Brain Metastases in Greater Size - Hypofractionated Options Trial (BIGSHOT)

Brain metastases are an increasingly common diagnosis, as cancer patients continue to live longer due to advances in systemic therapy. Up to 26% of patients with metastatic cancer will develop metastatic disease to the brain (Nayak 2012), most commonly in lung cancer, as well as melanoma, breast, and renal cell cancer (Singh 2020). Historically, brain metastases were treated with whole brain radiation therapy (WBRT). However, increasing evidence over the past 10-15 years, as well as technological advances, have created a shift in treatment toward stereotactic radiosurgery (SRS), which is a focused treatment targeting only the visible tumors. SRS has multiple advantages over WBRT. Most importantly, focused treatment with SRS provides significantly lower risk of neurocognitive toxicity compared with WBRT, with no difference in overall survival (Chang 2009, Brown 2016, Aoyama 2006). SRS is also more convenient, delivered in 1 to 3 treatments, as opposed to 2 weeks of therapy with WBRT. For these reasons, SRS is now the preferred option for patients with limited brain metastases, recognized in both the NCCN guidelines and ASTRO guidelines (Gondi 2022).

For intact metastases less than 2 cm, local control with SRS alone is excellent (Redmond 2021). However, for larger tumors, achieving long term local control with radiation is more difficult. Tumor dosing is based on risk of toxicity (specifically, radiation necrosis), and therefore for larger tumors, the dose is decreased (RTOG 90-05, Johannwerner 2023). This results in suboptimal control for tumors >2 cm. For single fraction SRS, local control is estimated around 70%, and for fractionated SRS (3-5 fractions), around 80% (Redmond 2021).

There are two common approaches for treating large intact brain metastases with radiosurgery alone. Fractionated SRS involves treating the tumor in 3-5 separate daily treatments. This allows for normal tissue recovery in between, and therefore may decrease the risk of toxicity (Minitti 2015). Staged SRS involves treating the tumor in two sessions, spaced apart by 3-6 weeks. This allows delivery of a lower dose for the first fraction (to minimize toxicity), and the second fraction can be dose escalated depending on interval tumor response. A recent meta-analysis compared SSRS to FSRT, and found no difference in local control, but a lower rate of re-treatment in the SSRS group (Harikar 2023). Radiation necrosis rate was 3.7% in the SSRS group and 6.4% in the FSRT group. The authors of this study concluded that randomized controlled trials examining the two options would be useful. A retrospective study conducted a propensity score-matched analysis of SSRS vs FSRT. This study showed comparable rates of local failure (15% at 6 months, and 25% at one year in both groups), as well as comparable rates of radiation necrosis (2.2% in SSRS vs 6.4% in FSRT) (Noda 2023).

In theory, treatment with SSRS would allow for a higher biological equivalent dose (BED) to the target lesion, while maintaining low toxicity rate, as time between fractions allows for normal tissue recovery. Retrospective data suggests that a BED10 > 50 predicts for better one year local control in hypofractionated SRS (Remick 2020). BED10 for 9 Gy x3 is 51.3Gy, with an EQD2 a/b 2 of 74.25. In comparison, 15 Gy x2 results in a BED10 of 75Gy, with EQD2 a/b 2 of 127.5. Allowing 3-6 weeks of recovery time in between the two fractions should theoretically allow for tissue recovery and mitigate the risk of higher normal tissue EQD2. Additionally, while data for 3 fraction FSRT is encouraging for larger tumors (2-5 cm), the local control for tumors on the larger end of this spectrum (>3 cm) may not be as good. Specifically, in one of the largest retrospective studies of 3 fraction FSRT for metastases >2cm, the overall local control was 91% at 1 year; however, the local control for lesions 3 cm or larger was only 73% (Minniti 2015).

Although there is encouraging retrospective data supporting the use of both SSRS and FSRT, there are no studies directly comparing the two approaches in a prospective fashion. Therefore, randomized data is needed to provide guidance on the best approach in this challenging patient population.

This study will compare two approaches for treating large brain metastases (2-5 cm): staged stereotactic radiosurgery (SSRS) and fractionated stereotactic radiotherapy (FSRT). These are both considered standard treatments and both used as standard of care for patients with large brain metastases.