Asymptomatic bone metastases: 2024 American Society for Radiation Oncology (ASTRO) education panel

It has long been recognised that incidental irradiation of bone sites with relatively low doses can reduce the likelihood of bone metastases developing in those sites. Examples are seen with older techniques for postoperative breast cancer, which included the internal mammary lymph node chain and resulted in radiation to the sternum and an exit dose to the dorsal spine. A marked reduction in later incidence of dorsal spine metastases was seen in these patients (1,2). Similarly, a more recent study in prostate cancer comparing 54 patients having prostate alone treated with 56 having prostate and regional lymph nodes irradiated demonstrated a significant reduction in the number of pelvic bone metastases in the cohort having nodal irradiation (3). A similar effect has been demonstrated with low-dose prophylactic radiotherapy delivering a single dose of 8 Gy to the pelvic girdle prior to prostate radiotherapy with none of the 32 patients in a pilot study having pelvic bone metastatic relapse (4). More extreme examples are seen after hemibody radiotherapy or systemic strontium (⁸⁹Sr) administration. Radiation Therapy Oncology Group (RTOG) 8206 was a phase III study evaluating the added benefit of hemibody irradiation added to local radiotherapy for a painful bone metastasis (5). Progression of bone metastases within the hemibody was seen in 19% of those who received hemibody irradiation and 26% of those who did not. In the TransCanada trial of strontium having a similar phase III design randomly comparing a cohort of patients having local radiotherapy for bone pain to receive strontium (6). The probability of being free from new sites of pain in the strontium group was 58.7% compared to 34% in the control group having just local radiotherapy.

Against this background, it is not surprising that the recently published phase II study of prophylactic irradiation to high-risk asymptomatic bone metastases demonstrated a reduction in subsequent skeletal-related events (SREs) (defined by pathological fracture, spinal cord compression and surgery or radiotherapy to the bone) from 29% to 1.6% (7). There was also an impact on survival which was increased from 1.0 to 1.7 years with a hazard ratio of 0.49. This was accompanied by an enthusiastic editorial suggesting that the results were so compelling a confirmatory phase III trial was not needed and this approach should be considered standard of care (8).

There are however, reasons to be a little more circumspect; this was a small trial of only 78 patients, of whom 35 and 36 respectively, were available for the final analysis in each arm. The population was heterogeneous both in terms of primary tumour and, more importantly, radiotherapy schedule with 4 different schedules given: 8 Gy single dose, 30 Gy in 10 fractions, 20 Gy in 5 fractions, and 27 Gy in 3 fractions. The definition of “high-risk” which was required for study entry included: bulky bone disease greater than 2 cm, involvement of the hip, shoulder or sacroiliac joints, involvement of a long bone involving one-third to two-thirds of the cortex, vertebrae of the junctional spine (C7–T1; T12–L1; L5–S1), or involvement of the posterior element of a vertebra. In addition, patients had to have more than five bone metastases to exclude oligometastatic disease.

This study then leaves more questions than answers and is clearly not evidence on which to base a new standard of care. Obviously, we should not and could not realistically offer all asymptomatic bone metastases radiotherapy. Can we identify “high-risk” metastases with confidence? The designation in the Gillespie trial seems somewhat arbitrary (7). What is the relative role of bisphosphonates or denosumab? Is systemic radioisotope therapy more rational than piecemeal local external beam fields? What is the optimal dose schedule? How would such an approach integrate with the use of long-term systemic treatment including immunomodulation?

Critically, what might be the benefit of prophylactic irradiation of “high-risk” bone metastases? A reduction in SREs is worthwhile, although it would be important to correlate this with quality of life and performance status. Functional activity is important to patients and if this can be maintained, that would be worthwhile. It is also worth considering the complexities surrounding the use of radiotherapy as an endpoint for SREs. In the Gillespie trial, radiotherapy was the most frequently triggered SRE (7). However, the decision to initiate or withhold radiotherapy is subject to physician judgment and may be influenced by prior treatments. Specifically, patients who had previously undergone prophylactic radiotherapy may have been less likely to receive subsequent palliative irradiation due to concerns about cumulative toxicity or marginal benefit. Conversely, patients in the control group who had not previously received radiotherapy may have been more readily offered it upon symptom development. As such, the reported incidence of radiotherapy-triggered SREs may not purely reflect underlying disease burden or symptomatic deterioration, but rather clinical caution or practice patterns. This potential bias calls into question the validity of radiotherapy-based SREs as an objective surrogate for clinical detriment and highlights the importance of including patient-reported outcomes and quality of life metrics in future trials. A substantial impact on survival was also seen in this phase II trial. Is this really credible or a reflection of secondary endpoint analysis in a very small study? In general, treatment of bone metastases alone has not been shown to impact survival, although in principle, given the relationship between performance status and survival, if patients can be enabled to remain active for longer, mortality could be reduced. Against this, neither RTOG 8206 nor the TransCanada study showed an improved survival in the treated groups despite a reduced incidence of progressive bone metastases. In contrast, the phase III studies of radium-223 in prostate cancer have shown a modest improvement in survival, attributed to a specific tumour cell kill effect, alongside a reduction in SREs (9). However, it is important to note that radium-223 is typically given as repeated doses at 4 weekly intervals and hence a much larger cumulative radiation dose to the metastases is delivered. This reflects the low penetration of alpha particles and limited bone marrow depression with radium-223, unlike the beta-emitting strontium.

These anomalies alone, in an era of improved systemic management and prolonged survival, surely demand that a large, adequately powered and well-designed study with appropriate endpoints will be undertaken to clearly define the role of prophylactic radiotherapy for asymptomatic bone metastases.

Acknowledgments

The data of this article were presented in part during a session of the American Society for Radiation Oncology (ASTRO) at the 66th ASTRO Annual Meeting in Washington DC, USA on Oct. 1st 2024.

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-25-5/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-5/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. P.J.H. is supported by the NIHR Manchester Biomedical Centre (NIHR203308), outside the submitted work. 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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