Preventing skeletal related events with radiation therapy in cancer patients with bone metastases

Bone metastases (BMs) are a common cause of morbidity and mortality in solid cancer patients (1). BM can result in pain, functional limitations, weakening of the bone matrix, and possible fractures. These elements can often negatively impact quality of life (QoL) and lead to incorrect adherence to proposed oncological therapies. Radiation therapy (RT) is often offered to relief these symptoms and hence has been widely used in this clinical setting.

National and international guidelines, such as those developed by ASTRO (2) and DEGRO (3), consistently use the term ‘palliative’ in relation to BMs. The use of this term restricts the role of radiotherapy to symptom relief and implies that the patient is in a non-curative phase. The goal of RT, as outlined in both guidelines, is consequently to reduce pain, stabilize bones at risk of impending fracture or other skeletal related events (SREs), prevent or control neurological deficits, and improve palliative care.

ESTRO (4) recently released a position paper on the management of uncomplicated BM. The publication recommends conventional RT for managing painful uncomplicated metastases, especially when pain control is inadequate with analgesic medications or when there is a need to adjust the schedule of pain-relieving drugs, particularly opioids. Patients with uncomplicated painful BM are generally treated with a single fraction of 8 Gy. A second course of RT with a further 8 Gy single dose may be considered, if the pain persists. RT should only be considered when the metastases become symptomatic, while current standard of care (SOC) for patients with minimally symptomatic BMs (who are not dependent on opioid medication) is to continue systemic therapy or observe with medical management for pain.

According to the ESTRO guidelines, there is no clear advantage in terms of pain response for higher-dose conventional RT or stereotactic body RT over single-dose conventional RT in cases of bone disease. Indeed, there has been much debate over the years about ‘new’ RT techniques. In this context, it is important to mention a randomized trial (5) that aims to assess the relative efficacy of high-dose, single-fraction stereotactic body RT versus standard RT for alleviating pain in patients with non-spine BMs. Stereotactic body RT offers the advantage of delivering significantly higher biologically effective doses (BEDs) than conventionally fractionated RT. This study is the first randomized clinical trial to demonstrate that stereotactic dose (12–16 Gy single fraction) results in a more durable pain response and improved local control compared to non-stereotactic techniques. Nguyen also demonstrated that a single stereotactic fraction of 12 to 16 Gy induced a better pain response and better local control.

Recent advances in immunotherapy, combination chemotherapy, and targeted therapies have changed the natural history of the disease. It is not uncommon to be referred patients with widespread metastases, but with new line of systemic therapy options and a longer potential life expectancy.

Within this apparently uncertain scenario, the management of BMs has become an increasingly complex clinical decision in a multidisciplinary setting, with valid options such as antiresorptive drugs (denosumab and bisphosphonates). These drugs have become increasingly popular even in the early stages of the disease (6). The toxicity of bisphosphonates, which can cause nausea, cytopenia, renal dysfunction and, rarely, osteonecrosis of the jaw, has been a concern, particularly as some patients with metastatic disease experience prolonged survival, and most trials looked at only 1–2 years of drug treatment (7). On the other hand, RT could offer long-lasting pain relief with minimal side effects and reasonable cost-effectiveness. Additionally, drugs could be considered as a second-line option if RT is not sufficient.

Few studies have investigated the efficacy of early, RT in managing asymptomatic or mildly symptomatic spine metastases. Zimmerman in 2014 observed that early RT interventions enhanced both the QoL and, in certain instances, the overall survival (OS) of metastatic cancer patients (8). The phase 2 SABR-COMET trial in 2019 demonstrated that irradiation of oligometastatic disease improved disease control, with an 8-year follow-up. The trial used a stereotactic technique to irradiate non-critical bone, lung, adrenal, and liver metastases of any primary, with no difference in overall QoL (9,10). About one third of the lesions treated were BMs. Stereotactic RT was found to be associated with a 22-month improvement in median OS and a doubling of median progression-free survival.

For the sake of completeness, it is also relevant to note that all patients in the SABR-COMET trial had a controlled primary tumor and a median time from diagnosis of at least 2 years. Prostate cancer was over-represented in the SBRT arm and femoral metastases were excluded. Therefore, the generalizability of the results might be limited.

Regardless of the dose and fractionation, the use of RT for asymptomatic bone lesions is not currently a SOC due to the lack of randomized controlled trial data, despite the increased interest in irradiation of metastases in patients with a ‘good prognosis’. Therefore, a new critical issue is the potential role of preventive RT in the management of BM.

To address this knowledge gap, the recent publication by Gillespie et al. titled “Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial” (11), provides insightful information. This trial investigates the role of a new treatment approach for high-risk BMs from solid tumors. The proposed treatment involves upfront RT before the metastases become symptomatic, either in the outpatient setting or before requiring inpatient admission for pain control or intervention. The primary of this study outcome was the incidence of SRE. Secondary outcomes included hospitalizations for SRE and OS.

The trial defined a high-risk lesion as a disease in any bone that is bulky (≥2 cm) and involves certain anatomical site, such as the hip (acetabulum, femoral head, and femoral neck), shoulder (acromion, glenoid, and humeral head), or sacroiliac joints. This study focuses also on disease that affects the long bones, occupying between one third and two thirds of the cortical thickness. The disease could also affect the vertebrae of the junctional spine (C7–T1, T12–L1, and L5–S1) and/or involves the posterior elements. To ensure that patients with oligometastatic disease are not enrolled due to competing trials, the study requires the presence of more than five metastatic lesions.

This study shows the effectiveness of prophylactic RT for asymptomatic high-risk BMs, which goes beyond the established indications for RT, such as pain relief and fracture risk reduction.

At 1 year, the incidence of SREs was significantly lower in the group receiving RT (1.6%) compared to the SOC group (29%) who received bisphosphonates, medical therapy, or a new line of systemic therapy.

The trial’s primary outcome guided the secondary endpoints. The reduction of SREs resulted in a decrease in hospitalizations and the use of pain-relieving drugs. Additionally, it led to significant economic savings for patients and their families. In fact, there was a decrease in morbidity and mortality potentially associated with surgery, as well as a reduced use of various anti-inflammatory drugs and opioids. Although subsequent RT may have been sufficient for some SOC patients, it is important to note that early RT prevented pathological fractures and cord compression during the study. The majority of SRE in the non-RT group occurred within the first 3 months after they were enrolled in the trial. Thus, the clinical relevance was increased beyond statistical significance.

Additionally, the RT performed in the study followed standard practices and did not necessarily involve the use of sophisticated approaches. The most common fractionation scheme used was 3×9 Gy, although most metastases were treated with conventional schemes such as 5×4, 1×8, and 10×3 Gy. Even a conventional, non-stereotactic, and non-hypofractionated treatment can achieve the desired outcome. The treatment-related toxicity was moderate, as expected. A comparison between RT and a historical meta-analysis (12), which used osteoprotective drugs, showed a significantly better effect of RT. The cited meta-analysis reported a hazard ratio of 0.7–0.87 for SRE. There was no effect on OS. In contrast, in the Gillespie trial, which had a median follow-up of 2.5 years, the OS was significantly higher in the prophylactic RT arm. Due to the small sample size (n=78) in the current study, any improvement in OS should be interpreted cautiously.

The study’s most noteworthy aspect is the observed improvement in QoL, evaluated with the 5-level EuroQoL-5D (EQ-5D-5L) composite score. Patients with widespread bone metastatic cancer are at a significantly higher risk of pain progression and the need for potent opioids. Additionally, pain associated with SREs may persist despite the use of strong opioids, resulting in incomplete recovery for some patients. Cancer-related pain can significantly reduce QoL, affecting mood, work, relationships, mobility, and sleep (13-15). These factors can exacerbate pain-related problems in a cyclical fashion.

The study conducted by Gillespie et al. suggests expanding the use of prophylactic RT to a wider range of patients to improve their QoL. Gillespie trial’s limitation is the small number of patients included. However, it is the first to focus on a well-defined group of patients with specific characteristics that are common in clinical practice, but undervalued by large trials. The non-oligometastatic patient with critical bone sites is a challenging area of clinical work that constantly makes us question the appropriate therapeutic choice. Focusing on this cohort is a key strength of this study.

A recent article describes a randomized clinical trial similar to Gillespie et al., but with a focus on high-risk spinal BMs (16). However, the endpoints of the trial include pain assessed using the Brief Pain Inventory (BPI) and health-related QoL assessed using the Functional Assessment of Cancer Therapy-General (FACT-G) and the EQ-5D-5L. The analysed studies help us to reflect on the treatment of BMs, which has always been considered a ‘simple’ treatment, reserved for patients with non-curative perspectives and in a ‘palliative’ setting, as repeatedly mentioned in this work. This preliminary phase II study suggests that there may be a prophylactic rationale for radiotherapy even in non-oligometastatic patients.

The analysed studies may not provide sufficient evidence to recommend prophylactic RT, and randomized phase III trials are needed to determine the true efficacy and confirm the clinical benefit. However, RT, according to these data, may be useful in all anatomical bone subsites, although it is expected to be most beneficial in spinal vertebrae. This is because SRE can negatively impact both prognosis and QoL. As the SINS score (17) is used to assess spinal stability and assist clinicians in determining the need for surgery, it may be beneficial to include additional parameters in prophylactic RT trials to objectively identify high-risk lesions and ensure the absence of subjective perspective. In future trials, it would be beneficial to differentiate between doses, RT techniques, and tumor primary. New irradiation modalities and the use of hypofractionation may impact the outcome.

Results of this article can certainly be spent within multidisciplinary board, where radiation oncologists should recommend RT also for patients with widespread bone lesions that are not yet painful or neurologically critical. Clinicians can use the promising data to support its use as a cost-effective and widely available treatment option, whether a more advanced technique such as stereotactic RT is appropriate for non-oligometastatic patients remains to be determined.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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