The high incidence of brain metastases in lung cancer can be partially explained by normal physiology. Fifteen percent of blood flow from the left heart goes directly to the brain. Lung cancer cells have direct access to the left side of the heart via the pulmonary veins. Cancer cells from other organs must pass through the pulmonary capillaries or be shunted from the right to left side of the heart before gaining access to the brain.

Cancer cells require complex capabilities of extravasation, evasion of the immune detection system, and establishing new blood vessels in the process of establishing brain metastases. This process is detailed in an excellent review article published by Gavrilovic and Posner.¹ Cells undergo genetic changes to allow for uncontrolled growth, angiogenesis, and intravasation into blood vessels. Cells must then survive circulation and reach the organ in question where the right biochemical environment is necessary for proliferation and development of metastases. Cancer cells destined to become brain metastases are caught in the CNS capillaries and then proliferate through the vessels into the brain parenchyma. Here, the blood-brain barrier protects them from many systemic cancer therapies. There is a variable period of dormancy during which time, genetic changes take place, enabling cells to proliferate and become clinically significant metastases. This period of protected dormancy explains why we see delayed brain metastases in patients with effectively treated lung cancer and why as treatment is improving and survival is lengthening, the rate of brain failures is increasing.

The incidence of brain metastases in patients with locally advanced non-small cell lung cancer (LA-NSCLC) varies between 13% and 54%.²,³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹ From various reports, a range from 18% to 52% of patients have a solitary brain lesion.¹¹,¹²,¹³,¹⁴,¹⁵ The risk of brain failure has been related to disease stage, 10 disease bulk,¹⁶ histology,¹⁰,¹⁷,¹⁸,¹⁹ length of survival from diagnosis,²⁰ female gender,²¹ age <60 years,¹²,¹⁶,²² type of therapy,¹⁰,¹⁷,²³ and serum lactate dehydrogenase.²¹

Histology The incidence of brain metastases is higher with adenocarcinoma and large cell carcinoma than with squamous cell carcinoma.¹⁷,¹⁸,¹⁹,²⁴ Consequently, some studies evaluating PCI for NSCLC have included only patients with nonsquamous histologies.⁵,⁷ Although a trend toward increased incidence of brain metastases in patients with adenocarcinoma is observed in most studies, not all studies have shown a significant correlation.⁴,⁸,¹⁰,¹¹,¹⁶,²¹,²⁵

Extent of Mediastinal Disease Ceresoli et al.¹⁶ reported borderline significance of bulky mediastinal disease (nodes >2 cm) and the incidence of brain disease by multiple regression analysis. Robnett et al.¹⁰ reported 2-year actuarial incidence of brain metastases of 36% with stage IIIB disease and 29% with Stage II/IIIA disease (p <0.04). Wang et al.^25a conducted a more extensive analysis of impact of nodal disease on brain failures in 223 patients treated surgically with stage IIIA/B disease. Brain metastases were greater in patients with more lymph nodes and more nodal regions involved.

Age Ceresoli et al.¹⁶ evaluated risk factors for brain metastases in 112 patients with LA-NSCLC. In multivariate analysis, age younger than 60 years was associated with an increased risk of brain metastases (31% vs. 9%; p = 0.03). In a series reported by Carolan et al.,¹² 25.6% of patients younger than age 60 failed first in the brain compared with 11.4% of patients older than 60 (p = 0.022). In a review of four Southwest Oncology Group (SWOG)²² studies, patients age 50 and younger were at increased risk for developing brain metastases with a hazard ratio of 1.8 (p = 0.046). Other series have not shown an increased risk of brain metastases with young age.¹⁰,¹³

Time to Brain Failure Most brain metastases occur within 2 years of diagnosis.¹⁰,¹¹,¹²,¹³,¹⁶,²⁰,²² Median time to relapse in the brain is 5.7 to 11.7 months.¹⁰,¹²,¹³,¹⁶,²⁰ Earlier relapse is associated with younger age (<60),¹²,¹⁶,²² bulky disease (>2 cm),¹⁶ and nonsquamous histology.¹²,²²

Duration of Survival The addition of chemotherapy to local regional therapy for LA-NSCLC has improved survival. Systemic therapy decreases the risk of visceral metastases¹⁷,¹⁸,²⁶,²⁷ but has limited impact on brain metastases.¹⁷,¹⁸,²⁷ In fact, as survival lengthens the risk of brain, metastasis increases. Review of Radiation Therapy Oncology Group (RTOG) and single-institution data has shown that longer survival for patients with LA-NSCLC treated with radiation alone²⁰,²⁴ or radiation and chemotherapy¹⁸ is associated with an increased incidence of brain metastases.

Review of 1415 patients treated on radiation therapy alone and 350 patients treated on radiation and chemotherapy on RTOG studies demonstrated a significant decrease in distant metastases with the addition of chemotherapy (41% vs. 19%; p <0.001). Brain metastases were not altered by chemotherapy (17% vs. 12%).¹⁸

Andre et al.¹⁷ reported the patterns of relapse in 81 patients with clinical N2 disease treated with preoperative chemotherapy to 186 comparable patients treated with primary surgery. Survival at 2 and 5 years was 35% and 17% for preoperative chemotherapy and 26% and 8% for primary surgery. Preoperative chemotherapy was associated with a better prognosis in multivariate analysis (p = 0.001). Additionally, patients treated with chemotherapy had a lower rate of visceral metastases (28% vs. 38%; p <0.05) and a higher rate of brain metastases (32% vs. 18%; p <0.05). The observation that neoadjuvant chemotherapy (or chemoradiotherapy) is associated with an increased risk of brain metastasis is bolstered by reports from Philadelphia and San Francisco.¹⁰,¹³ An explanation might be that as local and system disease are better controlled, and the untreated risk site, the brain, becomes a dominant site of failure.

Recursive partitioning analysis (RPA) of RTOG studies employing radiation therapy alone showed that patients in the RPA group with the longest survival had the highest incidence of brain metastases.²⁰ Median survival for class I and II was 12.6 and 8.3 months, and class III and IV was 6.2 and 3.3 months. First failure in the brain was significantly higher in class I (18%) compared with class III (9%) and IV (6%) (p = 0.0004 and 0.03, respectively).

Recently, several studies employing multimodality therapy for LA-NSCLC have reported excellent median and 3-year survival rates of 20 to 43 months and 34% to 37%.⁴,¹¹,¹²,¹³,¹⁶,²³,²⁸ These studies reported the brain to be a common site of failure. Overall brain failure rates were 22% to 55%, and rates of brain as first site of relapse were 16% to 43%. Studies with lower median survival (3 to 17 months) and 3-year overall survival (5% to 27%) report a lower incidence of brain metastases, suggesting that the later brain relapse in the longer-surviving patients occurs in a sanctuary site. Overall rates of brain failure are 6% to 21%, and rates of brain as first site of failure are 9% to 19% (Table 57.1).³,¹⁰,²⁰,²⁹,³⁰

Locoregional and Systemic Therapy Studies have shown an association between timing of local therapy incidence of brain metastases. Robnett et al.¹⁰ reported a near doubling of the 2-year actuarial risk of brain metastases of 39% in patients treated with sequential chemotherapy and radiation compared with 20% for patients treated with concurrent chemotherapy and radiation. Mamon et al.²³ reported results of patients treated preoperatively with chemotherapy or concurrent chemotherapy and radiation. Decreased risk of brain metastases was associated with preoperative +/− postoperative radiation versus postoperative radiation therapy only (p = 0.062), use of taxane-based chemotherapy (p = 0.044), and conversion to N0 status (p = 0.025). Conversely, Furuse et al.³¹ reported a higher rate of brain failures in patients treated with concurrent chemotherapy and radiation compared with patients treated sequentially, (19% vs. 9%; p = 0.018). The higher rate of brain metastases may be explained by longer survival in the concurrently treated patients (16.5 vs. 13.3 months; p = 0.04). Byhardt et al.³² reviewed the outcome in 461 patients treated on five RTOG studies and found no association between the incidence of brain metastases as first failure and sequential versus concurrent chemotherapy and radiation. Median survival for concurrent regimens was 16.3 and 15.8 months and for sequential therapy 13.6 months (p = 0.47).