Presently there is no standardized pathway for the management of multiple brain metastases. Treatment decision-making in this population is not straightforward, as patients can present with metastases of varying size and location, and variable severity of systemic disease [6, 26]. Surgery and SRS have demonstrated favorable outcomes, both as stand-alone therapies and in combination [2, 13, 15, 18, 21, 22, 24, 26, 27]. Current CNS guidelines for the treatment of multiple brain metastases list surgical resection, WBRT and SRS as viable first-line therapies, however there are few direct comparisons of up-front resection followed by SRS versus only SRS in this setting [7, 28]. Guidelines broadly state that surgical resection or debulking could be favorable among patients with good control of systemic disease whose lesions are symptomatic and accessible by craniotomy, but patient selection is left to the discretion of treating physicians [7, 12]. Traditionally, prevailing wisdom often favors surgical resection for symptomatic dominant lesions to relieve mass effect, while SRS is reserved for lesions that are surgically inaccessible and for patients with poor control of systemic disease [29].
In this single-institution, retrospective, cohort study, we compared surgery followed by GKS with standalone GKS for patients with multiple CNS metastases and one dominant lesion and found no significant difference in survival. Moreover, quality of life was not affected by treatment modality, as KPS scores did not differ significantly at follow-up for the two cohorts. As expected, pre-intervention KPS, adjuvant chemotherapy and immunotherapy as well as adjuvant or repeat radiotherapy were associated with improved survival.
There are few series reporting outcomes on surgical resection of multiple intracranial metastases, although evidence to date suggests they are comparable to those reported for patients undergoing resection of a single metastasis [7, 18, 24, 27]. Some groups have reported a survival benefit for patients with multiple metastases if all lesions are able to be resected [2, 18, 26]. Our findings suggest that upfront SRS to multiple metastases in the setting of a dominant lesion may be as efficacious as surgery followed by GKS in achieving long-term survival. Certain patients – particularly those requiring tissue diagnosis, and those with lesions >4cm in diameter which would otherwise not be able to be adequately treated with radiation alone – should still be treated with surgery upfront [12, 30]. However, in patients not meeting these prerequisites, SRS may be preferable given its similar long term outcomes and significantly less invasive nature.
In fact, SRS can lead to dramatic size reductions in the size of a dominant lesion as seen in Supplemental Figure 1, and requires shorter recovery time and offers fewer complications compared to surgery. In fact, unlike GKS, surgery also carries the risk of post-operative complications, including infection, as shown in Supplemental Figure 2. Avoiding the need for postsurgical recovery allows for rapid initiation of systemic therapies [12, 30]. As demonstrated in our study, only preoperative functional status and systemic therapy is associated with a decrease in all-cause mortality in patients with multiple intracranial metastases. Thus, it can be inferred that initiating systemic treatment more quickly, may promote survival in this patient population.
In it important to note that in certain cases, upfront SRS may predispose patients to increased risk of death from neurological causes. These patients may require neurosurgery after SRS due to post-procedure complications, such a radiation changes or rapid progression of CNS disease, as shown in Supplemental Figure 3 [3, 7].
In recent years, there has been a move toward adopting the practice of pre-operative SRS within 48 hours of surgical resection, which is not yet common practice at UPHS. Pre-operative SRS has been shown to decrease incidence of leptomeningeal (LMD) disease progression at one year follow up [31]. This finding suggests that preoperative SRS is capable of sterilizing tumor cells that could be spilled at the time of surgery and does not confer a higher risk of LMD than WBRT, which treats the entire intracranial CSF space.
There are several limitations to our study. Firstly, our small sample size limits the strength of our findings – in fact, a combined sample of 190 patients would have been necessary to detect a statistically significant different in mortality between the two cohorts. Secondly, while patients in the GKS and surgery cohorts had no significant difference in their background characteristics, it is possible additional confounders were missed. Moreover, this study is not a perfect comparison of surgery followed by GKS versus GKS as stand-alone treatment options, as there was a selection bias toward smaller diameter of dominant metastases in the GKS cohort, although our sensitivity analysis demonstrated excluding patients with larger dominant lesions did not lead to a survival difference between the groups. Furthermore, in the study period, 20% of patients in the surgical cohort did not undergo follow-up GKS, Cyberknife, or WBRT either due to rapid progression of cancer post surgery excluding them from additional treatment or due to loss to follow up. While approximately 80% of the surgical cohort received adjuvant GKS/WBRT/CK, 20% required repeat resection, which may have influenced overall mortality as well. The high repeat resection rate and lack of universal postop radiotherapy limits the generalizability of the results. In contrast, the up-front GKS cohort rarely required late-surgery or additional GKS.
In conclusion, in this single institution, retrospective cohort study, we found no significant difference in survival or postoperative performance status between patients with multiple CNS metastases and one dominant lesion who underwent surgery followed by GKS versus standalone GKS. In patients with advanced extra-CNS disease and medical comorbidities, the additional risks of anesthesia and open surgery for a dominant lesion may not be warranted. On the basis of this single-center retrospective analysis, SRS may offer a comparable, safer alternative for this population, and allow for the more rapid initiation of life prolonging systemic therapies.