The development of brain metastasis in a patient with non–small-cell lung cancer (NSCLC) is an ominous prognostic sign. About 30% of individuals with NSCLC eventually develop brain metastasis.¹ This number increases to about 50% in autopsy series.² When the metastases are multiple, palliative treatment in the form of radiation therapy is recommended. Solitary brain metastasis, however, can be approached surgically. The proportion of NSCLC patients that develops brain metastasis amounts to approximately 40,000 patients per year. The magnitude of this problem can be appreciated by comparing this number with the incidence of new primary cancers of the pancreas (n = 27,000), stomach (n = 24,000), and esophagus (n = 13,000). The median survival rate of untreated lung cancer with brain metastasis is approximately 1 month. Steroid therapy increases the median survival by 2 months. Whole-brain radiation increases survival by 3 to 6 months.³ Recent reports indicate longer survivals when surgical treatment is combined with whole-brain radiation.^4,5 The experience of several large centers that offer a surgical approach to lung cancer with brain metastasis is discussed herein, with an analysis of factors underlying prolonged survival.

In addition, other sites of metastatic disease also commonly present as oligometastases. Patients with lesions to the adrenals, liver, and bone are sometimes amenable to aggressive surgical and multimodality regimens. For the purposes of this chapter, data on brain and adrenal lesions will be presented.

Previous studies have reported 5-year survival rates of 11% to 21% in patients treated with cranial and thoracic resection.^5,6 Despite this, many patients are offered palliative treatment only with chemotherapy or radiotherapy after a brain metastasis has been detected. There is controversy regarding the ideal management of thoracic disease in this patient population, and there are few series that incorporate patients treated with craniotomy or stereotactic radiosurgery (SRS).⁷

In our prior series from the University of Maryland, 28 patients with solitary brain metastasis were treated by thoracotomy with resection of lung cancer and craniotomy with excision of brain metastasis or SRS. More recent patients in our series have undergone lung resection and gamma knife stereotactic radiosurgery (GK-SRS). The series consisted of 16 men and 12 women ranging in age from 42 to 70 years, with a mean age of 56.24 years.

The initial presenting symptom was neurologic in 50% of patients. The range of neurologic symptoms included hemiparesis, headaches, monoparesis, ataxia, visual disturbances, seizures, behavioral changes, and mild weakness. In these patients, the onset of the cerebral metastasis was synchronous with the primary in that the pulmonary lesion was identified on the chest x-ray concomitant with the initial presentation of the metastasis. The remainder presented with pulmonary complaints related to their bronchogenic carcinoma, including cough, hoarseness, and chest pain, but later developed symptoms related to both pulmonary and neurologic systems.

Patients with initial neurologic symptoms generally underwent craniotomy or, recently, SRS. After initiating steroid treatment, these patients were referred for initial treatment of their brain lesion. The lung lesion was generally approached later. Patients who were seen primarily for a pulmonary malignancy initially underwent a pulmonary resection. The types of pulmonary resections performed were lobectomy, bilobectomy, pneumonectomy, and wedge resection. A complete dissection of the mediastinal lymph nodes generally was carried out in conjunction with the pulmonary resection. We now use routine bronchoscopy and mediastinoscopy before deciding to proceed with pulmonary resection. Resections generally were considered curative (R0), with no gross tumor left behind. All resection margins were tumor-free microscopically, and the mediastinal nodes were removed.

The tumor cell type was most frequently adenocarcinoma, followed by squamous or adenosquamous, large-cell undifferentiated, or anaplastic carcinoma. In determining the staging of the tumor, only the status of the primary tumor and lymph nodes was considered because of the known presence of a solitary cerebral metastasis. Based on such consideration, in diminishing frequency, tumors were most often stage I, stage II, and stage IIIA.

Radiation therapy after lung resection or adjuvant chemotherapy often was tried. To date, 11 patients are alive and without evidence of recurrent cancer. Seventeen patients have died: 14 died of recurrent cancer, of whom seven died of widespread systemic metastases, four had recurrence in the chest, and three had central nervous system (CNS) metastases. One patient died of multiple-organ failure secondary to sepsis 47 days after lobectomy. One patient died 1 month after a left lower lobectomy of sudden cardiac arrest, and one patient died of respiratory failure complicating severe chronic obstructive pulmonary disease 17 months after craniotomy.

Survival after craniotomy often exceeds 5 years, with a 37% 5-year survival reported in prior studies. The difference in survival between those who received brain irradiation after craniotomy and those who did not was not significant in our series, although this finding has been challenged recently in reports of other similar series. Relief of neurologic symptoms after craniotomy is usually immediate.⁷

In prior series, the following factors were analyzed to determine the effects on survival: age, sex, order of presentation (i.e., cerebral, pulmonary, or synchronous presentation), interval between thoracotomy and craniotomy if the thoracotomy was done first, interval between craniotomy and thoracotomy if the craniotomy was done first, cell type of tumor, type of pulmonary resection (i.e., pneumonectomy, bilobectomy, lobectomy, or wedge resection), curative or palliative resection, T classification of the lung tumor, nodal status (N0, N1 vs. N2) of the lung primary, lung tumor stage, duration of neurologic symptoms prior to craniotomy, location of brain metastasis, brain irradiation after craniotomy versus no irradiation, and use of chemotherapy or radiation therapy for the lung lesion. By univariate analysis, three factors were found to correlate with longer survival: curative pulmonary resection (p = 0.001), nodal status (p = 0.001), and age less than 55 years (p = 0.006). However, when all the factors were analyzed by the Cox multivariate model, only curative resection remained a significant factor for prolonged survival (p < 0.01).

In a series from France, 94 of 4668 patients who underwent lung cancer surgery had oligometastatic disease. Metastasis occurred in brain (n = 57), adrenal gland (n = 12), bone (n = 14), liver (n = 5), and skin (n = 6). Sixty-nine metastases were resected. The 5-year survival rate was 16% (median, 13 months). Induction therapy, adenocarcinoma, N0 staging, and lobectomy were the criteria of better prognosis, but metastasis resection was not. The authors concluded this pattern may reflect a specific tumor biology in which a solitary metastasis would benefit both from surgical or non-surgical treatment.⁸

Dartevelle’s group published a series of 23 patients who underwent complete resection of an isolated adrenal metastasis after surgical treatment of NSCLC. There were 19 men and 4 women, with a mean age of 54 ± 10 years. The diagnosis of adrenal metastasis was synchronous with the diagnosis of NSCLC in 6 patients and metachronous in 17 patients. The median disease-free interval for patients with metachronous metastasis was 12.5 months (range, 4.5–60.1 months). The overall 5-year survival was 23.3%. Univariate and multivariate analysis demonstrated that disease-free interval of greater than 6 months was an independent and significant predictor of increased survival in patients after adrenalectomy. All patients with disease-free interval less than 6 months died within 2 years of the operation. The 5-year survival was 38% after resection of an isolated adrenal metastasis that occurred more than 6 months after lung resection.⁸ Although these authors believed that adjuvant therapy and pathologic staging of NSCLC did not affect survival, most physicians would treat with a full chemotherapy regimen to follow.

In a recent meta-analysis consisting of 10 publications that contributed 114 patients, 42% of patients had synchronous metastases and 58% had metachronous metastases. The median DFIs were 0 and 12 months, respectively. Patients in the synchronous group were younger than those in the metachronous group (median age 54 years vs. 68 years). Complications from adrenalectomy were infrequent. Median overall survival was shorter for patients with synchronous metastasis than those with metachronous metastasis (12 months vs. 31 months, generalized Wilcoxon p value < 0.02). However, the 5-year survival estimates were equivalent at 26% and 25%, respectively.⁹

A solitary brain metastasis associated with primary bronchogenic carcinoma can occur without producing any neurologic symptoms. In a recent study, 42 patients with a solitary brain metastasis were treated with GK-SRS from 1993 to 2006. There were 27 men and 15 women, and the median age was 58 years (range, 38–74 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). Thirty-eight patients (90.5%) presented with symptoms of solitary brain metastasis or were found to have brain metastasis on staging brain MRI within 1 month of histologic diagnosis of their primary NSCLC. The maximum diameter of the single brain metastasis was between 0.5 and 3.5 cm (median, 1.5 cm). Brain lesions were located as follows: parietal lobe (12), frontal lobe (10), temporal lobe (9), occipital lobe (7), cerebellum (3), and thalamus (1). Initial staging to evaluate the extent of thoracic and extracranial disease included CT scans of the chest and abdomen (n = 42) and PET scans (n = 13).

Surgical staging was performed on 27 of 42 patients using mediastinoscopy, mediastinal dissection, or transbronchial needle aspiration to identify positive hilar and mediastinal lymph nodes. Twenty-two patients (52.4%) had radiographically or pathologically involved hilar (N1) and/or mediastinal (N2/N3) lymphadenopathy; the thoracic disease thus was stage I, stage II, and stage III in 14, 9, and 19 patients, respectively.

The median dose prescribed was 18 Gy to the 50% isodose line (range, 11–25 Gy). Additional whole-brain radiation therapy (WBRT) was delivered to 33 of 42 patients based on physician and/or patient preference. Twenty-one patients had WBRT after GK-SRS and 12 before. WBRT preceded thoracic therapy or chemotherapy in 21 patients, whereas 12 patients received it after thoracic therapy or chemotherapy or at the time of CNS progression.

Patients were considered to have definitive thoracic therapy if they underwent surgical resection or received sequential or concurrent chemotherapy and external beam radiation with definitive intent. Twenty-six patients (62%) completed definitive thoracic therapy: 9 patients had sequential or concurrent chemotherapy and radiation, 12 patients underwent surgical resection with or without preoperative or postoperative therapy, and 5 patients underwent a planned trimodality approach with preoperative chemoradiation followed by surgical resection. The median dose of thoracic radiation delivered to patients treated definitively was 61.2 Gy (range, 45–68.4 Gy). Nondefinitive thoracic therapy (n = 16) included chemotherapy alone, palliative radiation therapy at doses greater than 2 Gy per fraction for an abbreviated course, radiation therapy followed by chemotherapy, and no therapy in six, four, three, and three patients, respectively.

The median overall survival for the 42 patients was 18 months (range, 1.5–150 months). The 1-, 2- and 5-year actuarial overall survival rates were 71.3%, 34.1%, and 21%, respectively. Currently, there are 8 patients alive with a median active follow-up of 64.5 months (range, 9–150 months). The cause of death was identified in 20 of 34 patients. Neurologic progression was determined to be the cause of death in 5 of 20 patients (20%). The sites of progression in these five patients were CNS alone (three), CNS and distant (one), and CNS and thoracic (one). Symptomatic radiation necrosis requiring intervention (resection) in the absence of intracranial progression was documented in one patient.