Abstract
Background/Aim: Resection of brain metastases is a well-established treatment modality that can prolong the survival of patients for whom surgery is indicated. Whole-brain radiotherapy (WBRT) has been the standard postoperative therapy. In recent years, however, clinicians have increasingly avoided WBRT due to its associated adverse events. This study investigated the impact of postoperative WBRT and systemic chemotherapy as prognostic factors on the survival of patients who had undergone resection of brain metastases. Patients and Methods: The study subjects were 172 patients who underwent surgical resection for brain metastases. Comparative analyses of survival after WBRT and systemic chemotherapy were performed. Results: Postoperative WBRT had no survival-prolonging effect, whereas postoperative systemic chemotherapy prolonged survival. A comparison based on the number of systemic chemotherapy regimens administered prior to surgery showed that fewer regimens correlated with a better prognosis. Conclusion: The addition of WBRT after surgical resection of brain metastases is no longer a standard treatment strategy and systemic chemotherapy after surgery is a positive prognostic factor.
The first treatment introduced as a monotherapy back in 1950’s for brain metastases was whole-brain radiotherapy (WBRT) (1). For a long time, no new treatment strategies emerged. However, in the 1990’s, the efficacy of tumor resection combined with WBRT for a single brain metastasis was reported, and tumor resection became an important surgical treatment option for brain metastases (2). Stereotactic radiosurgery (SRS) has been actively used to treat brain metastases since around 2000, and systemic chemotherapy including molecularly targeted therapy has shown efficacy in brain metastases since around 2010 (3, 4). We have now entered the era of multifaceted treatment strategies that combine these multiple modalities. Among these multifaceted approaches, tumor resection is the most invasive, but it is an excellent treatment for large tumors and has the major advantage of early symptomatic improvement. WBRT has been the standard treatment strategy after surgical resection, but in recent years, concerns about adverse events, such as cognitive dysfunction, have led clinicians to avoid using WBRT. Recent advances in systemic chemotherapy have also influenced the increasing number of negative reports on the survival impact of WBRT (5, 6). Therefore, we investigated the impact of WBRT and systemic chemotherapy as prognostic factors on the survival of 172 patients who underwent tumor resection of brain metastases.
Patients and Methods
This study was approved by the Ethics Committee (reference number, 25-211) of Kindai University Faculty of Medicine. The study subjects were 172 patients who underwent surgical resection for brain metastases at the Department of Neurosurgery of Kindai University Hospital between 2004 and 2019. Indications for surgical resection of brain metastases were the feasibility of safe general anesthesia and a lesion with a maximum diameter ≥25 mm. Postoperative adjuvant therapy was considered separately for each patient in consultation with a medical oncologist and a therapeutic radiologist. We performed comparative analyses of survival after WBRT and systemic chemotherapy. Survival was evaluated using Kaplan–Meier estimates. Prognostic factors were analyzed using the log-rank test for univariate analysis. Values of p<0.05 were considered statistically significant.
Results
Table I shows the characteristics of the 172 patients included in the study. Postoperative WBRT was performed in 92 patients (53.5%), and postoperative systemic chemotherapy was performed in 78 patients (45.3%). Median overall survival was 13 months, and the 1- and 5-year survival rates were 48% and 5%, respectively (Figure 1). Survival analysis according to treatment with postoperative WBRT showed a median survival of 12.5 months in the treated group and 13 months in the untreated group, with no significant difference (p=0.507). Survival analysis by treatment with postoperative systemic chemotherapy showed a median survival of 15 months in the treated group and 7 months in the untreated group (p=0.005). In patients who received postoperative systemic chemotherapy, survival was also compared between the group that received either no or 1st line systemic chemotherapy prior to surgery and the group that received two or more than lines systemic chemotherapy prior to surgery. The results showed that survival was 17 months in the group that received none or 1st line preoperative systemic chemotherapy and 11.5 months in the group that received two or more lines of preoperative systemic chemotherapy (p=0.023) (Table II).
Clinical characteristics of patients with brain metastases.
Kaplan–Meier curves for survival after resection of brain metastases. A) Overall survival of 172 patients after diagnosis of brain metastases. Median overall survival was 13 months, and the 1- and 5-year survival rates were 48% and 5%, respectively. B) In a comparison based on the presence/absence of postoperative WBRT, median survival was 12.5 months in the treated group and 13 months in the untreated group, with no significant difference (p=0.507). C) In a comparison based on the presence/absence of postoperative systemic chemotherapy, median survival was 15 months in the treated group and 7 months in the untreated group, with a significant difference (p=0.005). D) In a comparison based on the number of systemic chemotherapy regimens used before surgery in the postoperative systemic chemotherapy group, median survival was 17 months in the none or 1st line group and 11.5 months in the ≥ 2nd line group, with a significant difference (p=0.023).
Univariate analysis for overall survival.
Discussion
This study, consistent with recent reports, found that WBRT had an inferior effect in prolonging survival. This may be due to the fact that, although WBRT used to be the main treatment modality, several other treatment modalities have now been developed, allowing for a multifaceted approach to treatment. In other words, treatment modalities other than WBRT are now sufficiently capable of prolonging survival (3, 4). This prolongation of survival has also brought to light the adverse events associated with WBRT, mainly cognitive dysfunction, further driving the trend to avoid WBRT. As a result, WBRT after tumor resection is no longer considered the standard treatment (5-7). However, local recurrence rates are high when WBRT is not added after surgery (8). For this reason, stereotactic irradiation of the post-resection cavity has been used as a method to improve local control after tumor removal, and it has been described in several articles (9, 10). Mahajan et al. reported the results of a phase III trial in which SRS was applied to the post-resection cavity and achieved a good local control rate of 72% at one year (10). Neoadjuvant radiotherapy using SRS prior to tumor resection has also been reported in recent years, and it is expected to further improve local control rates and prevent intraspinal dissemination and radiation-induced brain necrosis (11).
The results of our study demonstrated that systemic chemotherapy for brain metastases after resection contributed to prolonged survival. In previous reports, worsening of the primary cancer was the cause of death in more than 50% of brain metastasis cases (12). This means that primary cancer control is important for achieving prolonged survival, and it is clear that the introduction of aggressive postoperative systemic chemotherapy is a prognostic factor for this. The present study also found differences in survival according to the number of systemic chemotherapy regimens used before surgery for brain metastases. Systemic chemotherapy is usually started with the most effective 1st line regimen for the patient’s primary cancer. Treatment is switched to other regimens while monitoring the effect of the systemic chemotherapy, but the response rate decreases with 2nd line and subsequent regimens because these drugs are not as effective as 1st line treatment. The present study also found differences in survival according to the number of systemic chemotherapy regimens used before surgery. Noyama et al. performed a prognostic analysis of patients who underwent gamma knife radiosurgery for brain metastases, and they found that a history of systemic therapy prior to treatment was a negative prognostic factor (13). This may be because systemic chemotherapy with a high response rate, for example 1st line systemic chemotherapy, could not be administered after treatment for brain metastases in cases where systemic therapy with a high response rate had already been administered before the development of brain metastases. This finding also supports the results of the present study.
In 1997, recursive partitioning analysis (RPA) was reported as a tool for analyzing prognostic factors in brain metastases (14). This RPA used the Karnofsky Performance Status (KPS) scale, age, and control of extracranial lesions as indicators, and in 2012, the diagnosis-specific Graded Prognostic Assessment (DS-GPA) was developed, adding cancer-specific features to this RPA (15). Subsequently, a GPA for the molecular diagnosis of lung cancer (lung-molecular GPA) was also added to the DS-GPA (16). As the treatment strategies for brain metastases have advanced, the prognostic factors have been modified. The results of the present study suggest that the presence or absence of postoperative systemic chemotherapy should also be added to the prognostic factors. In particular, the availability of a systemic chemotherapy regimen with a high response rate was also considered important as a positive prognostic factor.
The present study found that the introduction of postoperative systemic chemotherapy after tumor resection of brain metastases was a positive prognostic factor, whereas WBRT was not. The study also found that the prognosis was better when fewer systemic chemotherapy regimens were used before surgery.
Although the results of this study showed a negative benefit of WBRT, there are still some reports showing the effectiveness of WBRT (17). As this was a retrospective study, it would be desirable to examine the results in a prospective study in the future.
Footnotes
Authors’ Contributions
Design of the study: HY, TO; Data collection: HY, TN, TO; Data analysis: TO, MF, JT; HY and TO wrote the first draft, and all Authors contributed to improving the article. All Authors approved the final version.
Conflicts of Interest
All Authors have no conflicts of interest to disclose. The Authors received no financial support for the research, authorship, and/or publication of this article.
- Received May 21, 2024.
- Revision received June 12, 2024.
- Accepted June 13, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
