Radiation Management of Synchronous Brain Metastases from Non-Small Cell Lung Cancer

General Considerations for the Management of Brain Metastases

Brain metastases cause significant morbidity and mortality. Approximately one-quarter of NSCLC patients will develop clinically detectable brain metastases ( ). The outcomes for this population are generally poor; median survival in the absence of treatment is about 1 month and may be extended to 2 months by the use of steroids ( ). Symptoms that are associated with brain metastases may be a result of increased intracranial pressure from cerebral edema, resulting in headaches, nausea, and vomiting. Focal neurological symptoms due to brain metastases include seizures, focal motor and sensory deficits, ataxia, speech problems and cognitive deficits.

Standard treatment options for patients with brain metastases include comfort measures, steroids, anticonvulsants, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgical resection, or a combination of these modalities. The optimal treatment for brain metastases is highly dependent on individual patient characteristics, tumor factors, and treatment considerations. The clinician must take these factors into consideration to determine if the goal of treatment is palliation of symptoms or whether long-term disease control with more aggressive treatment modalities might be achievable.

For most patients with multiple brain metastases, WBRT is considered the standard of care. WBRT alone is most commonly used in patients with multiple brain metastases with a limited life expectancy due to poorly controlled extracranial disease or poor performance status. The use of WBRT in NSCLC patients with brain metastases improves quality of life ( ), neurologic function, and results in an improvement in median survival to approximately 3–6 months ( ). Various dose and fractionation schedules for WBRT have been investigated and no altered dose-fractionation schedule has proven to be superior to the commonly prescribed schedules of 20 Gy in five fractions or 30 Gy in 10 fractions with respect to survival or symptom control (neurologic functional status, symptom relief, palliative index or performance status) ( ). Other commonly used fractionation schedules routinely employed in clinical practice are 40 Gy in 20 fractions or 37.5 Gy in 15 fractions.

Management of Patients with Single Brain Metastases

For selected patients with a good performance status and a single brain metastasis, higher rates of local control and survival have been achieved with the use of SRS or surgical resection with WBRT compared to WBRT alone. The first trial to demonstrate a benefit to surgical resection randomized 48 patients with a single brain metastasis and a Karnofsky performance status (KPS) of≥70 to WBRT alone versus surgical resection followed by WBRT ( ). Those patients who received surgery had fewer recurrences at the site of the original metastasis (20 vs 52%, p <0.02), a higher overall median survival (40 vs 15 weeks, p <0.01) and remained functionally independent for longer (38 weeks vs 8 weeks, p <0.005) than those who had WBRT alone.

Stereotactic radiosurgery, a highly precise, typically single-fraction treatment of high dose radiation, has also been shown to improve local control and overall survival when combined with WBRT in patients with a single brain metastasis, as demonstrated by . Three-hundred and thirty-three patients with a KPS of at least 70 and one to three brain metastases from a variety of primary malignancies were randomized to WBRT or WBRT followed by SRS boost to the metastases. Metastases had to be less than 4 cm in diameter for the largest lesion and additional lesions could not exceed 3 cm. The addition of SRS resulted in a local control benefit at 1 year for all patients compared to WBRT alone (82% vs 71%, p =0.01). No survival benefit was observed for patients in the SRS group (6.5 vs 5.7 months) but, on subset analysis, patients with single metastases who received an SRS boost had a significantly better survival (median survival time 6.5 vs 4.9 months, p =0.0393). On multivariate analysis, RTOG RPA Class 1 patients had a survival advantage whether they had a single or multiple tumors. The use of SRS was not associated with any significant additional toxicity.

To summarize, the evidence suggests that the standard of care for patients with a KPS≥70 and a single brain metastasis should be SRS or surgical excision, integrated with adjuvant WBRT. Though these options have never been directly compared to each other in a randomized controlled trial, non-randomized data suggest that both options are considered equally effective. Unfortunately, the only randomized controlled trial designed to address the question failed to accrue enough patients to permit any firm conclusions ( ).

Surgery vs SRS for Single Brain Metastases

The choice of surgery vs SRS depends on several factors including: whether the patient is a surgical candidate; the presence of severe neurologic symptoms; the location, size and resectability of the lesion; and the need for histopathological confirmation. The ASTRO evidence-based guideline on the radiotherapeutic and surgical management of newly diagnosed brain metastases recommends that good prognosis patients with a single brain metastasis less than 3 or 4 cm in maximum dimension and amenable to surgical excision can be considered for either surgery or radiosurgery ( ). In general, surgical resection should be considered in patients who have a surgically accessible lesion, patients with severe neurologic deficits due to mass effect or in patients for whom histopathological confirmation is required ( ). Radiosurgery should be considered in good prognosis patients with single brain metastasis less than 3–4 cm in maximal dimension, in eloquent areas not amenable to safe total resection, or in patients who are unfit for surgery ( ).

Management of Patients with Multiple Brain Metastases

For patients with two to four brain metastases, the randomized data (RCT) have not demonstrated a survival advantage with the addition of SRS to WBRT. This fact is often used as the rationale for treating patients with multiple brain metastases with WBRT alone. Guidelines published by the American Association of Neurosurgeons suggest that the lack of survival benefit observed in the studies examining patients with more than two brain metastases may be due to crossover of study participants and insufficient power in the available RCTs ( ). Furthermore, some non-randomized data have demonstrated a survival advantage for patients with multiple brain metastases treated with SRS. A retrospective study by of 205 patients with four or more intracranial metastases from various primary cancers treated with SRS found a survival benefit compared to historical controls treated with WBRT alone. Total intracranial treatment volume was found to be an important predictor of survival and the authors suggest that this factor be of primary consideration, rather than the total number of metastases.

Though it is unclear whether a survival benefit exists for patients with multiple brain metastases, there is level I evidence that SRS boost results in improved local tumor control, reduced steroid dependence, and improved performance status. randomized 27 patients with two to four brain metastases measuring<2.5 cm and with a KPS≥70 to WBRT alone vs WBRT+SRS. The study was stopped early after an interim analysis revealed substantial improvements in the rate of local failure at 1 year (100% vs 8%) and median time to local failure (6 vs 36 months). No survival benefit was found with the use of SRS boost and WBRT compared to WBRT alone. The RTOG 9508 study ( ), discussed previously, found a statistically significant improvement in KPS and a reduction in steroid use with the addition of SRS to WBRT in patients with one to three brain metastases. This study did not find statistically significant differences in mental status, overall time to intracranial tumor progression, neurologic death rates, or toxicity between the two treatment arms.

Emerging Techniques in the Radiation Management of Brain Metastases

Various radiation therapy approaches (e.g. helical tomotherapy (HT), volumetric arc therapy, and intensity modulated radiation therapy) using image-guided fractionated radiotherapy regimens are being investigated as a non-invasive alternative to SRS in the management of patients with brain metastases. This technique combines intensity modulated fan-beam radiotherapy delivery with megavoltage computed tomography imaging, providing the capability of on-line image-guided conformal radiation delivery. The addition of SRS to WBRT requires separate localization and treatment procedures that add some cost and inconvenience to patients, caregivers and providers. Some SRS systems require invasive immobilization devices, which can add to patient discomfort and patients with multiple lesions can experience long treatment times.

For example, a phase II multi-institutional study ( ) assessing a simultaneous in-field boost HT technique for brain metastases (TOMO-BII) is now open for accrual. Patients with one to three brain metastases are treated with a simultaneous in-field boost technique yielding a total intralesional dose of 60 Gy with a surrounding whole brain dose of 30 Gy. Outcomes will be compared with historical controls treated with SRS and WBRT. The purpose of the trial is to provide patients with a shorter course, dose intense and non-invasive radiotherapy treatment with equivalent or improved CNS control, survival, quality of life and toxicity. Other clinical trials using alternative radiotherapy platforms are also accruing patients ( www.clinicaltrials.gov ).