- Email: [email protected]
Long-Term Survival in Patients With Synchronous, Solitary Brain Metastasis From Non–Small-Cell Lung Cancer Treated With Radiosurgery
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 1, pp. 19–23, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.12.031
CLINICAL INVESTIGATION
Brain
LONG-TERM SURVIVAL IN PATIENTS WITH SYNCHRONOUS, SOLITARY BRAIN METASTASIS FROM NON–SMALL-CELL LUNG CANCER TREATED WITH RADIOSURGERY TODD W. FLANNERY, M.D.,* MOHAN SUNTHARALINGAM, M.D.,* WILLIAM F. REGINE, M.D.,* LAWRENCE S. CHIN, M.D.,y MARK J. KRASNA, M.D.,z MICHAEL K. SHEHATA, M.D.,k MARTIN J. EDELMAN, M.D.,x MARNIE KREMER, B.A.,* ROY A. PATCHELL, M.D.,{ AND YOUNG KWOK, M.D.* Departments of *Radiation Oncology, y Neurosurgery, z Thoracic Surgery, and x Medical Oncology, University of Maryland School of Medicine, Baltimore, MD; Departments of kRadiation Oncology and { Neurosurgery, University of Kentucky School of Medicine, Lexington, KY Purpose: To report the outcome of patients with synchronous, solitary brain metastasis from non–small-cell lung cancer (NSCLC) treated with gamma knife stereotactic radiosurgery (GKSRS). Patients and Methods: Forty-two patients diagnosed with synchronous, solitary brain metastasis from NSCLC were treated with GKSRS between 1993 and 2006. The median Karnofsky performance status (KPS) was 90. Patients had thoracic Stage I-III disease (American Joint Committee on Cancer 2002 guidelines). Definitive thoracic therapy was delivered to 26/42 (62%) patients; 9 patients underwent chemotherapy and radiation, 12 patients had surgical resection, and 5 patients underwent preoperative chemoradiation and surgical resection. Results: The median overall survival (OS) was 18 months. The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively. For patients who underwent definitive thoracic therapy, the median OS was 26.4 months compared with 13.1 months for those who had nondefinitive therapy, and the 5-year actuarial OS was 34.6% vs. 0% (p < 0.0001). Median OS was significantly longer for patients with a KPS $90 vs. KPS < 90 (27.8 months vs. 13.1 months, p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (p = 0.020) and KPS (p = 0.001). Conclusions: This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with GKSRS. Definitive thoracic therapy and KPS significantly impacted OS. The 5-year OS of 21% demonstrates the potential for long-term survival in patients treated with GKSRS; therefore, patients with good KPS should be considered for definitive thoracic therapy. Ó 2008 Elsevier Inc. Synchronous brain metastasis, Solitary brain metastasis, Non-small cell lung cancer, gamma knife radiosurgery.
There is controversy regarding the ideal management of thoracic disease in this patient population, and there are few series that incorporated patients treated with stereotactic radiosurgery. In this article, we report our experience of patients who presented with a synchronous, solitary brain metastasis from NSCLC and were treated with gamma knife stereotactic radiosurgery (GKSRS).
INTRODUCTION Brain metastases outnumber all other primary intracranial tumors (1–3). Lung cancer is the most common primary site, with 30–50% of patients developing brain metastases during the course of their disease (4–6). Patients with a synchronous, solitary brain metastasis from non–small-cell lung cancer (NSCLC) represent a unique population of patients who have the potential for long-term survival. Previous studies have reported 5-year survival rates of 11–21% in patients treated with cranial and thoracic resection (7, 8). Despite these reported 5-year survival rates, many patients are only offered chemotherapy or radiation therapy in a palliative manner after their brain metastasis has been treated.
A retrospective analysis was performed after approval of the institutional review boards at the University of Maryland School of Medicine and University of Kentucky School of Medicine. All patients had histologically proven NSCLC and a synchronous, solitary brain metastasis detected by gadolinium-enhanced, thin slice
Reprint requests to: Young Kwok, M.D., Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201. Tel: (410) 328-9134; Fax: (410) 328-5279; E-mail: [email protected] Presented at the 48th Annual Meeting of the American Society of
Therapeutic Radiology and Oncology (ASTRO), Philadelphia, PA, November 5–9, 2006. Conflict of interest: none. Received Nov 8, 2007, and in revised form Dec 6, 2007. Accepted for publication Dec 11, 2007.
PATIENTS AND METHODS
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Table 1. Patient characteristics Characteristic Age (y) KPS Sex Men Women Thoracic stage* IA IB IIB IIIA IIIB Nodal status N0 N1 N2/3
n (42)
Volume 72, Number 1, 2008
Table 2. Treatment characteristics
Median
Range
Treatment
n (42)
58 90
38–74 70–100
GK-SRS WBRT Definitive thoracic management Chemoradiation Surgery Trimodality Thoracic Stage I/II Thoracic Stage III N1 N2/3 KPS $ 90 Total Nondefinitive thoracic management Thoracic Stage I/II Thoracic Stage III N1 N2/3 KPS $90 Total
42 33
27 15 5 9 9 10 9 20 6 16
Abbreviation: KPS = Karnofsky performance status. * AJCC 2002.
9 12 5 18 8 5 5 20 26 5 11 1 11 4 16
(1–3 mm) magnetic resonance imaging (MRI). In this series, synchronous is defined as having simultaneous brain and lung disease at diagnosis or within 3 months of histologic diagnosis. Solitary is defined as the single brain lesion representing the only extrathoracic disease burden based on computed tomography (CT) imaging of the chest and abdomen with or without positron emission tomography (PET) imaging.
Abbreviations: KPS = Karnofsky performance status; GK-SRS = gamma knife stereotactic radiosurgery; WBRT = whole-brain radiation therapy.
Patient Characteristics
Thoracic therapy
Forty-two patients were diagnosed with a synchronous, solitary brain metastasis and treated with GKSRS between 1993 and 2006. There were 27 men and 15 women, and the median age was 58 years (range, 38–74). The median Karnofsky performance status (KPS) was 90 (range, 70–100) (Table 1). Thirty-eight patients (90.5%) presented with symptoms of a 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). The location of these brain lesions were 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). The 2002 American Joint Committee on Cancer guidelines was used to stage the thoracic disease. Surgical staging was performed on 27/42 patients using mediastinoscopy, mediastinal dissection, or transbronchial needle aspiration to identify positive hilar and mediastinal lymph nodes. Twenty-two (52.4%) patients had radiographically or pathologically involved hilar (N1) or mediastinal (N2/N3) lymphadenopathy. Using clinical and pathologic information, the thoracic disease was Stage I, Stage II, or Stage III in 14, 9, and 19 patients, respectively (Table 1).
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 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 >2 Gy per fraction for an abbreviated course, radiation therapy followed by chemotherapy, and no therapy in 6, 4, 3, and 3 patients, respectively (Table 2).
Central nervous system therapy All patients (n = 42) received GKSRS to the solitary brain metastasis. Descriptions of the GKSRS procedure have been previously published (9, 10). The median dose prescribed was 18Gy 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 GKSRS and 12 before. WBRT preceded thoracic ther-
apy or chemotherapy in 21 patients, whereas 12 patients received it after thoracic therapy or chemotherapy or at the time of central nervous system (CNS) progression.
Statistical considerations Statistical analysis was carried out using SPSS (version 13.0). Factors included in statistical analysis were age, sex, KPS, thoracic therapy (definitive vs. nondefinitive), WBRT, and thoracic lymph node status (N0/N1 vs. N2/N3). The survival data were calculated using the Kaplan-Meier product limit method from the date of NSCLC diagnosis. Comparisons of the survival curves were calculated using the log–rank test. Multivariate analysis was performed using the Cox proportional hazards model. P # 0.05 was considered statistically significant.
RESULTS The median OS for the 42 patients was 18 months range, (1.5–150 months). The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively (Fig. 1). There are 8 patients alive with a median active follow-up of 64.5
Synchronous, solitary brain metastasis from NSCLC d T. W. FLANNERY et al.
Impact of Karnofsky Performance Status (KPS) on Overall Survival
Overall Survival for the Entire Cohort (N=42) 100%
21
100%
Actuarial Overall Survival 1-yr: 71.3% 2-yr: 34.1% 5-yr: 21.0%
60%
80% P<0.0001 60%
Percent
Percent
80%
40%
40% KPS >/= 90 20% 20% KPS < 90
0% 0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
0%
Fig. 1. Kaplan-Meier actuarial overall survival for the entire cohort from time of diagnosis.
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 (20%) patients. The sites of progression in these 5 patients were CNS alone (3), CNS and distant (1), and CNS and thoracic (1). Symptomatic radiation necrosis requiring intervention (resection) in the absence of intracranial progression was documented in 1 patient. Patients who had definitive thoracic therapy (n = 26) vs. those who had nondefinitive therapy (n = 16) had a median OS of 26.4 months (95% CI, 16.2–36.6 months) vs. 13.1 months (95% CI, 4.3–21.8 months) and a 5-year OS rate of 34.6% vs. 0% (p < 0.0001), respectively (Fig. 2). There was no statistical difference between those patients treated Impact of Thoracic Therapy on Overall Survival 100%
80%
0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
Fig. 3. Kaplan-Meier actuarial overall survival curves based on Karnofsky performance status.
definitively with (n = 18) or without surgery (n = 8) (p = 0.369). Patients with a KPS $90 had a median OS of 27.8 months compared with 13.1 months for those with a KPS <90 (p < 0.0001) (Fig. 3). In the cohort of patients treated with nondefinitive thoracic therapy, only 4 of 16 (25%) patients had a KPS $90. Their 5-year OS was 0%, because these patients died at 5.5, 13.9, 16.4, and 39.3 months, respectively. There was a clinical trend toward improved OS in patients with N0/N1 disease vs. patients with N2/N3 disease (21.1 vs. 14.1 months, p = 0.083). The median OS for patients with thoracic Stage I, II, and III disease was 18 months, 21.1 months, and 15 months, respectively (p = NS). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (RR = 2.97, p = 0.020) and KPS (RR = 5.85, p = 0.001). DISCUSSION
P<0.0001
Percent
60%
40% Definitive Therapy
20% Non-Definitive Therapy 0% 0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
Fig. 2. Kaplan-Meier actuarial overall survival curves based on definitive vs. nondefinitive thoracic therapy.
This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with SRS. The median OS of 18 months and the 5-year OS rate of 21% demonstrate the potential for long-term survival in this population and compares favorably with series that used surgical resection for the brain metastasis (Table 3) (7, 8, 11). At our institutions, patients presenting with brain metastasis are evaluated for surgical resection or GKSRS. This study confirms the option for GKSRS in the treatment algorithm for synchronous brain metastasis. Multiple series have demonstrated that thoracic therapy and extent of thoracic disease may impact 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 OS was 12.4 months, and the 5-year
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Volume 72, Number 1, 2008
Table 3. Synchronous, solitary brain metastasis from NSCLC series
Bonnette (7) Billings (8) Hu (11) Current
n
Brain therapy
Thoracic therapy
5-y overall survival
99* 28 84 42
Surgery Surgery Surgery/SRS SRS
Surgery Surgery Nonsurgical Surgery and/or chemo/XRT
11% 21% 8% 21%
* Total cohort of 103, but four had more than one lesion.
OS was 11% (7). Moreover, Billings et al. reported a median and 5-year OS of 24 months and 21.4%, respectively, for 28 patients who underwent surgical resection for their brain and thoracic disease. The superior OS in the Billings series may be attributed to the 15 patients (53.6%) with thoracic Stage I disease. Contrary to the Bonnette series, Billings reported a significant improvement in OS if the there was no pathologic evidence of lymph node metastasis (5-year OS 35% vs. 0%, p = 0.001) (8). Our data also showed a clinical trend toward improved OS based on clinical or pathological lymph node status (N0/N1 vs. N2/N3). 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 OS of 15.5 mos was significantly better for those who had thoracic therapy vs. 5.9 months for those who did not (p = 0.046) (11). Our study confirms that long-term survival is achievable. The only factors influencing survival on multivariate analysis were definitive thoracic management and KPS. Only patients with a KPS $90 who received definitive thoracic therapy were alive at 5 or more years. Therefore KPS should be strongly considered when deciding what thoracic therapy to offer a patient with a synchronous, solitary brain metastasis. It is difficult to make any definitive conclusions because of the limited number of patient with a KPS $90 treated nondefinitively, but KPS and definitive therapy both appear to be contributing to improved OS rates. The 5-year OS was 0% for the 4/16 patients treated with nondefinitive thoracic therapy that had a KPS $90 vs. 34.6% for the group treated with definitive thoracic therapy. A recent study by Tendulkar et al. further supports the importance of performance status, control of the primary disease, and lack of extracranial metastases. This series evaluated 271 patients who underwent surgical resection of a single brain metastasis. The patients were stratified by the Radiation Therapy Oncology Group recursive partition analysis developed for brain metastases (1). The survival for patients in recursive partition analysis class 1 (age <65 years, KPS $70, controlled primary, and no extracranial metastases) was significantly better than those in recursive partition analysis Class 2 and 3 (21.4 months vs. 9 months, p < 0.001). In addition, NSCLC was found to be a favorable histology on multivariate analysis (12). Our report has several potential limitations. There is a concern regarding the true cause of the single brain lesion, because the majority of patients were diagnosed on MRI without stereotactic-guided biopsy. Patchell et al. found
11% of patients with abnormal imaging had intracranial disease other than metastasis; however, this study included a heterogeneous collection of malignancies (13). 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 GKSRS or definitive thoracic therapy in our series. Despite the potential for long-term survival, many patients are only offered 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 PET/CT 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 (14, 15). Thus overall survival may actually be improved with PET imaging on all patients. In addition, surgical candidates will undergo surgical mediastinal staging. Patients are then selected for definitive brain and thoracic management based on the extent of intracranial and thoracic disease, presence of involved lymph nodes, and physiological/performance status. The timing of brain and thoracic therapy also depends on these factors. Patients with a good KPS are often recommended to receive GKSRS or surgical resection and WBRT. If patients have neurologic symptoms or a large brain metastasis and are not surgical candidates, we recommend GKSRS and WBRT before thoracic therapy or chemotherapy. WBRT may be delivered prior to GKSRS to decrease the volume of the lesion. This may allow a higher GKSRS dose to be delivered. If the brain lesion is small and asymptomatic, we perform GKSRS 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 2–3 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. In conclusion, this study supports the use of SRS in the treatment paradigm of patients with synchronous, solitary brain metastasis from NSCLC. The median OS of 18 months and 5-year OS of 21% are similar to surgical series and Stage III patients treated with concurrent chemoradiation.
Synchronous, solitary brain metastasis from NSCLC d T. W. FLANNERY et al.
Improved KPS at diagnosis and definitive thoracic therapy significantly impacted survival. This potential for longterm survival has influenced our treatment approach. Thus
23
patients should be considered for definitive thoracic therapy after undergoing SRS or surgical resection of their brain metastasis.
REFERENCES 1. Gaspar L, Scott C, Rottman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology (RTOG) brain metastasis trials. Int J Radiat Oncol Biol Phys 1997;37:745–751. 2. Posner JB. Management of brain metastases. Rev Neurol 1992; 148:477–487. 3. Wen PY, Loeffler JS. Management of brain metastasis. Oncology 1999;13:941–954. 4. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, lung, and melanoma. Cancer 2002;94:2698–2705. 5. Lagerwaard FJ, Levendag PC, Nowak PJ, et al. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys 1999;43:795–803. 6. Sorensen JB, Hansen HH, Hansen M, et al. Brain metastases in adenocarcinoma of the lung: frequency, risk groups and prognosis. J Clin Oncol 1988;6:1474–1480. 7. Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest 2001;119:1469–1475. 8. Billing PS, Miller DL, Allen MS, et al. Surgical treatment of primary lung cancer with synchronous brain metastases. J Thorac Cardiovasc Surg 2001;122:548–553.
9. Lindquist C. Gamma knife radiosurgery. Semin Radiat Oncol 1995;5:197–202. 10. Wu A, Lindner G, maitz AH, et al. Physics of gamma knife approach on convergent beams in stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 1990;18:941–949. 11. Hu C, Chang E, Hassenbusch SJ III, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998–2004. 12. Tendulkar RD, Liu SW, Barnett, et al. RPA classification has significant prognostic significance for surgically resected single brain metastasis. Int J Radiat Oncol Biol Phys 2006;66: 810–817. 13. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single brain metastases to the brain. N Engl J Med 1990;822:494–500. 14. Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999;44:275–281. 15. Schrevens L, Lorent N, Dooms C, et al. The role of PET scan in diagnosis, staging and management of non-small cell lung cancer. Oncologist 2004;9:633–643.
doi:10.1016/j.ijrobp.2007.12.031
CLINICAL INVESTIGATION
Brain
LONG-TERM SURVIVAL IN PATIENTS WITH SYNCHRONOUS, SOLITARY BRAIN METASTASIS FROM NON–SMALL-CELL LUNG CANCER TREATED WITH RADIOSURGERY TODD W. FLANNERY, M.D.,* MOHAN SUNTHARALINGAM, M.D.,* WILLIAM F. REGINE, M.D.,* LAWRENCE S. CHIN, M.D.,y MARK J. KRASNA, M.D.,z MICHAEL K. SHEHATA, M.D.,k MARTIN J. EDELMAN, M.D.,x MARNIE KREMER, B.A.,* ROY A. PATCHELL, M.D.,{ AND YOUNG KWOK, M.D.* Departments of *Radiation Oncology, y Neurosurgery, z Thoracic Surgery, and x Medical Oncology, University of Maryland School of Medicine, Baltimore, MD; Departments of kRadiation Oncology and { Neurosurgery, University of Kentucky School of Medicine, Lexington, KY Purpose: To report the outcome of patients with synchronous, solitary brain metastasis from non–small-cell lung cancer (NSCLC) treated with gamma knife stereotactic radiosurgery (GKSRS). Patients and Methods: Forty-two patients diagnosed with synchronous, solitary brain metastasis from NSCLC were treated with GKSRS between 1993 and 2006. The median Karnofsky performance status (KPS) was 90. Patients had thoracic Stage I-III disease (American Joint Committee on Cancer 2002 guidelines). Definitive thoracic therapy was delivered to 26/42 (62%) patients; 9 patients underwent chemotherapy and radiation, 12 patients had surgical resection, and 5 patients underwent preoperative chemoradiation and surgical resection. Results: The median overall survival (OS) was 18 months. The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively. For patients who underwent definitive thoracic therapy, the median OS was 26.4 months compared with 13.1 months for those who had nondefinitive therapy, and the 5-year actuarial OS was 34.6% vs. 0% (p < 0.0001). Median OS was significantly longer for patients with a KPS $90 vs. KPS < 90 (27.8 months vs. 13.1 months, p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (p = 0.020) and KPS (p = 0.001). Conclusions: This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with GKSRS. Definitive thoracic therapy and KPS significantly impacted OS. The 5-year OS of 21% demonstrates the potential for long-term survival in patients treated with GKSRS; therefore, patients with good KPS should be considered for definitive thoracic therapy. Ó 2008 Elsevier Inc. Synchronous brain metastasis, Solitary brain metastasis, Non-small cell lung cancer, gamma knife radiosurgery.
There is controversy regarding the ideal management of thoracic disease in this patient population, and there are few series that incorporated patients treated with stereotactic radiosurgery. In this article, we report our experience of patients who presented with a synchronous, solitary brain metastasis from NSCLC and were treated with gamma knife stereotactic radiosurgery (GKSRS).
INTRODUCTION Brain metastases outnumber all other primary intracranial tumors (1–3). Lung cancer is the most common primary site, with 30–50% of patients developing brain metastases during the course of their disease (4–6). Patients with a synchronous, solitary brain metastasis from non–small-cell lung cancer (NSCLC) represent a unique population of patients who have the potential for long-term survival. Previous studies have reported 5-year survival rates of 11–21% in patients treated with cranial and thoracic resection (7, 8). Despite these reported 5-year survival rates, many patients are only offered chemotherapy or radiation therapy in a palliative manner after their brain metastasis has been treated.
A retrospective analysis was performed after approval of the institutional review boards at the University of Maryland School of Medicine and University of Kentucky School of Medicine. All patients had histologically proven NSCLC and a synchronous, solitary brain metastasis detected by gadolinium-enhanced, thin slice
Reprint requests to: Young Kwok, M.D., Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201. Tel: (410) 328-9134; Fax: (410) 328-5279; E-mail: [email protected] Presented at the 48th Annual Meeting of the American Society of
Therapeutic Radiology and Oncology (ASTRO), Philadelphia, PA, November 5–9, 2006. Conflict of interest: none. Received Nov 8, 2007, and in revised form Dec 6, 2007. Accepted for publication Dec 11, 2007.
PATIENTS AND METHODS
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Table 1. Patient characteristics Characteristic Age (y) KPS Sex Men Women Thoracic stage* IA IB IIB IIIA IIIB Nodal status N0 N1 N2/3
n (42)
Volume 72, Number 1, 2008
Table 2. Treatment characteristics
Median
Range
Treatment
n (42)
58 90
38–74 70–100
GK-SRS WBRT Definitive thoracic management Chemoradiation Surgery Trimodality Thoracic Stage I/II Thoracic Stage III N1 N2/3 KPS $ 90 Total Nondefinitive thoracic management Thoracic Stage I/II Thoracic Stage III N1 N2/3 KPS $90 Total
42 33
27 15 5 9 9 10 9 20 6 16
Abbreviation: KPS = Karnofsky performance status. * AJCC 2002.
9 12 5 18 8 5 5 20 26 5 11 1 11 4 16
(1–3 mm) magnetic resonance imaging (MRI). In this series, synchronous is defined as having simultaneous brain and lung disease at diagnosis or within 3 months of histologic diagnosis. Solitary is defined as the single brain lesion representing the only extrathoracic disease burden based on computed tomography (CT) imaging of the chest and abdomen with or without positron emission tomography (PET) imaging.
Abbreviations: KPS = Karnofsky performance status; GK-SRS = gamma knife stereotactic radiosurgery; WBRT = whole-brain radiation therapy.
Patient Characteristics
Thoracic therapy
Forty-two patients were diagnosed with a synchronous, solitary brain metastasis and treated with GKSRS between 1993 and 2006. There were 27 men and 15 women, and the median age was 58 years (range, 38–74). The median Karnofsky performance status (KPS) was 90 (range, 70–100) (Table 1). Thirty-eight patients (90.5%) presented with symptoms of a 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). The location of these brain lesions were 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). The 2002 American Joint Committee on Cancer guidelines was used to stage the thoracic disease. Surgical staging was performed on 27/42 patients using mediastinoscopy, mediastinal dissection, or transbronchial needle aspiration to identify positive hilar and mediastinal lymph nodes. Twenty-two (52.4%) patients had radiographically or pathologically involved hilar (N1) or mediastinal (N2/N3) lymphadenopathy. Using clinical and pathologic information, the thoracic disease was Stage I, Stage II, or Stage III in 14, 9, and 19 patients, respectively (Table 1).
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 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 >2 Gy per fraction for an abbreviated course, radiation therapy followed by chemotherapy, and no therapy in 6, 4, 3, and 3 patients, respectively (Table 2).
Central nervous system therapy All patients (n = 42) received GKSRS to the solitary brain metastasis. Descriptions of the GKSRS procedure have been previously published (9, 10). The median dose prescribed was 18Gy 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 GKSRS and 12 before. WBRT preceded thoracic ther-
apy or chemotherapy in 21 patients, whereas 12 patients received it after thoracic therapy or chemotherapy or at the time of central nervous system (CNS) progression.
Statistical considerations Statistical analysis was carried out using SPSS (version 13.0). Factors included in statistical analysis were age, sex, KPS, thoracic therapy (definitive vs. nondefinitive), WBRT, and thoracic lymph node status (N0/N1 vs. N2/N3). The survival data were calculated using the Kaplan-Meier product limit method from the date of NSCLC diagnosis. Comparisons of the survival curves were calculated using the log–rank test. Multivariate analysis was performed using the Cox proportional hazards model. P # 0.05 was considered statistically significant.
RESULTS The median OS for the 42 patients was 18 months range, (1.5–150 months). The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively (Fig. 1). There are 8 patients alive with a median active follow-up of 64.5
Synchronous, solitary brain metastasis from NSCLC d T. W. FLANNERY et al.
Impact of Karnofsky Performance Status (KPS) on Overall Survival
Overall Survival for the Entire Cohort (N=42) 100%
21
100%
Actuarial Overall Survival 1-yr: 71.3% 2-yr: 34.1% 5-yr: 21.0%
60%
80% P<0.0001 60%
Percent
Percent
80%
40%
40% KPS >/= 90 20% 20% KPS < 90
0% 0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
0%
Fig. 1. Kaplan-Meier actuarial overall survival for the entire cohort from time of diagnosis.
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 (20%) patients. The sites of progression in these 5 patients were CNS alone (3), CNS and distant (1), and CNS and thoracic (1). Symptomatic radiation necrosis requiring intervention (resection) in the absence of intracranial progression was documented in 1 patient. Patients who had definitive thoracic therapy (n = 26) vs. those who had nondefinitive therapy (n = 16) had a median OS of 26.4 months (95% CI, 16.2–36.6 months) vs. 13.1 months (95% CI, 4.3–21.8 months) and a 5-year OS rate of 34.6% vs. 0% (p < 0.0001), respectively (Fig. 2). There was no statistical difference between those patients treated Impact of Thoracic Therapy on Overall Survival 100%
80%
0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
Fig. 3. Kaplan-Meier actuarial overall survival curves based on Karnofsky performance status.
definitively with (n = 18) or without surgery (n = 8) (p = 0.369). Patients with a KPS $90 had a median OS of 27.8 months compared with 13.1 months for those with a KPS <90 (p < 0.0001) (Fig. 3). In the cohort of patients treated with nondefinitive thoracic therapy, only 4 of 16 (25%) patients had a KPS $90. Their 5-year OS was 0%, because these patients died at 5.5, 13.9, 16.4, and 39.3 months, respectively. There was a clinical trend toward improved OS in patients with N0/N1 disease vs. patients with N2/N3 disease (21.1 vs. 14.1 months, p = 0.083). The median OS for patients with thoracic Stage I, II, and III disease was 18 months, 21.1 months, and 15 months, respectively (p = NS). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (RR = 2.97, p = 0.020) and KPS (RR = 5.85, p = 0.001). DISCUSSION
P<0.0001
Percent
60%
40% Definitive Therapy
20% Non-Definitive Therapy 0% 0
12
24
36
48
60
72
84
96
108 120 132 144 156
Time (months)
Fig. 2. Kaplan-Meier actuarial overall survival curves based on definitive vs. nondefinitive thoracic therapy.
This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with SRS. The median OS of 18 months and the 5-year OS rate of 21% demonstrate the potential for long-term survival in this population and compares favorably with series that used surgical resection for the brain metastasis (Table 3) (7, 8, 11). At our institutions, patients presenting with brain metastasis are evaluated for surgical resection or GKSRS. This study confirms the option for GKSRS in the treatment algorithm for synchronous brain metastasis. Multiple series have demonstrated that thoracic therapy and extent of thoracic disease may impact 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 OS was 12.4 months, and the 5-year
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I. J. Radiation Oncology d Biology d Physics
Volume 72, Number 1, 2008
Table 3. Synchronous, solitary brain metastasis from NSCLC series
Bonnette (7) Billings (8) Hu (11) Current
n
Brain therapy
Thoracic therapy
5-y overall survival
99* 28 84 42
Surgery Surgery Surgery/SRS SRS
Surgery Surgery Nonsurgical Surgery and/or chemo/XRT
11% 21% 8% 21%
* Total cohort of 103, but four had more than one lesion.
OS was 11% (7). Moreover, Billings et al. reported a median and 5-year OS of 24 months and 21.4%, respectively, for 28 patients who underwent surgical resection for their brain and thoracic disease. The superior OS in the Billings series may be attributed to the 15 patients (53.6%) with thoracic Stage I disease. Contrary to the Bonnette series, Billings reported a significant improvement in OS if the there was no pathologic evidence of lymph node metastasis (5-year OS 35% vs. 0%, p = 0.001) (8). Our data also showed a clinical trend toward improved OS based on clinical or pathological lymph node status (N0/N1 vs. N2/N3). 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 OS of 15.5 mos was significantly better for those who had thoracic therapy vs. 5.9 months for those who did not (p = 0.046) (11). Our study confirms that long-term survival is achievable. The only factors influencing survival on multivariate analysis were definitive thoracic management and KPS. Only patients with a KPS $90 who received definitive thoracic therapy were alive at 5 or more years. Therefore KPS should be strongly considered when deciding what thoracic therapy to offer a patient with a synchronous, solitary brain metastasis. It is difficult to make any definitive conclusions because of the limited number of patient with a KPS $90 treated nondefinitively, but KPS and definitive therapy both appear to be contributing to improved OS rates. The 5-year OS was 0% for the 4/16 patients treated with nondefinitive thoracic therapy that had a KPS $90 vs. 34.6% for the group treated with definitive thoracic therapy. A recent study by Tendulkar et al. further supports the importance of performance status, control of the primary disease, and lack of extracranial metastases. This series evaluated 271 patients who underwent surgical resection of a single brain metastasis. The patients were stratified by the Radiation Therapy Oncology Group recursive partition analysis developed for brain metastases (1). The survival for patients in recursive partition analysis class 1 (age <65 years, KPS $70, controlled primary, and no extracranial metastases) was significantly better than those in recursive partition analysis Class 2 and 3 (21.4 months vs. 9 months, p < 0.001). In addition, NSCLC was found to be a favorable histology on multivariate analysis (12). Our report has several potential limitations. There is a concern regarding the true cause of the single brain lesion, because the majority of patients were diagnosed on MRI without stereotactic-guided biopsy. Patchell et al. found
11% of patients with abnormal imaging had intracranial disease other than metastasis; however, this study included a heterogeneous collection of malignancies (13). 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 GKSRS or definitive thoracic therapy in our series. Despite the potential for long-term survival, many patients are only offered 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 PET/CT 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 (14, 15). Thus overall survival may actually be improved with PET imaging on all patients. In addition, surgical candidates will undergo surgical mediastinal staging. Patients are then selected for definitive brain and thoracic management based on the extent of intracranial and thoracic disease, presence of involved lymph nodes, and physiological/performance status. The timing of brain and thoracic therapy also depends on these factors. Patients with a good KPS are often recommended to receive GKSRS or surgical resection and WBRT. If patients have neurologic symptoms or a large brain metastasis and are not surgical candidates, we recommend GKSRS and WBRT before thoracic therapy or chemotherapy. WBRT may be delivered prior to GKSRS to decrease the volume of the lesion. This may allow a higher GKSRS dose to be delivered. If the brain lesion is small and asymptomatic, we perform GKSRS 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 2–3 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. In conclusion, this study supports the use of SRS in the treatment paradigm of patients with synchronous, solitary brain metastasis from NSCLC. The median OS of 18 months and 5-year OS of 21% are similar to surgical series and Stage III patients treated with concurrent chemoradiation.
Synchronous, solitary brain metastasis from NSCLC d T. W. FLANNERY et al.
Improved KPS at diagnosis and definitive thoracic therapy significantly impacted survival. This potential for longterm survival has influenced our treatment approach. Thus
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patients should be considered for definitive thoracic therapy after undergoing SRS or surgical resection of their brain metastasis.
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