Letter: Impact of Extent of Resection on Survival in Brain Metastasis: An Analysis of 867 Patients

To the Editor: We read with great interest the article published in Neurosurgery by Hulsbergen et al,1 titled “Impact of Extent of Resection on Survival in Brain Metastasis: An Analysis of 867 Patients” which investigated the impact of the extent of resection (EOR) on intracranial progression-free survival (IC-PFS) and overall survival (OS) in 867 patients with brain metastases (BM) from multiple primary tumors. Using a multivariable model, the authors demonstrated that subtotal resection was significantly associated with decreased IC-PFS and OS, as well as with a higher incidence of leptomeningeal disease. After correcting for relevant confounders, including age, performance status, number of BMs, size of the resected BM, infratentorial vs supratentorial location, primary tumor origin, extracranial metastases, presence of a targetable mutation, newly diagnosed vs recurrent BM status, year of surgery, and adjuvant radiation, gross total resection (GTR) remained significantly associated with improved PFS and OS. Interestingly, the authors reported that, even in patients receiving stereotactic radiosurgery, postoperative tumor residue on MRI scans independently correlated with decreased IC-PFS compared with GTR.1 This highlights the role of surgical EOR in limiting local recurrence. The strengths of the current study include among others its large cohort size and its correction for multiple relevant known confounders.1 These are important aspects that were not always achieved in recent studies on this topic.2 As discussed by the authors, differently from gliomas where the postoperative treatment guidelines are homogenous and well defined, perioperative treatment algorithms of BMs include an increasing number of systemic and local therapies, with consequent challenges in analyzing the prognostic role of complete surgical resection in this patient population.3,4 These factors include mainly—but not only—different tumor histologies, extracranial disease status, and the aforementioned heterogeneous treatment algorithms.3 Despite this, improvements in microsurgical techniques allow to reach virtually any anatomical location with an acceptable adverse event rate, as demonstrated by our group and others, thus prompting the re-evaluation of the role of surgical resection of BMs beyond traditional indications in improving patient outcomes.2,5 It is worth noting that the study population included patients with single (49.7%) and multiple (50.3%) BMs. With this respect, volumetric analysis of residual tumor accounting for the total intracranial tumor volume (especially when it comes to patients with multiple lesions) was not performed as also acknowledged in the limitations. GTR was defined based on the surgically targeted lesion, while not considering total intracranial tumor burden or residual tumor volume. Consistently, and likely for this reason, the effect was found to be not significant in the subgroup analysis for OS in patients with multiple BMs, while it maintained significance for PFS. Given that patients with BMs often present with multiple lesions, terms like GTR, near-total resection, and subtotal resection may not sufficiently capture the surgical impact. A more precise metric might be the EOR relative to total intracranial tumor burden or, even more accurately, the residual intracranial tumor volume (RV)—a concept gaining traction in the recent literature as a more relevant prognostic factor.2 When considering resection of multiple metastases to reduce overall intracranial tumor burden—even if this requires multiple craniotomies—it is crucial to weigh the potential benefits against the risk of surgical complications. Encouragingly, recent studies suggest that, with appropriate patient selection at specialized tertiary care centers, these procedures can be performed with comparable good safety profiles.6,7 Recent studies—although largely retrospective and single-center—have suggested potential tumor-specific differences in the benefit of resection. For example, GTR appears to offer a survival benefit in patients with BMs from melanoma,8,9 while findings in lung cancer are conflicting,10-14 and no benefit has been observed in BMs from gastrointestinal primary tumors15 and in breast cancers metastases—with the caveat that a well-selected subgroup of patients may still benefit from complete surgical resection.16 Unfortunately, owing to the timing of publication, this study was not included in a recent systematic review and meta-analysis on this topic by our group. In that, we examined the role of reducing intracranial tumor burden in patients with BMs. The random-effects meta-analysis confirmed similar findings: GTR was associated with improved OS and PFS in studies that performed multivariable Cox regression analysis. However, we also noted that key prognostic factors—such as extracranial disease status, postoperative local and systemic therapies, and perioperative steroid use—remain inconsistently and rarely reported across the literature.2 In conclusion, we commend the authors for providing evidence on the role of EOR in patients with BM, in one of the largest studies to date that addresses this clinical question.1,2 Future studies should aim to analyze data more granularly, ideally through multicenter collaboration, to determine the impact of intracranial surgical volume reduction on patients with different primary histologies and with adequate control of confounding factors including postoperative local and systemic therapies. In the future, we foresee more personalized approaches to BM resection, especially in cases involving multiple lesions or beyond classic indications, with the decision-making process increasingly informed by the molecular profile of the primary tumor, the patient's clinical status and extent of systemic disease, as well as the options and effectiveness of available adjuvant treatments.2