Re-treatment of bone metastases for pain control: 2023 ASTRO education panel
Shing Fung Lee1
, Charles B. Simone II2
, Dirk Rades3, Henry C. Y. Wong4, Edward Chow5
Contributions: (I) Conception and design: E Chow; (II) Administrative support: CB Simone 2nd, E Chow; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Abstract: Bone metastases are a common and debilitating consequence of advanced cancer, often necessitating palliative radiation therapy (RT) for pain relief. Reirradiation (reRT) of bone metastases is often considered after lack of pain relief following an initial course of RT, after a partial but unsatisfying pain response to an initial course of radiotherapy, or after pain recurrence following a complete or partial pain response to an initial course of RT. The NCIC CTG SC.20 trial, a landmark multicenter, randomized, non-blinded, controlled non-inferiority trial, addressed the critical question of optimal dose fractionation for reRT in this patient population. This trial compared the efficacy and toxicity of a single 8 Gy fraction to multiple fractions totaling 20 Gy in 850 patients with painful bone metastases requiring reRT. The primary endpoint was overall pain response at 2 months, with secondary endpoints of quality of life (QoL) measures, functional interference, and toxicity profiles assessed using patient-reported questionnaires and the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. The intention-to-treat analysis revealed no significant difference in pain response between the two arms, meeting the pre-specified non-inferiority criteria. The per-protocol analysis suggested a potential benefit for a subset of patients receiving multiple fractions, although this was not statistically robust. Acute toxicities were more prevalent in the multiple fractions arm, with implications for patient comfort and healthcare utilization. Importantly, responders to reRT reported significant improvements in functional interference and QoL. The trial’s findings support the use of a patient-centric approach to palliative RT, highlighting the viability of a single 8 Gy fraction as a less toxic and more convenient treatment option, albeit with consideration for individual patient circumstances. These results have significant implications for clinical practice, potentially reducing healthcare burdens while optimizing patient convenience during palliative care for painful bone metastases.
Keywords: Bone metastases; reirradiation (reRT); radiation therapy (RT); pain management; quality of life (QoL)
Submitted Feb 02, 2024. Accepted for publication Apr 19, 2024. Published online Jun 11, 2024.
doi: 10.21037/apm-24-15
Pain management in patients with bone metastases is a cornerstone of palliative care in oncology. Bone metastases, a common manifestation in advanced cancers, particularly of the breast, prostate and lung, significantly impair quality of life (QoL) due to the moderate to severe pain and skeletal-related events they cause (1). Radiation therapy (RT) has long been established as an effective modality for palliating pain in these patients. However, the optimal dose fractionation, especially in the setting of reirradiation (reRT), remained a subject of clinical inquiry (2).
The survival of cancer patients has markedly improved due to advances in systemic therapies and supportive care, leading to an increased incidence of patients outliving the pain control benefits of their initial RT course and subsequently requiring reRT for palliative management (3). The challenge lies in balancing efficacy and symptom control with toxicity, especially considering the general frailty of this patient population and their overall often limited prognostic outlook.
Significant advancements have been made in our understanding of reRT for painful bone metastases using single fraction RT over the past decades. The 1994 retrospective cohort study by Mithal et al. revealed that reRT of bone metastases can yield pain responses comparable to initial irradiation, with success rates approaching 80% (4). This research underscored that no major differences were found in dose-fractionation schedules, showing that single doses were equally effective (4). Additionally, it was observed that the type or site of the primary tumor did not markedly affect outcomes, providing a foundational basis for advocating reRT in cases where initial irradiation elicited a response (4).
Subsequent research by Jeremic et al., beginning with their 1998 study, identified 8 Gy as the most effective minimal single fraction dose for initial treatment, surpassing the efficacy of 4 and 6 Gy doses (5). This study also recognized the potential benefits of a 4 Gy dose in situations necessitating reRT or when treating large fields, considering its 45–60% overall response rates (5).
Further investigations by Jeremic et al. in 1999 and 2002 expanded on the utility of 4 Gy in re-treatment (6,7). The 1999 study demonstrated a 74% response rate for 4 Gy re-treatment after initial single fraction RT of 4, 6, or 8 Gy (6). Notably, 46% of those who did not initially respond showed a positive response upon reRT, with patients who had previously experienced complete responses more likely to do so again (6). The 2002 study confirmed the efficacy and minimal toxicity of a second 4 Gy reRT following two prior single fraction RTs, evidenced by an 80% overall response rate (7).
These findings were further supported by an analysis of the original Dutch Bone Metastasis Study, which showed equivalent pain relief from a single 8 Gy fraction and 24 Gy administered in six fractions (8). Single fraction RT proved to be an effective re-treatment strategy for both initial non-responders and responders (8). Additionally, a systematic review and meta-analysis by Huisman et al. observed a pain response in 58% of patients undergoing reRT for painful bone metastases (9). However, it is important to note that this evidence is primarily derived from retrospective or prospective cohort studies, with a limited number of randomized controlled trials (RCTs) exploring the dose-response relationship for reRT. Collectively, these studies underscore the effectiveness and safety of reRT for painful bone metastases, establishing its role in palliation.
ReRT may be required in several scenarios (10): (I) no pain relief after initial RT, (II) partial response to initial RT with a desire for further improved response, and (III) pain relapse after partial or complete response to initial RT. Despite the acknowledgement of reRT as an effective treatment for specific patients, until recently, evidence on the optimal dose fractionation schedules for painful bone metastases had been lacking.
This review aims to summarize findings from the NCIC CTG SC.20 study that was used as teaching material for a presentation at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting. This study, with its secondary analyses, synthesizes evidence from comparing single versus multiple fraction dose schedules for reRT for symptomatic bone metastases, evaluating not only the pain response but also the impact on QoL and function (11). Table 1 summarizes the cited studies with pain response rates and dose-fractionation.
Table 1
| Study | Country | Study type | Recruitment period | Sample size | Dose-fractionation (experimental arm) | Pain response rate at 1st reRT (experimental arm) | Pain response rate at 2nd reRT (experimental arm) | Dose-fractionation (control arm) | Pain response rate (control arm) | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CR | PR | CR | PR | CR | PR | ||||||||
| Jeremic 1999 | Yugoslavia | Secondary analysis of randomized clinical trial | 1988–1993 | 135 | 4 Gy/1 Fr | †28% (31/109) | 45% (49/109) | – | – | – | – | – | |
| Jeremic 2002 | Yugoslavia | Secondary analysis of randomized clinical trial | 1988–1993 | 25 | 4 Gy/1 Fr | – | – | 40% (10/25) | 40% (10/25) | – | – | – | |
| Mithal 1994 | United Kingdom | Retrospective cohort study | 1991 | 105 (280 treatment sites) | 8 Gy/1 Fr, 10 Gy/1 Fr, other 1 Fr; 26 Gy/6 Fr, 28 Gy/7 Fr, 30 Gy/10 Fr, other multiple fractions | 14% (8/57) | 70% (40/57) | 25% (2/8) | 63% (5/8) | – | – | – | |
| van der Linden 2004 | The Netherlands | Secondary analysis of randomized clinical trial | 1996–1998 | §173 | Single fraction | 72% (38/53) if first RT was single fraction; 44% (14/32) if first RT was multiple fractions | – | – | Multiple fractions | 66% (71/108) if first RT was single fraction; 75% (6/8) if first RT was multiple fractions | |||
| Chow (Lancet Oncol) 2014 | Canada, Australia, New Zealand, USA, Israel, Switzerland, United Kingdom, The Netherlands, France | Randomized clinical trial | 2004–2012 | 850 | 8 Gy/1 Fr | ‡8% (36/425) | ‡19% (82/425) | – | – | 20 Gy in multiple fractions | ‡7% (30/425) | ‡25% (105/425) | |
†, only data of initial responders were reported separately for CR and PR; 46.2% overall response (CR + PR) for initial non-responder to initial RT; ‡, intention-to-treat analysis; §, because of missing data, response to second treatment was calculated in 145 patients. reRT, reirradiation; CR, complete response; PR, partial response; RT, radiation therapy.
The NCIC CTG SC.20 trial, a multicenter, non-blinded, randomized controlled non-inferiority trial, set out to determine the optimal ReRT dose-fractionation for alleviating pain from bone metastases. The study enrolled 850 adult cancer patients from nine countries with confirmed painful bone metastases [brief pain inventory (BPI) score ≥2] and a Karnofsky performance status of at least 50. Eligibility for the study required that patients’ treatment sites and previous therapies met specific criteria. For those with treatment sites involving an extremity or rib, eligibility was confined to those who had previously received one of the following regimens: a single fraction of 6, 7, or 8 Gy; 18 Gy in 4 fractions; 20 Gy in 5 fractions; 24 Gy in 6 fractions; 27 Gy in 8 fractions; or 30 Gy in 10 fractions. Patients with treatment sites on the spine or pelvis were eligible only if their prior therapy consisted of a single fraction of 6, 7, or 8 Gy; 18 Gy in 4 fractions; or 20 Gy in 5 fractions. For sites on the acetabulum, hip, or proximal femur, previous treatment had to be 24 Gy in 6 fractions, 27 Gy in 8 fractions, or 30 Gy in 10 fractions, with the stipulation that the medial field border did not cross the midline. Patients were excluded if they were receiving treatment to the spine or any part of the pelvis affecting the small or large intestine or the rectum, and their previous treatment involved higher fractionation schemes of 24 Gy in 6 fractions, 27 Gy in 8 fractions, or 30 Gy in 10 fractions. After stratification by initial RT response and fractionation method, participants were randomized to receive either an 8 Gy single fraction or 20 Gy in multiple fractions, with a minimum interval of 4 weeks between first course and reRT.
Primary outcomes were centered around pain response rates two months post-treatment, with acute side effects, functional interference, progression, and QoL measured through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. Analysis of pain severity and analgesic use was assessed in alignment with International Consensus Endpoints (12). In the intention-to-treat analysis, response rates at 2 months were assessable in 62% of patients (528/850), with 11% (98 patients) deceased before assessment. The response rate was 28% (118/425) in the 8 Gy single fraction group and 32% (135/425) in the 20 Gy multiple fractions group, with the difference not reaching statistical significance (P=0.21). The upper limit of the 95% confidence interval for the response rate difference was 9.2%, which is below the pre-specified 10% non-inferiority margin. In a per-protocol sensitivity analysis of 521 evaluable patients, the 2-month response rate was 45% with a single 8 Gy fraction (116/258 patients) and 51% with multiple 20 Gy fractions (134/263 patients), with no significant difference between the two (P=0.17). The 95% confidence interval for the difference in response rates had an upper limit of 13.2%, exceeding the non-inferiority margin of 10%.
Acute toxicities were assessed on Day 7 and Day 14 post-treatment. On Day 7, significantly more patients in the multiple fractions arm experienced skin reddening (22% vs. 16%, P=0.03) and nausea (24% vs. 17%, P=0.04). By Day 14, the multiple fractions arm continued to report higher incidences of skin reddening (24% vs. 14%, P=0.002), along with increased occurrences of lack of appetite (66% vs. 56%, P=0.01), vomiting (23% vs. 13%, P=0.001), and diarrhea (31% vs. 23%, P=0.02). These findings may have significant implications for patient well-being and the potential for increased healthcare utilization. These findings are consistent with the systematic review by Huisman et al., which highlighted the effectiveness of reRT for painful bone metastases, albeit without a clear consensus on the optimal fractionation scheme (9). Noteworthy is that responders in both groups reported enhanced functional outcomes and quality-of-life on multiple items of Functional interference scale of the BPI and EORTC QLQ-C30 respectively (13). These improvements underscore the significant role of effective pain management in enhancing patients’ daily functioning and psychological well-being (13). Despite some challenges in the per-protocol analysis, the NCIC CTG SC.20 trial provides strong evidence for the non-inferiority of a single 8 Gy compared to 20 Gy in 5 fractions in terms of overall pain response for reRT of painful bone metastases. The results challenged the traditional preference for multiple fractions in this clinical setting.
A critical aspect of the trial was the per-protocol sensitivity analysis, which revealed a response rate difference exceeding the non-inferiority margin (11). This suggests that while the single fraction regimen is generally effective, there may be a subset of patients who could benefit from the multiple fractions approach. The decision to use one treatment over the other fractionation regimens should, therefore, be individualized, considering factors such as previous response to RT, the potential for acute toxicities, and the patient’s overall health status and preferences.
The NCIC CTG SC.20 trial contributes valuable evidence to the ongoing debate regarding the optimal reRT dose fractionation for managing painful uncomplicated bone metastases. The results favor single-fraction reRT not only for its non-inferior efficacy but also for its lower toxicity profile and greater convenience for patients. We advocate for a patient-centered approach to palliative RT, where the simplicity of treatment and patient comfort are pivotal considerations. These benefits are especially pertinent given the often limited life expectancy associated with metastatic cancer and the desire to minimize healthcare visits and treatment-related discomfort. The 2-month pain control endpoint from the NCIC SC.20 trial continues to provide a meaningful metric. However, we must continually reevaluate its relevance in the context of contemporary systemic therapies that extend the survival of metastatic patients. We propose that RT trials evolve to incorporate endpoints that capture long-term outcomes and QoL, particularly in light of longer patient survival and the implications of multiple treatment courses.
The study further reinforces the critical role of quality-of-life assessments in evaluating the success of palliative interventions. The improvement in daily functioning and well-being reported by patients responding to reRT emphasizes the value of such treatments beyond mere symptom control, particularly pain. It highlights the need for oncology care that prioritizes patient-reported outcomes as much as clinical metrics.
Besides considering efficacy, safety is paramount. The two studies on human spinal cord ReRT tolerance provide critical insights into the risks and feasibility of this treatment approach. Nieder et al. expanded their data set, reaffirming the predictive power of cumulative biologically effective doses (BEDs), the highest BED from all treatment series, and treatment intervals in assessing the risk of developing radiation myelopathy (14). The findings suggest a minimal risk of radiation myelopathy following a BED less than 135.5 Gy2, provided the interval between treatments is no shorter than 6 months and each course maintains a BED below 98 Gy2 (14). A separate bi-institutional retrospective analysis reported that all 32 patients included remained free of radiation myelopathy over follow-up periods ranging from 6 to 97 months, even though reRT doses exceeded the initial doses for most of them (15). This indicates that higher cumulative doses may be more tolerable than previously understood, underscoring the importance of tailored treatment decisions and the potential for delayed myelopathy manifestations. Such scenarios necessitate meticulous planning and informed consent, especially when weighing the risks of myelopathy against the imperative of tumor control.
In conclusion, reRT may be considered following insufficient pain relief after an initial course of RT, an unsatisfactory partial pain response, or pain recurrence after a complete or partial response to initial RT. The NCIC CTG SC.20 trial, along with other studies, supports a patient-centered approach to palliative RT, emphasizing the importance of treatment simplicity and patient comfort. The reported improvements in quality-of-life and functionality by patients responding to reRT highlight the value of these treatments beyond mere symptom control. However, reRT may be ineffective or pose challenges due to the dose constraints of adjacent organs-at-risk or a patient’s inability to tolerate simulation. In such cases, alternative approaches, such as consulting a pain specialist, should be considered. Notably, stereotactic body radiotherapy (SBRT) is increasingly utilized for its ability to precisely target pain sites while minimizing exposure to adjacent organs-at-risk, offering an advanced option for both pain and tumor control in the reRT setting. In addressing spinal metastases, current evidence suggests that SBRT provides improved local control relative to conventional external beam radiation therapy (cEBRT) (16). Notably, studies have indicated that dose escalation beyond 24 Gy in 2 fractions may enhance this benefit (17,18). Similarly, for non-spinal metastases, SBRT demonstrates a superior local control compared to cEBRT (19). This modality may be most beneficial for patients with a favorable prognosis who are likely to experience the long-term benefits of enhanced local control. However, SBRT and other more conformal RT techniques, despite their potential benefits, have not been compared prospectively in reRT setting with cEBRT, which can be set up more quickly but may not always satisfy the dose constraints necessary to protect normal tissues in some reRT scenarios. Integrating these insights into clinical practice requires oncologists and other healthcare providers to thoughtfully balance the advantages of treatment simplicity against individual needs and clinical profiles of patients.
Acknowledgments
The data of this article were presented, in part, during a joint session of the American Society for Radiation Oncology (ASTRO) and the Society for Palliative Radiation Oncology (SPRO) at the 65th ASTRO Annual Meeting in San Diego, CA on Oct. 2nd, 2023.
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-24-15/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-15/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 from October 2023 to September 2025 and served as the unpaid co-Guest Editor of the series. C.B.S. serves as the co-Editor-in-Chief of Annals of Palliative Medicine from April 2014 to April 2027. D.R. reports that he received grants from the European Development Fund (Interreg), honoraria as Guest Editor for Elsevier, and support for attending meetings from Spanish Society for Radiation Oncology (SEOR), outside the submitted work. E.C. served as the unpaid former co-Guest Editor of the series. The authors have no other conflicts of interest to declare.
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References
- Macedo F, Ladeira K, Pinho F, et al. Bone Metastases: An Overview. Oncol Rev 2017;11:321. [PubMed]
- Rich SE, Chow R, Raman S, et al. Update of the systematic review of palliative radiation therapy fractionation for bone metastases. Radiother Oncol 2018;126:547-57. [Crossref] [PubMed]
- De Felice F, Piccioli A, Musio D, et al. The role of radiation therapy in bone metastases management. Oncotarget 2017;8:25691-9. [Crossref] [PubMed]
- Mithal NP, Needham PR, Hoskin PJ. Retreatment with radiotherapy for painful bone metastases. Int J Radiat Oncol Biol Phys 1994;29:1011-4. [Crossref] [PubMed]
- Jeremic B, Shibamoto Y, Acimovic L, et al. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys 1998;42:161-7. [Crossref] [PubMed]
- Jeremic B, Shibamoto Y, Igrutinovic I. Single 4 Gy re-irradiation for painful bone metastasis following single fraction radiotherapy. Radiother Oncol 1999;52:123-7. [Crossref] [PubMed]
- Jeremic B, Shibamoto Y, Igrutinovic I. Second single 4 Gy reirradiation for painful bone metastasis. J Pain Symptom Manage 2002;23:26-30. [Crossref] [PubMed]
- van der Linden YM, Lok JJ, Steenland E, et al. Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 2004;59:528-37. [Crossref] [PubMed]
- Huisman M, van den Bosch MA, Wijlemans JW, et al. Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys 2012;84:8-14. [Crossref] [PubMed]
- Chow E, Hoskin PJ, Wu J, et al. A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) SC 20. Clin Oncol (R Coll Radiol) 2006;18:125-8. [Crossref] [PubMed]
- Chow E, van der Linden YM, Roos D, et al. Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol 2014;15:164-71. [Crossref] [PubMed]
- Chow E, Hoskin P, Mitera G, et al. Update of the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Int J Radiat Oncol Biol Phys 2012;82:1730-7. [Crossref] [PubMed]
- Chow E, Meyer RM, Chen BE, et al. Impact of reirradiation of painful osseous metastases on quality of life and function: a secondary analysis of the NCIC CTG SC.20 randomized trial. J Clin Oncol 2014;32:3867-73. [Crossref] [PubMed]
- Nieder C, Grosu AL, Andratschke NH, et al. Update of human spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys 2006;66:1446-9. [Crossref] [PubMed]
- Doi H, Tamari K, Oh RJ, et al. New clinical data on human spinal cord re-irradiation tolerance. Strahlenther Onkol 2021;197:463-73. [Crossref] [PubMed]
- 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;22:1023-33. [Crossref] [PubMed]
- Zeng KL, Abugarib A, Soliman H, et al. Dose-Escalated 2-Fraction Spine Stereotactic Body Radiation Therapy: 28 Gy Versus 24 Gy in 2 Daily Fractions. Int J Radiat Oncol Biol Phys 2023;115:686-95. [Crossref] [PubMed]
- 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;114:293-300. [Crossref] [PubMed]
- Nguyen QN, Chun SG, Chow E, et al. Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy for Pain Relief in Patients With Predominantly Nonspine Bone Metastases: A Randomized Phase 2 Trial. JAMA Oncol 2019;5:872-8. [Crossref] [PubMed]
