Abstract
BACKGROUND
We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS).
OBJECTIVE
To determine whether tumor histology predicts patient outcomes.
METHODS
Between July 1, 2000, and December 31, 2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. Included in our study were 44 squamous cell carcinoma (SCC), 31 small cell carcinoma (SCLC), and 138 adenocarcinoma (ACA) patients; 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole-brain radiation therapy (WBRT) before their GKRS, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of 2 lesions were treated per patient with median marginal dose of 20 Gy.
RESULTS
Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC patients (P = .008). The 1-year local control rates were 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (P = .027). The 1-year distant failure rates were 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (P = .057). The likelihood of dying of neurological death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (P = .027). The median time to WBRT was 11 months for SCC and 24 months for ACA patients (P = .04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (hazard ratio [HR]: 6.46, P = .025) and distant failure (HR: 3.32, P = .0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR: 2.552, P = .01) and worsened overall survival (HR: 1.77, P < .0121).
CONCLUSION
Histological subtype of lung cancer appears to predict outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.
Keywords: Cranial metastases, Lung cancer, Stereotactic radiosurgery
Overall survival of patients with brain metastases has improved in the past decade.1,2 Such improvement can often be offset by the late toxicities of whole-brain radiotherapy (WBRT), for which the likelihood and severity of cognitive decline continues to worsen with time.3 Multiple randomized trials have now shown that using radiosurgery as an upfront single modality and without WBRT does not affect overall survival in select patients.4,5 However, there are patients who will experience early or multiple distant brain failures, and these patients will likely need WBRT earlier in the course of their disease. As a result, an increasing emphasis is being placed on prognostic factors that may distinguish populations that benefit more from upfront radiosurgery from those that may benefit from upfront WBRT.
Recent data from the scientific literature have suggested that the natural history of brain metastases can depend on the histological subtype of the primary cancer. Some histologies such as renal cell carcinoma have proved more radioresistant.6 Even for tumors of the same primary histology, such as invasive ductal carcinoma of the breast, there can be variability in the natural history of brain metastases depending on the Her2 receptor status of the individual patient’s cancer.7 It has been suggested that patients with melanoma and triple-negative breast cancers may have higher rates of distant brain failure after radiosurgery.8,9
Within lung cancer, there are several known differences between the various histological subtypes with regard to the natural history of the disease. Small cell lung cancer (SCLC) has a high rate of metastatic brain disease, and prophylactic cranial irradiation has in fact resulted in survival benefits both in limited- and extensive-stage disease.10,11 Adenocarcinoma appears to have a survival advantage over squamous cell carcinoma (SCC) within the non-small cell subtypes in the setting of locally advanced disease.12 It has been previously unknown, however, whether biological differences in various subtypes of lung cancer affect the biological behavior of brain metastases.
Objectives
To this end, we present a single-institution retrospective review of patients with lung cancer and first diagnosis of brain metastases treated with Gamma Knife radiosurgery (GKRS) and without previous therapeutic WBRT. Our analysis focuses on variations of clinical outcomes caused by histological differences of the primary cancer. Furthermore, we evaluate factors that may predict survival, distant brain failure, and neurological death.
MATERIALS AND METHODS
Study Design, Setting, and Participants
This retrospective study was approved by the Wake Forest University Institutional Review Board. The Wake Forest University Department of Radiation Oncology Gamma Knife Tumor Registry was searched for all patients who received radiosurgical treatment for a brain metastasis from a primary lung cancer between July 1, 2000, and December 31, 2010. Because the goal of the analysis was to determine patterns of failure in patients receiving radiosurgery alone, patients who had received previous WBRT for known brain metastases were excluded. Patients with SCLC were included if they had undergone previous prophylactic cranial irradiation (PCI), but not if they had received therapeutic WBRT for known metastases. Patients were also excluded if their pathology reports did not clearly indicate adenocarcinoma (ACA), small cell, or squamous cell histology. A total of 271 patients with brain metastases from a primary lung cancer were treated with GKRS at our institution during that time interval. Median survival was calculated from the date of GKRS. Patient outcomes were determined using electronic medical records. Dosimetric data were obtained using plans archived from the GammaPlan treatment planning system (Elekta, Norcross, Georgia).
Patient Characteristics
Patient characteristics are summarized in Tables 1 and 2. There were 44 patients with SCC, 31 patients with SCLC, and 138 patients with ACA included in the study. Of the 31 patients with SCLC, 26 underwent previous PCI. One SCLC patient was treated with GKRS to prevent an interruption in chemotherapy, and the remaining patients declined PCI. Forty-two patients with insufficient pathology and 16 patients with tumors too poorly differentiated to accurately determine the subtype were excluded from the analysis. The following patient factors were included: age, histology, recursive partitioning analysis class, status/control of primary and extracranial metastatic disease, local or distant failure within the brain, the ultimate need for WBRT, number of lesions treated by GKRS and dose, cause of death, and survival after GKRS. Recursive partitioning analysis class was defined according to the Radiation Therapy Oncology Group analysis reported by Gaspar et al.13 The status of extracranial metastatic disease was classified as none, oligometastatic (≤5 total metastases), or widespread. The median age for patients according to histology was as follows: ACA (65 years), SCC (63 years), and SCLC (63 years). In terms of extracranial metastatic disease, 18% of patients had widespread disease, 35% of patients had no metastatic disease, and the remaining 47% of patients had oligometastatic disease. Surgery relates specifically to a neurosurgical resection before GKRS. Pemetrexed and erlotinib were given after GKRS.
TABLE 1.
Patient Demographicsa
| Characteristic | No. (%) |
|---|---|
| Total | 213 (100) |
| Histology | |
| Adenocarcinoma | 138 (65) |
| Squamous cell | 44 (21) |
| Small cell | 31 (15) |
| Sex | |
| Male | 116 (55) |
| Female | 97 (45) |
| RPA class | |
| I | 4 (2) |
| II | 181 (85) |
| III | 17 (8) |
| Unknown | 11 (5) |
| Initial surgery | |
| Yes | 50 (23) |
| No | 163 (77) |
| No. of lesions treated | |
| 1 | 115 (54) |
| 2–4 | 82 (39) |
| 5–8 | 13 (6.1) |
| ≥9 | 3 (1.4) |
| Erlotinib | |
| Yes | 42 (20) |
| No | 171 (80) |
| Pemetrexed | |
| Yes | 39 (18) |
| No | 174 (82) |
| Age, y | |
| Adenocarcinoma | 65 |
| Small cell | 63 |
| Squamous cell | 63 |
| Extent of extracranial metastases | |
| None | 74 (35) |
| Oligometastatic | 100 (47) |
| Widespread | 38 (18) |
RPA, recursive partitioning analysis.
TABLE 2.
Patient Characteristicsa
| Adenocarcinoma | Squamous Cell | Small Cell | |
|---|---|---|---|
| Total | 138 | 44 | 31 |
| RPA class, no. (%) | |||
| I | 3 (2) | 0 (0) | 1 (3) |
| II | 124 (90) | 37 (84) | 20 (65) |
| III | 10 (7) | 5 (11) | 2 (6) |
| Unknown | 1 (,1) | 2 (5) | 8 (26) |
| Median time, from diagnosis to CNS metastases, mo (range) | 1.35 (0–127.7) | 5.17 (0–36.37) | 13.27 (0–44.63) |
| Lesions treated, no. (%) | |||
| 1 | 75 (54) | 19 (43) | 21 (68) |
| 2–4 | 51 (37) | 24 (55) | 7 (23) |
| 5–8 | 9 (7) | 1 (2) | 3 (9) |
| ≥9 | 3 (2) | 0 (0) | 0 (0) |
| Median marginal dose, gray | 20 | 20 | 20 |
| Patients receiving WBRT, no. (%) | 32 (23) | 13 (30) | Not applicable |
| Patients experiencing local failure, no. (%) | 17 (12) | 5 (11) | 6 (19) |
| Patients experiencing distant failure, no. (%) | 49 (36) | 17 (39) | 11 (36) |
| Patients experiencing neurological death, no. (%) | 28 (20) | 12 (27) | 12 (39) |
RPA, recursive partitioning analysis; CNS, central nervous system; WBRT, whole-brain radiation therapy.
Radiosurgery Technique, Study Size, and Bias
Patients were treated on a Leksell Model C unit (Elekta, Stockholm, Sweden) before May 2009. After May 2009, the Leksell Gamma Knife Perfexion unit was used. Before radiosurgery, patients underwent a high-resolution contrast-enhanced stereotactic magnetic resonance imaging (MRI) study of the brain. Treatment planning was performed using the Leksell GammaPlan Treatment Planning System. A median dose of 20 Gy (range, 11–24 Gy) was generally prescribed to the 50% isodose line at margin of each metastasis. The median time from diagnosis of lung cancer to discovery of brain metastases was 1.35 months for ACA, 5.17 months for SCC, and 13.27 months for SCLC. Brain metastases were generally treated 1 to 3 weeks after discovery of metastases. Dose prescription was based on guidelines published by Shaw et al.14 A median of 2 lesions were treated per patient.
Variables, DataSources/Management
Patient Follow-up, Response Assessment, and Salvage Therapy
Patients typically were followed with repeat MRI of the brain approximately 6 weeks after the initial GKRS procedure and then approximately every 3 months thereafter. Local failure was defined as either a pathologically proven recurrence within the GKRS treatment field or a combination of imaging and clinical characteristics of local treatment failure. Patients with suspected local treatment failure were generally followed initially with short interval imaging and treated conservatively before determination of a treatment failure to rule out radiation necrosis. Local failures were treated with surgical excision, whole-brain irradiation, or observation. Distant brain failures were generally treated with GKRS, and WBRT was generally reserved for 5 or more total brain metastases over time or short-interval distant failures. Neurological death was defined as had been reported by Patchell et al.15 Specifically, neurological death was defined by progressive neurological impairment with stable systemic disease.
Statistical Methods and Quantitative Variables
Kaplan-Meier analysis was performed to determine actuarial freedom from local failure, freedom from distant brain failure, WBRT, and overall survival for the patient population. Log-rank tests were performed to assess for differences in survival endpoints among histologies. Multivariate analysis using Cox proportional hazards regression was performed to determine factors that predicted improved survival, local control, freedom from distant failure, and freedom from WBRT. A model using logistic regression was used to analyze time to neurological death. A Wilcoxon model was used to determine whether there was any difference between the minimum GKRS dose for small cell vs non-small cell lesions. Multivariate models were built by a priori consideration of the factors for which data were gathered. For local control, distant failure, time to WBRT failure, time to neurological death, and overall survival, each of the following variables were included: histological subtype, age, time from diagnosis of primary to metastatic central nervous system disease, sex, extent of extracranial disease, and number of metastases. All statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, North Carolina), and Stata software version 10.1 (StataCorp LP, College Station, Texas). Neurological death is calculated using an odds ratio with logistic regression.
RESULTS
Participants, Descriptive Data, Outcome Data, and Main Results
Survival
The Kaplan-Meier method was used to determine overall survival for patients based on histology. The Kaplan-Meier estimates of overall survival are shown in Figure 1. The median survival was 10.2 months, 5.4 months, and 5.9 months for patients with ACA, SCC, and SCLC, respectively (log rank P = .008). Overall survival at 1 year was 56% for patients with ACA and 20% for patients with SCC and SCLC.
FIGURE 1.
Kaplan-Meier plot of overall survival. ACA, adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
Of 213 patients, 184 had died at the time of the analysis. Of these, cause of death was unknown in 34 patients. Cause of death was determined to be neurological in 28 of 95 patients with ACA (29%), 12 of 22 patients with SCLC (55%), and 12 of 33 patients with SCC (36%) (P = .027). Kaplan-Meier analysis of time interval to neurological death revealed freedom from neurological death at 1 year to be 75%, 57%, and 40% for ACA, SCC, and SCLC patients, respectively.
Patterns of Failure
The Kaplan-Meier method was used to determine freedom from local failure and freedom from distant brain failure. Kaplan-Meier estimates for freedom from local and distant failure stratified by histology are found in Figures 2 and 3, respectively. Freedom from local failure at 1 year was 86%, 86%, and 54% for ACA, SCC, and SCLC patients, respectively (log-rank P = .027). At 2 years, freedom from local failure was 57%, 66%, and 54% for ACA, SCC, and SCLC patients, respectively.
FIGURE 2.
Kaplan-Meier plot of local control. ACA, adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
FIGURE 3.
Kaplan-Meier plot of distant control. ACA, adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
Freedom from distant brain failure at 1 year was 52%, 35%, and 37% for ACA, SCC, and SCLC patients, respectively (log-rank P = .057). Distant control at 2 years was 32%, 35%, and 23% for ACA, SCC, and SCLC patients, respectively.
Time Delay to WBRT
The Kaplan-Meier method was used to estimate time delay to WBRT for patients stratified by NSCLC tumor histology. Kaplan-Meier curves are depicted in Figure 4. Patients with SCLC were excluded from this portion of the analysis because they had undergone previous PCI and were thus less likely to receive further WBRT as salvage therapy. Freedom from WBRT at 1 year was 73% and 33% for ACA and SCC, respectively (P = .040). Freedom from WBRT at 2 years was 43% and 33% for ACA and SCC, respectively. Median time to WBRT was 11 months for SCC and 24 months for ACA.
FIGURE 4.
Kaplan-Meier plot of time to whole-brain radiation therapy for patients with adenocarcinoma vs squamous cell carcinoma ACA, adenocarcinoma; SCC, squamous cell carcinoma.
Era of Treatment
To determine the effect of possible recent advances in therapy on patient outcomes, Kaplan-Meier survival plots of local control, distant brain failure, and overall survival were compared between cohorts that were treated before and including 2005 and those treated after 2005. Log-rank tests showed no differences in the rates of local control (P = .58), distant brain failure (P = .48), or overall survival (P = .64).
Multivariate Analysis
Cox proportional hazard regression was used to determine factors that predicted overall survival, local failure, and neurological death (Table 3). SCC histology was significantly predictive of worsened overall survival on multivariate analysis (hazard ratio [HR]: 1.77, P = .01). Furthermore, the presence of widespread metastatic disease was predictive of worsened overall survival (HR: 2.082, P = .0066). Small cell histology was predictive of increased likelihood of local failure (HR: 6.46, P = .02). Small cell histology was also predictive of increased likelihood of distant brain failure (HR: 3.32, P = .003). In addition, increasing number of brain metastases was predictive of worsened distant control (P = .003). Finally, small cell histology showed a nonsignificant trend that was predictive of neurological death (P = .11), along with minimal dose (P = .0055) and extent of extracranial disease (P = .0015). SCC histology predicted time to whole-brain failure (HR: 2.552, P = .011) along with increasing number of brain metastases (P = .04). Finally, there was no difference in the minimal dose for GKRS between non-small cell histology and SCLC. Age, time from diagnosis of primary tumor to development of brain metastases, and sex were not predictive in the multivariate analysis.
TABLE 3.
Multivariate Analysis of Factors Affecting Local Control, Distant Control, Overall Survival, and Time to Whole-Brain Radiationa
| Hazard Ratio (95% CI) | P Value | |
|---|---|---|
| Local control | ||
| Histology | ||
| Adenocarcinoma | 1.0 (Reference) | .025 |
| Small cell | 6.46 (1.68–29.9) | |
| Squamous cell | 1.46 (0.46–4.64) | |
| Distant control | ||
| Histology | ||
| Adenocarcinoma | 1.00 (Reference) | .002 |
| Small cell | 3.32 (1.53–7.22) | |
| Squamous | 1.89 (1.03–3.46) | |
| No. of brain metastases | ||
| 1 | 1.00 (Reference) | .003 |
| 2 | 1.65 (0.855–3.20) | |
| 3 | 2.62 (1.39–4.95) | |
| 4 or more | 3.21 (1.57–6.57) | |
| Time to WBRT | ||
| Histology | ||
| Adenocarcinoma | 1.00 (Reference) | .011 |
| Squamous cell | 2.55 (1.23–5.27) | |
| No. of brain metastases | ||
| 1 | 10 (Reference) | .04 |
| 2 | 1.32 (0.55–3.20) | |
| 3 | 2.51 (1.11–5.68) | |
| 4 or more | 3.11 (1.22–7.91) | |
| Overall survival | ||
| Histology | ||
| Adenocarcinoma | 1.00 (Reference) | .012 |
| Squamous cell | 1.77 (1.20–2.63) | |
| Small cell | (0.84–2.58) | |
| Extent of extracranial metastases | .007 | |
| None | 1.0 (Reference) | |
| Oligometastatic | 1.08 (0.76–1.54) | |
| Widespread | 2.08 (1.28–3.39) | |
CI, confidence interval; WBRT, whole-brain radiation therapy.
Toxicity
Five patients experienced grade III radionecrosis. Four of these patients underwent resection. The fifth patient experienced persistent balance disturbance and blurry vision and required long-term steroids until time of death.
DISCUSSION
Key Results, Limitations, Interpretation, and Generalizability
The current study illustrates the fact that the natural history of brain metastases after radiosurgical management can be profoundly affected by the histology of the primary tumor. Patients with primary lung SCC and lung ACA have not previously been thought to have greatly different outcomes when these cancers present either with localized or metastatic disease, although there is suggestion from the RTOG 9508 trial that ACA with brain metastases have improved survival times over SCC. In this randomized trial, patients with NSCLC were identified as a cohort with improved outcomes. However, when patients with NSCLC were separated by histology, patients with SCC appeared to have worsened survival compared with patients with ACA after WBRT. In the current series, patients with ACA had 56% 1-year survival rate compared with 20% for patients with SCC.
Two possible explanations for the profound difference in survival seen between SCC and ACA in this series of patients are that (1) squamous cell lung cancers may present with lung cancer late in their natural history or (2) the systemic therapies for ACA have improved recently and the relative improvements over squamous cell lung cancers have not yet been well documented in the scientific literature. To further investigate the aforementioned hypotheses for the differential outcomes of SCC and ACA, we examined outcomes for patients treated before and after 2005. This date coincides with the advent of novel systemic agents used for lung ACA including pemetrexed and erlotinib. The analysis failed to show any improvement in outcomes in the patients more recently treated in our series.
The fact that SCC had a more rapid rate of distant brain failure suggests that there may be a role for earlier use of WBRT, either as a salvage regimen after failure of radiosurgery or in the upfront setting without the use of radiosurgery. There have been recent reports that both melanoma and triple-negative (ER negative, PR negative, Her2 negative) breast cancers represent other high-risk populations for early distant brain failure after use of upfront radiosurgery for the treatment of brain metastases.8,9 The lack of effective systemic treatment options for these populations likely lead to uncontrolled systemic disease and an increased rate of distant brain failure.
The finding that SCLC has a worsened local control and a higher likelihood of neurological death suggests the biology of SCLC brain metastases may be different from those of NSCLC. It also implies that brain-directed therapies, such as systemic agents and local ablative therapies, need to continue to improve and that dose escalation strategies may warrant investigation. A retrospective series from the University of Pittsburgh suggested that patients with SCLC who underwent a combined WBRT with radiosurgical boost had improved outcomes over patients who received either WBRT or SRS alone.16 The mechanism for decreased local control in SCLC is unclear, but a population of radioresistant clonogens or increased invasion into parenchymal brain has been proposed.17,18 Even in the chest, local failure of SCLC is substantial after conventional chemoradiotherapy, suggesting that this tumor can fail locally after an initial good response.19
The potential clinical applications of the data from the current study are wide-ranging. Given the observed survival differences between ACA and SCC, histology could represent a new variable for current prognostic indices. The current lung cancer–specific prognostic index for patients with brain metastases has identified KPS, age, presence of extracranial metastases, and number of brain metastases as the dominant factors that affect survival after diagnosis of brain metastases.20 In its analysis, multiple large institutions analyzed outcomes of more than 2000 patients with brain metastases from lung cancer. Future analyses may even consider molecular factors such as the rearrangements of anaplastic lymphoma kinase gene (ALK), which has proved to be prognostic in lung cancer.
There were several limitations to this study. Given the nature of retrospective series, the results of this study are limited to hypothesis generation. Although patient selection bias was a concern, the populations of patients with the various histologies were relatively balanced. An additional concern would be that 31 patients were not included due to insufficient pathology (generally acquired by fine-needle aspiration), and 16 others had tumors too poorly differentiated to determine pathology. The effect of disallowing these patients and whether their data would have changed the conclusions are unclear. Prospective trials are necessary to determine whether histology should be considered a major factor for tumor-specific prognostic indices.
CONCLUSION
Histological subtype of lung cancer appears to predict patterns of failure and outcomes. SCLC has worsened local and distant brain failure rates after GKRS. SCC appears to need earlier salvage WBRT and also has worsened overall survival compared with other histologies. Future trials and prognostic indices may need to take these histology-specific patterns into account.
ABBREVIATIONS
- ACA
adenocarcinoma
- GKRS
Gamma Knife radiosurgery
- NSCLC
non-small cell lung cancer
- PCI
prophylactic cranial irradiation
- SCC
squamous cell carcinoma
- SCLC
small cell carcinoma
- WBRT
whole-brain radiotherapy
Footnotes
Disclosure
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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