The Efficacy of Postoperative Chemotherapy for Patients with Metastatic Brain Tumors from Non-Small Cell Lung Cancer

Whole brain radiotherapy (WBRT) after resection of brain metastasis has been long considered as a standard treatment which is effective in achieving local disease control without survival prolongation, but it is frequently burdened with significant neurotoxic side effects [1]. In the presence of oligo-metastasis to the brain (one to three lesions), the treatment of choice may be radiosurgery or surgical removal, which is known to prolong survival [2]. However, the evidence on the efficacy of chemotherapy for brain metastasis is limited, with data reported in various studies showing response rates ranging from 15 to 30% [3]. The effect of systemic chemotherapy for brain metastasis has been believed to be limited due to the presence of blood brain barrier (BBB) [3, 4]. However, BBB is known to be broken down in contrast enhancing lesions, and chemotherapeutic agents may cross the BBB in patients with established brain metastases as reported in some studies [4]. We hypothesized that microscopic remnant tumor cells after resection of a metastatic tumor may be controlled by systemic chemotherapy without WBRT. This retrospective analysis evaluated the therapeutic impact of the postoperative systemic chemotherapy after resection of metastatic brain tumors from non-small cell lung cancer (NSCLC) compared with WBRT. Surgical resection is the standard treatment modality for single, large, surgically accessible lesion; however, the reported local recurrence rate after metastatic brain tumor resection was significantly high, up to 34% [5]. Local recurrence after surgical resection is believed to develop from infiltrating remnant tumor cells [5]. To reduce local recurrence, we reported a novel surgical method referred to as microscopic total resection (MTR) [5]. The key feature of this method is to remove both the tumor and surrounding brain tissue until multiple margin biopsies are negative for cancer cells [5]. Through this technique, the local recurrence rate was reduced even without WBRT [5]. Previously, we also reported the therapeutic efficacy of frontline systemic chemotherapy for minimally symptomatic synchronous brain metastasis [4]. In our study, systemic chemotherapy group showed survival that was not inferior compared to the WBRT group, and, primary and metastatic brain tumors showed almost the same response rates. There was close correlation noted between intracranial and extracranial tumor responses. Moreover, the goal in the treatment of metastatic brain tumors should be simultaneous control of both brain and systemic disease, since about 70% of the patients die from primary disease progression. Also, recovery of neurologic deficits and preserving patients' qualities of life are important issues. In 2001, a French group reported the results of a phase III study on early versus delayed WBRT in patients with synchronous brain metastasis [6]. One hundred and seventy six patients were randomized to receive chemotherapy alone for at least the two first cycles, or chemotherapy and concurrent WBRT. The overall survival (OS) and progression free survival rates were similar in the two groups. The timing of brain radiotherapy (RT) did not have any effect on survival when the patients were treated with chemotherapy. They showed similar chemo-response between the cerebral and systemic lesions. In a recent review paper, the response rate of brain metastases from NSCLC to systemic chemotherapy have been reported to be up to 50% [3]. Primary and metastatic brain tumors showed similar chemo-sensitivities. There was close correlation between intracranial and extracranial tumor responses. Novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors showed higher response rates up to 70-80% and longer progression free and OS in a subset of patients with EGFR mutations. Since most of clinical trials on these agents have excluded patients with brain metastasis, few prospective data are available on the effect of these agents in this setting. However, in recent years, several authors have reported a growing number of cases of partial and complete response in brain metastasis patients treated with EGFR tyrosine kinase inhibitor especially those with EGFR mutations [3, 7, 8, 9, 10, 11, 12, 13, 14, 15]. The above findings stimulated us to evaluate the role of systemic chemotherapy as a postoperative adjuvant treatment in patients with brain metastases from NSCLC. We hypothesized that microscopic remnant tumor cells after resection of metastatic tumors may be controlled by systemic chemotherapy without WBRT. This retrospective analysis evaluates the therapeutic impact of the adjuvant systemic chemotherapy after resection of metastatic brain tumor from NSCLC compared with WBRT.

Several treatment modalities have been reported to be effective as an adjuvant therapy after surgical resection of metastatic brain tumor from NSCLC. For solitary brain metastasis, surgery plus WBRT have been considered as a standard treatment modality that resulted in reduced brain disease recurrence [16, 17, 18, 19, 20]. However, it has been reported that WBRT does not improve OS and functional independence. WBRT may impair cognitive function due to leukoencephalopathy and brain atrophy, and as the survival of patients with brain metastasis become longer, there is increasing concern regarding quality of life and tendency to defer WBRT with close brain image follow ups. Our hypothesis is that chemotherapy after surgery for metastatic brain tumor enables concurrent treatment of systemic disease and remnant microscopic metastatic brain tumors, and that radiation therapy after brain disease progression may also be effective. Brem et al. [21] reported that carmustine wafer on the resection cavity after resection of a single brain metastasis resulted in reduced risk of a local recurrence without WBRT independent of the primary cancer site of origin. Also, the patients showed improved memory and other executive cognitive function [21]. The local control rate (78%) was comparable to reported rates after surgery with WBRT and superior to reports of WBRT alone [21]. These results showed that chemotherapy may be effective against microscopic remnant metastatic brain tumor cells if enough drug delivery can be achieved. However, there are no previous reports about the effect of postoperative adjuvant systemic chemotherapy in metastatic brain tumors. Previously, we suggested that brain metastases may be treated with frontline systemic chemotherapy alone, and frontline chemotherapy may be helpful for patients with metastatic brain tumors in terms of cognitive function and quality of life compared with WBRT [4]. Systemic treatment for patients with NSCLC including chemotherapy and molecular-targeted therapy improved dramatically recently, such progress initiate us to evaluate the role of systemic treatment as a postoperative adjuvant setting for brain metastasis from NSCLC.

In this retrospective analysis, we demonstrated that there was no significant difference in terms of patients' survival between patients who received postoperative systemic chemotherapy and those who received adjuvant brain RT. Distant recurrence occurred more frequently in the chemotherapy group. However, the DRF survival was not different between the two groups. This is probably because the causes of death were mostly primary cancer progression rather than brain metastasis progression. In our cases series, 70% of patients died of primary cancer progression, and we had also reported previously the growth rate of metastatic brain tumor from NSCLC. The volume doubling time was about 3 months [22, 23]. After resection of metastatic brain tumors, we usually followed up patients with brain MRI or CT every 3 months, and since most of the local or distant brain metastases appeared as small asymptomatic lesions, administration of radiation therapy after brain disease progression is discovered may also be effective. Postoperative chemotherapy is more feasible and may be an appropriate option for simultaneous control of both primary and metastatic lesions. Among the adjuvant RT group, 67% of all patients received chemotherapy after RT. Among the chemotherapy group, 59% of all patients received RT for brain lesion progression. As a result, 41% of all patients did not receive RT until death or last follow-up. Therefore, this suggests that we may avoid unnecessary radiation therapy in almost 40% of patients with this strategy.

In conclusion, there is no significant difference in terms of patients' survival between patients who received postoperative systemic chemotherapy and those who received adjuvant brain RT. Although these findings are thought provoking, these must be interpreted cautiously because of the nature of the retrospective analysis and relatively small number of cases in the present study. For further evaluation, prospective randomized phase III clinical trials for larger number of patients are surely needed.