Does early adjuvant brain metastasis SRS increase mortality?

I read with interest the recent paper by Yaghi et al on the timing of adjuvant radiotherapy following brain metastasis resection.¹ This is an area of key importance given recent studies demonstrating lower risk of local recurrence with radiation within approximately 1 month of surgery than at later time points.^2,3 However, the authors’ main conclusion that a cavity irradiation delay “is required” because “delaying RT initiation at least 22 days decreases all-cause mortality” requires further evaluation, in part because of (1) the burden of making a causative claim from retrospective review and (2) the high potential that the increased mortality is unrelated to the intervention. As such, these data do not in isolation support prescription of an optimal radiation window limited to days 23-30 only.

Unlike glioblastoma, extracranial disease is the most common cause of death for the brain metastasis population, making expedited focal brain metastasis treatments unlikely to be fully or even partially responsible for shortened survival.^4–6 Indeed, the key endpoint for studies of brain metastasis local therapies has traditionally been treated-field local control and not overall survival because of this significant confounder.^7,8 The cause of death is not included in this study. If early CNS radiation is posited to be causative, it would be helpful to report the proportion of patients succumbing to CNS radiation-associated causes. Furthermore, if deaths in the early radiation cohort are related to systemic disease progression as one would expect, the discussion should address the purported mechanisms associated with early postoperative brain radiation on overall survival.

Despite the small sample size and an inherently heterogeneous patient population, several potential confounders of the observed association would allow deeper insight. Firstly, while the authors describe populations roughly matched in terms of cancer type among patients treated within vs beyond 22 days, and with similar proportions harboring solitary vs multiple metastases, the study included patients operated on over a 9-year span beginning in 2009, a period over which cancer treatments have significantly improved. The survival for patients with brain metastases has been transformed over that period and since, with survival for patients with the best and worst graded prognostic assessment scores rising from 2 to 12 months in the late 2000s to up to 48 months in recent years for the commonest brain metastases.^9,10 Indeed, the 10-month survival for this overall cohort is substantially lower than that of more contemporary brain metastasis resection experiences of 18 months reported in large series, reflecting a significant potential source of heterogeneity over the long inclusion period.² Other studies have also shown the association between a larger number of brain metastases—a negative prognostic—as a continuous variable (ie, stratifying beyond 1 vs >1 metastasis) and early irradiation.² Additionally, the stratification of “progressive” vs “stable” extracranial disease does not fully reflect cancer burden when not in the context of disease type and using validated radiology instruments.

Secondly, despite this series including several high-risk operations including 4 tumor resections from the pons, basal ganglia, and other “deep brain structures,” it would be important to describe whether neurologic or other surgical complications or lesion-level risk factors (such subtotal resections or larger tumors, which carry higher risk of recurrence) were overrepresented in the group undergoing early radiation.¹¹ Postoperative deficits or even unrelated medical issues portending subsequent decline in this population with metastatic cancer may have prompted in-hospital radiation due to anticipated prolonged rehabilitation (as has been shown in other series), with early mortality reflecting these issues instead of vice versa.² Preoperative KPS alone would not account for this. Relatedly, only 18 patients/year who successfully underwent resection plus radiation were included, excluding an unknown number of potentially sicker patients who were planned for, but unable to complete the adjuvant stereotactic radiosurgery (SRS). Inclusion of patients on an intended-treatment basis may have provided additional data informing the true baseline survival of this population. Other prior treatment history is also an important factor: removal because of recurrence after prior SRS would portend a greater risk of radiation necrosis.¹²

Importantly, we would also highlight another association that was not discussed in the manuscript: patients with SRS beyond 56 days also had poor overall survival (supplementary figure S1), validating other recent work and which is plausibly explained by poorer CNS control with delayed radiation.²

While we applaud the evaluation of this critical question, the questions raised serve as a reminder of the complexity of this population and the need for multifaceted consideration of the lesion-level, procedural, and extracranial issues at play, and for a higher level of evidence standard when making prescriptive treatment recommendations.

Funding

This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Conflict of interest statement. The author denies any conflicts of interest regarding this letter and makes the following disclosures: consulting fees for advisory board participation: AstraZeneca; trial funding (to institution) from GT Medical Technologies.