STI is the primary treatment for newly diagnosed brain metastases, especially if they are small and inaccessible. Local progression of brain metastases after upfront treatment with STI is seen more often now because of better survival of these patients, and the demand for salvage treatment is now more than ever [16]. In our study, salvage surgery was done for 20 patients in the first 8 years, and for 34 patients in the recent 8 years.
Median OS after upfront STI was 37.5 months for all 48 patients, 37.5 months for recurrences with pure or combined histology (n=42), and 40.3 months for patients with pure radiation necrosis (n=6) (p=0.13). Median OS noted in previously published studies was much lower at 7.5 to 19 months (Table 4) [10, 11, 17-20]. The longer median survival in our study can be attributed to the development of systemic therapy, improved care of cancer patients, and advances in surgical techniques.
Overall survival of patients with brain metastases also depends on the outcome of systemic primary cancers. However, these patients’ functional outcome depends essentially on the CNS lesions. The goal of CNS treatment is to delay neurological progression long enough to facilitate the treatment of primary systemic metastases. Therefore, we should consider functional outcomes along with OS while considering treatment options for individual patients with brain local progression. [21].
Treatment decisions for brain local progression should be based on the functional status, lesion volume and surrounding edema, previous treatments, and the type of primary cancer [21]. Surgical removal, repeated in-field radiosurgery, WBRT, systemic therapy, or a combination of these can be chosen, depending on these factors.
Surgery remains an effective salvage treatment option with two important benefits: immediate reduction of the mass effects and histological confirmation. Salvage surgery led to overall local control rates of 69 to 100%, and a median OS of 7.5 to 20.2 months, even for large lesions (Table 4).
Genetic and molecular information of cancer cells has become a recent clinical focus, because of reports showing drafting and variation of genetic markers in metastatic cancer cells [22, 23]. Pathological analysis of surgical specimens may present new opportunities for targeted therapy.
In our study, histological examination revealed that 13% of the local progression lesions were radiation necrosis alone, and 87% were a heterogeneous combination of necrosis and cancer cells. Previous studies have shown pure radiation necrosis in 0-50% of lesions obtained by salvage surgery (Table 4). The preoperative differential is not always easy, because both radiation necrosis and tumor recurrence present similar clinical and radiological findings, and a majority of these lesions comprise a combination of necrosis and cancer cells [20, 24]. Without histological confirmation, repeated irradiation can lead to deterioration of necrosis and brain edema.
Retrospective studies on the one-year outcome of repeated radiosurgery for local progression reported that local control was 61 to 88%, and OS was 37 to 90.6% [25-27]. Toxicity was reported as overall necrosis rates 9.2 to 19% after the repeated SRS or SRT [25, 26]. Necrosis after repeated STI was shown to be significantly associated with the irradiated volume and the cumulative dose [16]. For large lesions with surrounding edema, repeat SRS may lead to a risk of local progression as the majority of these lesions consist of a combination of radiation necrosis and cancer cells, surrounded by the injured brain. In our study, repeated in-field STI was used for cancer cells remaining after minimal resection, in eloquent areas only. The risk of radiation necrosis due to repeated STI is reduced after decompressive surgery, because of less target volume and less involved normal tissue volume in the intended field.
We treated patients even if their prognostic scores were poor. 50% of patients in our cohort were RPA class 3, whereas these advanced class patients were maximum of 30% in previous studies (Table 4). RPA classes were significantly correlated with the median OS (Table 2). Interestingly, the median OS of the whole cohort in our study was longer than the median OS in previous studies. We offered surgical resection to patients with lower KPS when we expected that neurological improvement would lead to a better general condition. Very little has been reported about postoperative functions after salvage surgery. In our study, 23 of 54 cases showed improvement in KPS after salvage surgery(Fig. 3). Sixteen patients returned to their systemic therapy for primary cancer soon after recovering from salvage surgery.
Although the numbers of patients presenting with local progression are increasing in recent years, most studies on salvage surgery, published before 2014, comprised of small cohorts (Table 4). This lack of recent data may be due to patients assuming upon a high risk of surgical resection and general anesthesia in heavily treated patients with brain metastases.
Surgical resection is safe for local progression after STI in selected patients. Surgical mortality rates range from zero in Telera’s series [20] and ours, to 3% in the series of Vecil [17] and Truong [10] (Table 4). Although these surgical mortality data are of patients with heavily treated cancer, the rates were not worse than the data of general patients who underwent craniotomy for brain tumors. If we compare surgical morbidity data, previous studies reported little regarding postoperative neurological function, KPS or QOL. In our study, for lesions in eloquent areas, the minimum resection technique was used to preserve surrounding normal tissue, to achieve the best possible neurological function and KPS. Postoperative STI was used only if active cancer cells had invaded the surrounding brain and leptomeningeal layers. This combination strategy was as effective as resection with free margin and no postoperative radiation, in achieving local control and preventing dissemination (Table 3). This result emphasizes that proper selection of surgical technique contributes to a better functional outcome as well as curability. Although resection with free margin is an effective surgical technique for metastatic lesions with tissue invaded by cancer cells, it can be employed only in non-eloquent areas.
Two of our patients showed a deterioration of KPS, which occurred due to unexpected and rapid progression of primary cancer after salvage surgery, and clearly not due to neurological progression. Preoperative thorough assessments are complex challenges, especially in patients with heavily treated cancer. In this study, NLR has proven itself once again as a reliable marker to evaluate the general condition of patients with local progression. Previously, this was indicated in our study on upfront surgery for brain metastases [13]. NLR is a simple peripheral blood sample method and would help in the decision-making for resection surgery. We have various assessment tools to predict the survival prognosis of patients with brain metastases [28, 29]. However, we do not yet have any assessment tools to predict the functional outcome of brain metastases patients after local or systemic treatments. Long-term observation of large cohorts is necessary to predict the functional outcome of brain metastases patients.
Our study has some limitations, as it was a retrospective study of therapeutic outcomes with surgical resection only. We had a concrete plan to select patients for resection, and observe in the postoperative period with MR imaging. Planning for a control group was not ethical for this relatively rare, progressive and devastating condition. The patient cohort was small because this is a study in a single cancer center. A majority of the patients had primary cancers of lung and breast, but only a few had melanoma as a primary. This is an ethnical tendency that might taint a direct comparison of our outcomes with previous studies on Western populations.