Brain Metastases from Lung Cancer

Surgical Resection

The surgical resection of brain metastases has traditionally been reserved for palliation of symptomatic lesions or for situations in which pathologic confirmation is necessary. However, some subsets of patients with favorable prognostic factors have undergone surgical resection with the intent of improving survival. A pivotal trial conducted in the 1980s by evaluated the use of surgery for 48 patients with a single brain metastasis who were also receiving WBRT. Specifically, patients with a suspected brain metastasis were randomly assigned to undergo either biopsy followed by WBRT or surgical resection followed by WBRT. WBRT was to be delivered to a dose of 36 Gy in 12 fractions. Resection was found to improve local recurrence rates (52% vs 20%) and quality of life (9 months vs 2 months of functional independence). Surgery was also found to extend overall survival time (9 months vs 3 months) and time to death from neurologic causes (14 months vs 6 months). Rates of operative mortality (4%) and morbidity (8%) in that study were deemed acceptable.

Another phase III trial conducted in the Netherlands involved patients with a single brain metastasis who were given WBRT (40 Gy in 2-Gy fractions twice a day) either alone or with surgical resection ( ). Surgical resection was again associated with extended median survival time (10 months vs 6 months), with particular benefit seen among those with stable extracranial disease. Indeed, local therapy is generally advocated for those with favorable performance status, a single brain metastasis, and stable extracranial disease. The need for adjuvant radiotherapy after surgical resection to maintain intracranial disease control is discussed further later in this chapter.

Stereotactic Radiosurgery

The neurosurgeon Lars Leksell formulated the principles of radiosurgery in 1951, about 17 years before the launch of the first Gamma knife prototype at the Karolinska Institute. SRS is commonly defined as a single high dose of radiation directed by stereotaxis conformally to the target, minimizing the dose to the normal surrounding tissue. The first Gamma knife unit in the USA was installed at the University of Pittsburgh Medical Center in 1987. Today, brain metastases represent the most common indication for SRS ( ). The goals of SRS can be achieved with several types of technologies, including the Gamma knife, linear accelerators, or the Cyberknife.

The Radiation Therapy Oncology Group (RTOG) has conducted several trials investigating SRS for brain metastases. The prospective trial RTOG 90-05 sought to determine the optimal dose for radiosurgery of brain metastases by evaluating the maximum tolerated radiosurgical dose in 168 patients who had previously undergone irradiation for primary or metastatic brain lesions ( ). The maximum tolerated doses depended on the size of the lesion, being 24 Gy for tumors≤20 mm in diameter, 18 Gy for those 21–30 mm, and 15 Gy for tumors 31–40 mm. However, the actual maximum tolerated dose for lesions≤20 mm was not met because the investigators were reluctant to exceed 24 Gy. Notably, the rate of radionecrosis at 2 years was 11%. Subsequent research suggested that treating tumors≤20 mm with 20 Gy rather than 24 Gy produced equivalent control with lower complication rates ( ).

RTOG 95-08 was a randomized controlled trial comparing WBRT alone versus WBRT with SRS for 333 patients with one to three brain metastases ( ). The WBRT dose was 37.5 Gy delivered in 15 fractions, and the SRS dose was delivered according to the guidelines established by RTOG 90-05. Although no difference was found in overall survival between the two groups, subgroup analyses revealed that SRS improved overall survival for patients with a single brain metastasis. The addition of SRS to WBRT also led to higher response rates and better local control rates at 1 year (82% vs 71%); receipt of SRS was the only factor predictive of local control in a Cox proportional hazards analysis. The risk of developing a local recurrence was 43% greater in the WBRT-alone group relative to the WBRT with SRS group. Moreover, patients receiving SRS were more likely to have had stable or improved Karnofsky performance status scores at 6 months after treatment.

To date, no randomized controlled trials have been undertaken to compare surgery with SRS for single brain metastases. Findings from retrospective analyses are mixed and fraught with selection bias. The indications for SRS remain controversial, with factors contributing to the choice of treatment including the number of metastases, performance status, status of extracranial disease, and tumor histology. Further clinical trials are necessary to define an SRS treatment algorithm for patients with brain metastases.