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.
Patients who had definitive thoracic therapy (n = 26) versus those who had nondefinitive therapy (n = 16) had a median overall survival of 26.4 months (95% confidence interval 16.2–36.6 months) versus 13.1 months (95% confidence interval 4.3–21.8 months) and a 5-year overall survival rate of 34.6% versus 0% (p < 0.0001), respectively. There was no statistical difference between patients treated definitively with (n = 18) or without (n = 8) surgery (p = 0.369). Patients with a KPS of 90 or greater had a median overall survival of 27.8 months compared with 13.1 months for those with a KPS of less than 90 (p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (relative risk = 2.97, p = 0.020) and KPS (relative risk = 5.85, p = 0.001).
Since the brain is affected by metastatic disease in 30% to 50% of patients, routine CT scan or MRI of the brain is recommended by our group in all cases of bronchogenic carcinoma, at least when greater than clinical T1N0. Likewise, many surgeons advocate routine brain CT or MRI for all adenocarcinomas. The diagnosis of brain metastasis in the past was made by nuclear isotope brain scanning or arteriography or both early in the study. CT scanning has been used in all patients since 1976. MRI has been used since 1985. For patients suspected of having cerebral metastases, double-dose delayed CT has proved significantly more sensitive than CT scans obtained immediately after the administration of a lesser dose of iodinated contrast material. Davis et al.10 reported that MRI with enhancement proved superior to double-dose delayed CT for lesion detection, anatomic localization of lesions, and differentiation of solitary versus multiple lesions.
Brain metastasis has been considered an advanced progression of the disease and has been treated historically with corticosteroids and irradiation. Although corticosteroids produce rapid improvement in the neurologic symptoms, they prolong life for a median of 2 months only. Radiation therapy provides 80% relief of symptoms, but the median survival rate is only 3 to 6 months.3 Ballantine and Byron11 in 1948 and Flavell12 in 1949 were the first to carry out staged surgical excision of a solitary non–small-cell intracranial metastasis with the primary intrathoracic lesion. Magilligan et al.4 in 1976 introduced the modern approach of combined lung/brain resection with a 5-year survival rate of 21% and a low mortality rate of 3%. Subsequently, large series of patients treated with the combined modality of resection of cerebral metastasis followed by brain radiation were reported. Burt et al.5 reported 185 consecutive patients undergoing combined therapy. The overall survival rate was 55% at 1 year, 27% at 2 years, 18% at 3 years, and 13% at 5 years, with a median survival of 14 months. Vecht et al.13 reported 63 patients receiving combined treatment of neurosurgery and WBRT with a median survival rate of 10 months. Lonjon et al.14 reported 36 patients receiving such treatment with a median survival of 9.6 months.
Our past studies of combined treatment confirm these results. The survival rate of 28 patients undergoing this treatment was 58% at 1 year and 37% at 5 years, with a median survival of 1.60 years. Most of these patients received postoperative WBRT in the range of 3000 to 4500 rads. In 10 patients, a small-field boost of 900 to 2500 rads to the tumor-bearing area was added after completion of the WBRT. Two patients developed radiation fibrosis of the brain, one with incapacitating ataxia and the other with deterioration of memory. The advisability of postoperative WBRT remains unanswered.6
Armstrong et al.15 evaluated 185 patients with NSCLC who underwent resection of brain metastases. Forty-two patients who received preoperative WBRT (23%) were excluded. Sixty-four patients were equally divided into two groups, one (n = 32) received no WBRT; the other was prognostically matched to the first group (n = 32). A third group consisted of all other WBRT patients (n = 79). Most patients received 3000 rads in 10 fractions. Overall brain failures occurred in 38% of the first group, 47% of the second group, and 42% of the third group. The use of WBRT had no apparent impact on survival or on overall brain failure rates. The only impact of WBRT was the reduction of focal failure, defined as failure within the brain adjacent to the site of resected brain metastasis.
However, Vecht et al.13 compared the effect of neurosurgical excision plus radiotherapy with radiotherapy alone in a prospective, randomized test of 63 patients. WBRT was given in two fractions per day for a total of 4000 rads. The combined treatment compared with radiotherapy alone led to a longer survival. Median survival was 10 months in patients treated with the combined approach and 6 months in patients treated with radiotherapy alone (p = 0.04).
The factors contributing to prolonged survival have been addressed by various authors. Magilligan et al.4 found a wedge resection to be a significant predictor of improved survival; because this type of resection generally is reserved for small peripheral tumors with no hilar or mediastinal adenopathy, it suggests that the size of the primary tumor directly influenced survival. Rossi et al.16 found that the vigor of the patient, as assessed by Karnofsky and Zubrod scales and absence of nodal disease, influenced survival rate. Burt et al.5 found no significant difference in age, locoregional stage (TN), or histologic features in patients with synchronous versus metachronous lesions. However, multivariate analysis demonstrated that complete resection of the primary disease significantly prolonged survival. Lonjon et al.14 found that the postoperative clinical status (Karnofsky score) and the postoperative neurologic grading were significant factors to determine survival. Nakagawa et al.17 found that the variables significantly associated with a favorable prognosis included surgical excision of the primary lesion, adenocarcinoma as the histologic diagnosis, the use of adjuvant treatment, a preoperative score of over 80% on the Karnofsky scale, and metastasis confined to the brain. Additional but nonsignificant contributors to a good prognosis included younger than 65 or 70 years, early-tumor stage, curative lung cancer surgery, a single metastatic brain tumor, a solid versus cystic tumor, and a supratentorial location of the brain metastasis. Our series agrees with those of Hankins et al.6 and Burt et al.,5 namely that the most significant factor in prolonged survival following combined surgery and radiation for solitary brain metastasis was curative excision of the primary lung tumor.
However, despite prolonged survival and improvement in the quality of life after surgery and radiation therapy, recurrence of the brain metastasis contributes to the death of these patients. Patchell et al.18 reported that the recurrence at the site of the original brain metastasis was 20% in the surgery group and 52% in the radiation group. Nakagawa et al.17 reported that 19% of patients treated with surgery or radiation died directly because of the brain metastasis, and 3.6% died of treatment-related complications.
Nakagawa et al.17 recommended that adjuvant treatment generally should follow excision of brain metastasis, considering that metastatic lesions smaller than 1.0 cm, which are not seen on CT scan, can be shown by MRI postoperatively. Radiation-insensitive tumors might disappear on MRI after combined chemotherapy and irradiation owing to enhancement of the radiation effect by chemotherapy. A significantly longer survival was found in patients who received adjuvant treatment than in those who did not. Chemotherapeutic regimens were divided into those involving platinum based nitrosoureas, and other anticancer agents. Patients given platinum had a significantly longer mean survival time (468 days) than patients given other anticancer agents (243 days) (p < 0.05). Hypothetically, these patients' tumors have gone through the layers of the brain coverings, and the blood supply as well as the blood-brain barrier have already been compromised. This had led many authors to initiate the use of chemotherapy in addition to localized SBRT or WBRT for treatment of oligometastatic disease. Finally, with the advent of newer agents, especially the tyrosine-kinase inhibitors (TKIs) and other oral agents, delivery of adequate dose of chemosuppressive therapy is possible even to the brain.
Another recent approach to solitary brain metastasis is the use of a gamma knife with precise localization of the tumor by stereotactic method, which is promising, especially in patients who are not good surgical candidates.19
Multiple series have demonstrated that thoracic therapy and extent of thoracic disease may have an impact on survival. In a series by Bonnette et al., 99 of 103 patients had surgical resection of their synchronous solitary brain metastasis and primary NSCLC. The median overall survival was 12.4 months, and the 5-year overall survival was 11%.20 Moreover, Billings et al. reported a median and 5-year overall survival of 24 months and 21.4%, respectively, for 28 patients who underwent surgical resection for their brain and thoracic disease. The superior overall survival in the series of Billings et al. may be attributed to the 15 patients (53.6%) with thoracic stage I disease. Contrary to the series of Bonnette et al., Billings et al. reported a significant improvement in overall survival if there was no pathologic evidence of lymph node metastasis (5-year overall survival 35% vs. 0%, p = 0.001).21 Hu et al. reviewed 84 patients who underwent surgical resection or SRS for their brain metastasis, but only 44 patients received any therapy for their thoracic disease. The median overall survival of 15.5 months was significantly better for those who had thoracic therapy versus 5.9 months for those who did not (p = 0.046).22
A different approach to minimize brain atrophy and mental deterioration following radiotherapy is the use of intraoperative radiation therapy at the time of surgical intervention. Nakamura et al.23 reported 1-year survival of 59% in 14 patients undergoing surgery and intraoperative radiation therapy, which is similar to the result obtained in 71 patients receiving surgical excision and whole-brain irradiation. The frequency of remote recurrence after the new therapy was 20% in 1 year, which was almost the same as that of the usual therapy (surgery plus whole-brain irradiation).
The use of hyperthermia plus nitrosoureas has been reported in 17 patients with NSCLC with brain metastasis. Sixteen (94%) responded with clinical improvement, radiologic regression, or disease stabilization. The survival time of the improved patients was 12.7 months.24
There is a concern regarding the true cause of the single brain lesion because the majority of patients were diagnosed on MRI without guided biopsy. Patchell et al. found that 11% of patients with abnormal imaging had intracranial disease other than metastasis; however, this study included a heterogeneous collection of malignancies.18 The frequency of false-positive MRI findings with more modern imaging in patients with NSCLC is probably lower. In addition, KPS, age, extent of thoracic disease, and other patient characteristics may have influenced the decision to offer GK-SRS and/or definitive thoracic therapy in our series.
The results of RTOG 0214 were recently published in JCO. Three hundred fifty-six patients were accrued of the targeted 1058. The study was closed early because of slow accrual. There was no significant difference in survival (overall or disease-free) between those receiving prophylactic cranial irradiation (PCI) and those observed (these were the primary endpoints). Interestingly, however, there was a major difference in the incidence of brain metastasis and the number of lesions between the two groups. The 1-year rates of brain metastasis were significantly different, 7.7% versus 18.0% for PCI versus observation (p < 0.004). Patients in the observation arm were 2.52 times more likely to develop brain metastasis than those in the PCI arm. Finally, this was achieved with minimal neurologic toxicity.25
Another form of SRS recently reported in patients with brain metastases is CyberKnife (CK). In a series from China, clinical symptoms 1 week after CK were evaluated in 40 patients including 26 with lung cancer metastasis. Complete remission (CR), remission, stabilization, and aggravation occurred in 26 of 40 cases, 10 cases, 3 cases, and 1 case, respectively. Three months after CK treatment, CT and MRI showed complete remission, partial remission (PR), no change (NC), and progressive disease (PD) of 32 cases, 21 cases, 11 cases, and 4 cases, respectively, The local control rate was 77.8% (53/68) and the therapeutic effective rate was 94.1 (64/68). All patients were followed for more than 14 months. Four patients died of recurrent brain metastasis and other metastasis, and five patients died of a primary tumor. The 3-month, 6-month, and 1-year survival rates were 97.5% (39/40), 82.5% (33/40), and 67.5% (27/40), respectively. Three months after treatment, 14 patients had neuropathy, a lesion outside the original metastasis, on CT or MRI, a ratio of 35.0% (14/40). Six patients were treated effectively by repeated CK.26
The most recent guidelines from the American Society of Therapeutic Radiology and Oncology (ASTRO) 2005 state that based on Level I–III evidence, for selected patients with small (up to 4 cm) brain metastases (up to three in number and four in one randomized trial), the addition of radiosurgery boost to WBRT improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain metastasis, the radiosurgery boost with whole-brain radiotherapy improves survival. Local and distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I–III evidence). There was no statistically significant difference in overall toxicity between those treated with radiosurgery alone versus whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized study.27
Despite the potential for long-term survival, many patients are offered only chemotherapy or palliative radiation therapy for their thoracic disease without considering their thoracic stage and performance status. At our center, an aggressive staging and treatment paradigm has been instituted when approaching patients with a synchronous solitary brain metastasis. Patients undergo a brain MRI and CT/PET scan to appropriately determine the extent of intracranial and extracranial disease. Studies have shown that CT scans often underestimate the extent of intracranial disease and that PET scans may identify metastases in approximately 25% of patients thought to have thoracic disease only.28 Thus, overall survival actually may be improved with PET scanning in all patients.29 In addition, surgical candidates will undergo surgical mediastinal staging. Patients then are selected for definitive brain and thoracic management based on the extent of intracranial and thoracic disease, presence of involved lymph nodes, and physiologic/performance status. The timing of brain and thoracic therapy also depends on these factors. Patients with a good KPS are often recommended to receive GK-SRS or surgical resection and WBRT. If patients have neurologic symptoms or a large brain metastasis and are not surgical candidates, we recommend GK-SRS and WBRT prior to thoracic therapy or chemotherapy. WBRT may be delivered prior to GK-SRS in order to decrease the volume of the lesion. This may allow a higher GK-SRS dose to be delivered. If the brain lesion is small and asymptomatic, we perform GK-SRS prior to thoracic therapy. If the patients do not progress extracranially, we proceed with WBRT after thoracic therapy or chemotherapy. If patients require further evaluation over a 2- to 3-week period to assess their surgical candidacy and extent of thoracic and extrathoracic disease, we may proceed with WBRT before thoracic therapy for logistical reasons.