL as a primary endpoint should consider comparing SBRT with cEBRT planned by IMRT/VMAT. QOL assessment tools also need to be updated to address the side effects of SBRT such as pain flare, compression fractures, and esophagitis (when treating cervical and thoracic spine metastases) (43,44).

Summary

The conclusions of the four systematic reviews are summarized in Table 3. The conflicting results and methodology of these trials result in uncertainty whether overall pain response at 3 months is better with SBRT than cEBRT. However, SBRT may result in a higher rate of complete pain response at 3 months and beyond and offer improved local control. Additionally, SBRT appears as safe as cEBRT at least in the short term, although SBRT may increase the risk of a pain flare.

Cost effectiveness of SBRT

SBRT is typically more expensive and more labour-intensive than cEBRT for several reasons. First, magnetic resonance imaging, which may not be conveniently available due to resource limitations, is often paramount to accurately delineate the tumour target and the organs at risk (8). Additionally, immobilisation devices are needed to avoid geographical miss, and sophisticated quality assurance programs are necessary to ensure the accuracy of dose calculations and delivery (8). Both of these may not be required to the same degree for cEBRT treatments. The estimated cost of spine SBRT based on the US national Medicare reimbursement rate for 2020 is US $9,400 and US $11,100 for single and two-fraction treatments respectively (45). These rates are more than double the cost of a five-fraction cEBRT treatment (US $4,330) and more than triple that of a single-fraction treatment (US $3,000) (45).

Kowalchuk et al. assessed the cost-effectiveness of SBRT using a cost-utility model, based on the estimates of cEBRT and SBRT to achieve complete pain response at 3 months in the studies of Sahgal et al. and Sprave et al. The incremental cost-effectiveness ratio (ICER) for two-fraction SBRT treatment compared to single-fraction cEBRT was US $194,145 per quality-adjusted life-year (QALY) gained, which was nearly double the commonly employed willingness-to-pay threshold of US $100,000 per QALY gained (45). Therefore, two-fraction SBRT was concluded to be not cost-effective. Single fraction SBRT had a lower treatment cost and was cost-effective with the ICER of US $92,833 per QALY gained (45). If two-fraction SBRT resulted in improved overall survival, the treatment becomes cost-effective after 3 months (45), suggesting appropriate patient selection for this treatment is essential.

Assessment of cost-effectiveness with ICER, however, does not address the opportunity costs incurred by SBRT (46). The additional manpower and machine time allocated for SBRT may affect some patients’ access to timely treatment, although the time to perform SBRT treatments may vary depending on the treatment centres’ prior experience with advanced radiation techniques. Oncology centres already using IMRT or VMAT in the palliative or curative setting may find the burden of implementing SBRT to be modest, but the cost of introducing SBRT may be substantial in other centres where 2D or 3D conformal techniques are predominantly used. Therefore, resource allocation should be individualised for each cancer centre based on its expertise in performing advanced radiation techniques and its budget.

The number needed to treat (NNT) is an intuitive measure of the relative efficacy of different treatments and may help guide decisions on resource allocation (47). Table 4 summarises the NNT for complete pain response at 3 months with SBRT, based on the randomised trials of treatment of spine metastases. Arifin et al. estimated that one-third of patients treated with cEBRT in a large-volume tertiary centre in Canada would be eligible for SBRT based on the inclusion criteria of Sahgal et al. (48). This could substantially increase the workload and resource utilisation for the treatment facility if all of these patients were treated with SBRT. Yet, based on the NNT, only 1 in 5 SBRT treatments would result in complete pain response beyond that expected from cEBRT. It is important that oncology centres perform comprehensive cost-benefit analyses specific to their capacity to carry out SBRT before routinely offering SBRT to every suitable patient. An example on how to employ this is to use league tables. This approach ranks all the available intervention based on their ICER in the form of a table and implements them beginning at the top of the league table until the budget is exhausted (49,50). Using this approach, the ICER of radiotherapy using 2D, IMRT/VMAT or SBRT can all be calculated and ranked. Whether SBRT should be adopted would depend on both its ICER and the size of the budget.

Although the randomised studies cannot be directly compared because of the different inclusion criteria and definitions for pain response, the lower number to treat for complete pain response at 3 and 6 months for Sprave et al.’s study may suggest that dose escalation could achieve greater pain control relative to cEBRT. It should be highlighted that the vertebral compression fracture rates were however more than doubled in Sprave et al.’s study (27.8%) compared to Sahgal et al. (11%) (10,11). Delivering 24 Gy in only a single fraction (BED10 81.6 Gy) may have contributed to this increase. A retrospective analysis by Zeng et al. compared patients treated with 28 Gy in 2 fractions (BED10 67.2 Gy) to those treated with the schedule in Sahgal et al.’s study (24 Gy in 2 fractions, BED10 52.8 Gy) (51). This study demonstrated that this two-fraction high-dose regimen was associated with a lower risk of magnetic resonance imaging (MRI)-assessed local failures, while not increasing the risk of vertebral compression fractures. Prospective studies are needed to compare the efficacy and safety of a single-fraction dose scheme (for example, 21 Gy, BED10 65.1 Gy₁₀) to 24 Gy or 28 Gy delivered in 2 fractions.

Future research directions

Routinely using SBRT for all patients with painful bone metastases would add significant workload and cost to the health care system. Hence, it is very important to determine which patients benefit meaningfully from it.

Problems in analysing trials comparing SBRT to cEBRT include the need for longer follow-up, attention to more endpoints with uniform definitions, and performing subgroup analyses, as have been discussed above. Another major issue is to understand patients’ preferences for the choice of radiation technique. For example, some of the immobilisation devices used to ensure a reproducible set-up for SBRT may be more uncomfortable for patients. Patients with a poor performance status or highly symptomatic disease may not be able to tolerate the longer treatment time of SBRT. Additionally, a relatively longer preparation time is required for SBRT treatment, which may result in patients in some centers needing to wait for weeks to begin radiation instead of days or hours. Patients may also develop higher rates of pain flare with SBRT. In the randomised trial by Pielkenrood et al., 27% of patients randomised to the SBRT arm declined the offer of SBRT due to its less efficient planning logistics. For patients who consented to receive SBRT, 21% of them could not complete the treatment. Reasons for this included increased pain due to the long waiting time, severe pain flare after first treatment and inability to complete MRI planning due to pain (14). Hence, some patients may decide to receive cEBRT instead of SBRT, accepting a lower chance of complete pain response in the long term but quicker access to radiation treatment, with the option of repeating cEBRT or SBRT later if there is suboptimal or short duration of pain response. It would be helpful to understand patients’ preferences for treatment with a large-scale prospective survey and collect patient feedback on their experiences before, during and after SBRT.

Another unsettled issue is whether SBRT improves outcome for patients with non-spine bone metastases. The randomised phase II study by Nguyen et al. had the largest number of patients with non-spine bone metastases (154 patients) (12). This study showed that giving 12 or 16 Gy in a single fraction by SBRT was non-inferior to multi-fraction cEBRT (30 Gy in 10 daily fractions). The higher dose of 16 Gy was associated with a higher rate of pain control and improved local control (12,52). On the other hand, the randomised phase II study by Pielkenrood, which included 45% of patients with non-spine bone metastases, showed that SBRT did not improve pain response (14). One can argue that pain response was better in the 16 Gy group in the study by Nguyen et al. because the lesions were smaller than the 12 Gy group (≤4 versus >4 cm) (12). However, the reason why the study by Pielkenrood et al. was negative is still unknown because the SBRT dose used was even higher (BED10 50.4 to 60 Gy in Pielkenrood et al. versus 26.4 to 41.6 Gy in Nguyen et al.) (12,14). As for spine SBRT, further studies are needed to determine the timing of pain flare and limiting radiation dose for radiation-related fractures. Studies also are needed to determine indications for when surgical stabilization of non-spine bones should be performed to reduce risks of radiation-induced fractures.

The publication of Sahgal et al. triggered different opinions in the radiation oncology community on whether to adopt its results for patients with painful spine metastases. Cellini et al. suggested that only selected patients should be offered SBRT since there are still many unanswered questions about the technique, such as the optimal dose and the need for a simultaneous integrated boost (53). In response, Sahgal et al. advocated for SBRT as the standard of care and that that future studies should focus on improving SBRT technique instead of comparing the efficacy of SBRT and cEBRT (54). van der Velden et al. concurred with Cellini et al. that patients should be carefully selected for SBRT, given that this treatment is more time-consuming and expensive. Their team suggested that patients at least should have an expected long life expectancy before offering the option of SBRT (55).

It would seem reasonable to preferentially offer SBRT to patients with a longer expected survival. However, estimating the length of survival of patients with bone metastases is very complex, as many factors that come into play. Zeng et al. found that less radiosensitive histology, presence of paraspinal disease, Eastern Cooperative Oncology Group (ECOG) score 2 or higher, the presence of polymetastatic disease, and the presence of pain were independent prognostic factors for survival of fewer than 3 months in patients treated with spinal SBRT (56). Jensen et al. developed a Prognostic Index for Spine Metastases (PRISM) based on patients treated with spinal SBRT in clinical trials. Factors in the scoring system included gender, performance status, previous therapy at the intended treatment site, number of organ systems involved, the time elapsed between diagnosis and metastasis, and number of spine metastases (57). This scoring system was validated with a retrospective cohort but has not been used to stratify patients in clinical trials. Further prospective validation studies of relevant prognostic factors and prognostic indices for patients with both spine and non-spine bone metastases are warranted to support their use in the clinic.

The use of SBRT for painful bone metastases may be most justified in the oligometastatic setting (58), especially if resources are limited. Local control can be maximised with SBRT, which may in turn translate into improved overall survival (59). Prospective studies are needed to confirm the survival, pain control and QOL benefits of SBRT in different patterns of oligometastatic bone disease.

The above questions may warrant several prospective trials to answer, which will take several years to perform. A meta-analysis of individual participant data from existing randomised controlled trials would be helpful in providing some preliminary data to guide treatment decisions in the interim. Firstly, this allows for reassessing patients’ pain responses based on a common set of definitions. Secondly, patients can be regrouped based on the SINS and Mirels’ scores for spine and long bone lesions, respectively. Those who have an unstable spine or impending fractures can be included in a sensitivity analysis. Prognostic factors for pain outcomes, such as the number of spine lesions and size of soft tissue mass, can be studied with a larger patient number as well. In addition, separate analyses can be performed in patients with spine and non-spine bone metastases, and patients with radioresistant and radiosensitive histologies. We encourage Ryu et al. to publish their full results to allow researchers to better understand why a benefit was not observed in their SBRT arm. When individual patients treated with different SBRT dose schedules are pooled together, we may be able to show a clearer relationship between radiation dose and pain response. A dose threshold above which further escalation would result in deleterious effects on pain control or toxicities may also be defined.

Conclusions

Based on the systematic reviews on RCTs published to date, SBRT may produce a better complete pain response at 3 and 6 months compared to cEBRT in painful bone metastases. However, the effect on overall pain response, especially at earlier time points, is uncertain. Future studies need to focus on selecting the optimal candidate and dose schedule for SBRT. Table 5 summarizes our current understanding of SBRT for the treatment of painful bone metastases and areas where further research should focus on. While we await the results of prospective studies, the international community should consider developing consensus guidelines with a Delphi study to guide SBRT use. Routine use of SBRT for all patients with painful bone metastases, however, may postpone effective pain treatment in patients with poor prognoses and put added strain on healthcare systems.

Acknowledgments

Funding: 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-23-218/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-23-218/coif). The series “Palliative Radiotherapy Column” was commissioned by the editorial office without any funding or sponsorship. C.B.S. serves as the co-Editor-in-Chief of Annals of Palliative Medicine. C.J. serves as the unpaid co-chair for the Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from February 2022 to January 2024 and served as the unpaid Guest Editor of the series. Q.N.N. serves as the unpaid member of Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from February 2022 to January 2024. E.C. serves as the unpaid co-chair for the Palliative Radiotherapy Subcommittee and unpaid Editorial Board Member of Annals of Palliative Medicine from February 2022 to January 2024 and served as the unpaid Guest Editor of the series. E.O. serves as the unpaid member of Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from December 2022 to November 2024. 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.

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^※Special series on Palliative Radiotherapy Column.

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