The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline

Three case series addressed the question of whether re-administration of WBRT was beneficial for patients in whom previously treated brain metastases recurred/progressed [5‐7] (Table 1). These studies are retrospective analyses of 52, 72 and 86 patients, respectively, and they offer only very limited data as to whether patients died from neurologic causes versus systemic disease progression. The average re-irradiation dose for these patients was in the range of 20–25 Gy over multiple fractions. The post-re-irradiation median survival was 4 or 5 months in all of the series.

In the largest of the case series (n = 86), 70% of patients had either complete or partial resolution of neurological symptoms following re-irradiation. In the two other case series, the percentage of patients whose neurologic function improved following re-irradiation was 42% and 31%, respectively [5, 6].

One patient experienced symptoms of dementia attributed to radiation therapy in each of the two series reporting information on longer term adverse effects [6, 7].

No studies were identified that evaluated the use of WBRT in the setting of recurrent/progressive brain metastases for patients whose initial management did not include WBRT.

Four cases series addressed the use of surgical resection for recurrent/progressive brain metastases [8‐11], as outlined in Table 2. Two of these retrospective studies reported outcomes for patients who underwent surgical resection for recurrent/progressive brain metastases who also had previously been treated with SRS ± WBRT [10, 11]. In the study by Vecil et al. 61 patients with three or fewer recurrent brain metastases underwent surgical resection for at least one index brain metastasis [11]. Treatment of non-index brain metastases varied. Major surgical complications occurred in seven patients. From the date of resection, median survival was 11.1 months and median time to any recurrence in the brain was 5 months. Cause of death was neurologic in 15% of patients and neurologic/systemic combined in 34%. The second study, conducted by Truong et al., included 32 patients who had previously been treated with SRS and who had MRI and/or clinical evidence of brain metastasis progression. To be considered for surgical resection, patients needed to have a KPS ≥60 and stable or absent systemic disease. Median survival from the time of resection was 8.9 months. Seven patients experienced surgical complications. Cause of death was neurologic in 48% of patients [10].

Two case series evaluated the outcome of re-operation for recurrent brain metastases [8, 9]. Bindal et al. reported on 48 patients who had surgical resection of a brain metastasis as part of their initial treatment and then underwent resection for recurrent disease. From the time of re-operation, median survival was 11.5 months and the median time to recurrence was 7.7 months. Of the 26 patients who developed a second recurrence, 17 underwent another surgical resection. For the 25 patients in which cause of death was known, it was neurologic in 48% and combined neurologic/systemic in 12% [9]. As part of a larger study, Arbit et al., provide retrospective data on 32 patients with non-small cell lung cancer (NSCLC) who underwent re-operation for recurrent brain metastases. From the date of re-operation, median survival was 10 months. Time to recurrence/progression was not reported [8].

Thirteen studies addressed the role of SRS for recurrent/progressive brain metastases [12‐24]. Nine studies evaluated the use of SRS for recurrent/progressive disease in patients whose initial management included WBRT [12, 14‐17, 19‐22]. One of these studies was prospective [16]. This single-arm phase I/II study enrolled 12 patients whose life expectancy was ≥3 months and who had both clinical and radiologic evidence of brain metastases progression following treatment with WBRT. All patients were followed to recurrence at the SRS treated site or until death. In total, 20 brain metastases in the 12 patients were treated by radiosurgery. From the date of SRS treatment, median survival was 6 months. Nine patients developed evidence of progressive disease at SRS treated sites. Time to progression was not reported. Of the other eight studies that addressed the role of SRS for recurrent disease in patients whose upfront treatment included WBRT, four specifically evaluated SRS treatment for recurrent/progressive brain metastases from particular primary tumor types–breast cancer (2 case series [12, 14]), small cell lung cancer (SCLC) (1 case series [22]) and lung cancer, predominantly NSCLC (1 case series [17]). See Table 3 for details.

The only comparative study that met the eligibility criteria for the systematic review evaluated single-dose SRS versus split-dose (2 dose) SRS for recurrent/progressive disease in 104 patients whose initial management included WBRT [15]. In this retrospective cohort study with historical controls, median survival was significantly longer for patients who received split-dose SRS compared to single-dose SRS (30 vs. 16 weeks; p = 0.015). Time to recurrence/progression was not reported.

Four case series evaluated the use of SRS for recurrent/progressive brain metastases in patients whose previous treatment included radiosurgery [13, 18, 23, 24], as outlined in Table 3. Only two of these case series provide survival data from the date of SRS for recurrent disease [13, 18]. In the series by Kwon et al., of 43 patients who underwent salvage SRS, median survival from the time of SRS for recurrent/progressive disease was 32 weeks and the local control rate at 6 months was 91% [18]. In the case series by Chen et al., of 45 patients, median survival from the time of SRS for recurrent brain metastases was 28 weeks [13]. The 1 year freedom from progression rate was 94%.

Ten studies evaluated the role of chemotherapy in patients with recurrent/progressive metastatic brain disease [25‐34]. Of these, five are prospective single arm phase II studies [25, 27, 29, 31, 32] and five are case series [26, 28, 30, 33, 34]. Refer to Table 4 for details. The agents used in these studies varied from intracarotid administration of cisplatin, to temozolomide alone or with thalidomide, vinorelbine, fotemustine or cisplatin. Five of the studies investigated the role of chemotherapy specifically for patients with recurrent/progressive brain metastases from particular primary tumor types—melanoma (3 studies) [26, 28, 31], NSCLC (1 study) [29], and SCLC (1 study) [30].

Median survival in patients with recurrent/progressive brain metastases treated with chemotherapy ranged from 3.5 to 6.6 months [25‐34]. The median time to recurrence after retreatment with chemotherapy in these studies ranged from 2 to 4 months. These studies indicate that some patients with recurrent or progressive brain metastases will have an objective radiographic response and/or improvement in functional status after treatment with chemotherapy.

No studies were identified that met the eligibility criteria for this question.