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Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation

Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis... Background: Brain metastases occur in 30-50% of Non-small cell lung cancer (NSCLC) patients and confer a worse prognosis and quality of life. These patients are usually treated with Whole-brain radiotherapy (WBRT) followed by systemic therapy. Few studies have evaluated the role of chemoradiotherapy to the primary tumor after WBRT as definitive treatment in the management of these patients. Methods: We reviewed the outcome of 30 patients with primary NSCLC and brain metastasis at diagnosis without evidence of other metastatic sites. Patients were treated with WBRT and after induction chemotherapy with paclitaxel and cisplatin for two cycles. In the absence of progression, concurrent chemoradiotherapy for the primary tumor with weekly paclitaxel and carboplatin was indicated, with a total effective dose of 60 Gy. If disease progression was ruled out, four chemotherapy cycles followed. Results: Median Progression-free survival (PFS) and Overall survival (OS) were 8.43 ± 1.5 and 31.8 ± 15.8 months, respectively. PFS was 39.5% at 1 year and 24.7% at 2 years. The 1- and 2-year OS rates were 71.1 and 60.2%, respectively. Three-year OS was significantly superior for patients with N0-N1 stage disease vs. N2-N3 (60 vs. 24%, respectively; Response rate [RR], 0.03; p= 0.038). Conclusions: Patients with NSCLC and brain metastasis might benefit from treatment with WBRT and concurrent thoracic chemoradiotherapy. The subgroup of N0-N1 patients appears to achieve the greatest benefit. The result of this study warrants a prospective trial to confirm the benefit of this treatment. Keywords: NSCLC, brain metastases, chemoradiotherapy, survival Introduction combination, which have achieved a median survival Brain metastases occur in 30-50% of patients with Non- time that ranges from 6.5-10 months [7-11]. small-cell lung cancer (NSCLC) and confer upon the As improvements are made in the management of patient a worse prognosis and quality of life [1-6]. Med- brain metastases, the question arises on how to manage ian survival of patients who receive supportive care and patients with NSCLC who have solely stable brain meta- are treated only with corticosteroids is approximately 1- static disease and on whether treatment should be con- 2 months [2]. Primary approaches to the treatment of sidered for the primary lung lesion. Long-term survival brain metastases include Whole-brain radiation therapy has been achieved in some patients who have undergone (WBRT), surgery, stereotactic radiosurgery, or a either cranial surgery or radiotherapy and aggressive thoracic management with lung tumor resection, with studies reporting 5-year survival rates between 10 and * Correspondence: ogar@servidor.unam.mx Clinic of Thoracic Oncology, Instituto Nacional de Cancerología (INCan), 20% [12-16]. Few studies have evaluated the role of Mexico City, Mexico thoracic radiation or chemoradiotherapy as definitive Full list of author information is available at the end of the article © 2011 Arrieta et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Arrieta et al. Radiation Oncology 2011, 6:166 Page 2 of 7 http://www.ro-journal.com/content/6/1/166 treatment in the management of patients with NCSLC Systemic and thoracic treatment and synchronous solitary brain metastasis, and some of Initially, two cycles of systemic chemotherapy were these have shown promising results [17,18]. Despite administered with paclitaxel 175 mg/m Intravenously (IV) > 3 h and cisplatin 75 mg/m IV on day 1 every 21 these findings, the majority of patients are only offered days. Following response assessment after the first two chemotherapy or radiation therapy in a palliative man- cycles of chemotherapy and in the absence of progres- ner [18]. sion either at the primary lung tumor or Central ner- In an effort to clarify such conflicting data and in vous system (CNS), chemoradiotherapy was indicated. order to identify patients who may benefit from Thoracic radiotherapy was administered with a linear aggressive management, we reviewed the outcome of 30 patients with either unresectable single or multiple accelerator (energy 6 and/or 15 MV), and the treatment brain metastases treated with WBRT, who were volume for the primary tumor was based on initial diag- managed subsequently with definitive thoracic nosis volume. The ipsilateral hilum was treated for N0- chemoradiotherapy. N2 disease, while for N3, the contralateral hilum was also included. Clinical target volume (CTV) included Methods gross tumor volume plus 2-cm margin and the dose to In a retrospective review of patients treated at the Insti- the primary tumor was 60 Gy (BED). tuto Nacional de Cancerología (INCan) in Mexico City Concurrently with radiotherapy, weekly paclitaxel 60- from May 2005 to March 2009, we identified 30 patients 80 mg/m and carboplatin at a dose of AUC 2, accord- with histologically proven NSCLC and synchronous ing to Calvert, were administered. If disease progression brain metastases. All patients selected for this analysis was ruled out, four chemotherapy cycles followed, using had the following characteristics: (1) synchronous diag- the same schedule as that of the induction regimen. nosis of NSCLC and brain metastasis (within 2 months Response assessment of the lung primary diagnosis); (2) absence of neoplastic Follow-up for primary disease was performed with CT, spread elsewhere in the body at the time of NSCLC and generally every 2 months. Follow-up for brain metas- brain metastases detection, and (3) patients with either tases was conducted by MRI, usually every 2 months. All patients were evaluated according to Response Eva- one unresectable lesion or multiple brain metastases, luation Criteria in Solid Tumors (RECIST) criteria every who were not candidates for surgery or stereotactic two cycles: Complete response was defined as resolution radiosurgery treated with WBRT. of all disease, partial response constituted a 30% Patients ’ hospital records and office charts were decrease in the sum of the longest diameter of target reviewed. Variables collected for analysis included age, gender, Karnofsky performance status (KPS), Radiation lesions, progressive disease was defined as 20% increase Therapy Oncology Group Recursive partitioning analysis in the sum of the longest diameter of target lesions, and (RPA) class, primary Tumor-node-metastasis staging stable disease comprised neither sufficient shrinkage to (TNM, according to the American Joint Committee on qualify for partial response nor sufficient increase to Cancer Staging Manual, sixth edition [19]), primary his- qualify for progressive disease. Response assessment was tology, and number of brain metastases. performed before chemoradiotherapy was indicated. Diagnosis of brain metastases was made based on Statistical analysis brain imaging using either Computed tomography (CT) For descriptive purposes, continuous variables were sum- or Magnetic resonance imaging (MRI). These studies marized as arithmetic means and Standard deviation (SD), were obtained as a routine staging procedure or in the and categorical variables as relative frequencies and propor- evaluation of suspicious symptomatology. Thoracic stage tions. Progression-free survival (PFS) was calculated from and nodal status were determined by means of chest date of diagnosis of NSCLS until progression. Overall survi- Computed tomography (CT) with or without Positron val(OS)wasdefinedastimefromdiagnosisof NSCLS emission tomography (PET) imaging. until death or until the patient was censored at time of last follow-up. Median time to progression, median probability Treatment plan of survival, and 1- and 2-year survival rates were estimated Whole-brain radiotherapy by the Kaplan-Meier method. Significance value was set at p < 0.05. SPSS software package version 17 (SPSS, Inc., Conventional megavoltage external beam radiotherapy Chicago, IL, USA) was employed to analyze the data. was administered with a linear accelerator (energy 6 MV) or with a cobalt bomb (1.25 MV). For WBRT, two Results lateral opposed fields were used, covering up to C2 ver- Patient Characteristics tebral body. Dose administered was 30 Gy/10 fractions. Patient characteristics are summarized in Table 1. Med- Once patients received WBRT, systemic chemotherapy ian patient age at time of diagnosis was 57 years, and was started. Arrieta et al. Radiation Oncology 2011, 6:166 Page 3 of 7 http://www.ro-journal.com/content/6/1/166 Table 1 Baseline characteristics of patients and disease Median age (years) 57 ± 11.1 Gender (Female) 17 (56.7%) ECOG 0 8 (26.7%) 1 19 (63.3%) 2 3 (10%) Comorbidities EPOC 4 (13.3%) Diabetes 3 (10%) Hypertension 3 (10%) Histology Adenocarcinoma 24 (80%) Squamous 4 (13.3%) Other 2 (6.7%) Smoking history Yes 23 (76.7%) No 7 (23.3%) Nodal status N 0-1 (n) 16 (53.3%) N 2-3 (n) 14 (46.7%) RPA class 2 30 (100%) Median brain metastatic lesions 3±2 ECOG: Eastern Cooperative of Gynecologists; RPA: Radiation Therapy Oncology Group Recursive partitioning analysis (RPA). 56.7% of patients were females. Smoking history was documented in 76.7% of patients. The majority of patients had an Eastern Cooperative of Gynecologists (ECOG) performance status of 0 or 1 (90%). The most Figure 1 A) Kaplan-Meier Progression-free survival (PFS) curve common histology was adenocarcinoma (80%), and all for patients with NSCLC treated with WBRT and concurrent patients were RPA 2 class. Twenty patients (66.7%) were chemoradiotherapy (n = 30). B) Kaplan-Meier Overall survival (OS) evaluated with PET CT to rule out other sites of meta- curve for patients with NSCLC treated with WBRT and concurrent static disease. The number of brain metastatic lesions chemoradiotherapy (n = 30). varied between 1 and 5, with a median of three CNS metastases. local progression, whereas 10 (33%) developed distant sites of metastases. The 1- and 2-year OS rates were Response 71.1 and 60.2%, respectively. Three-year OS was signifi- With regard to response after WBRT, all patients cantly superior for patients with N0-N1 stage disease vs. received the planned radiotherapy dose. Twelve patients N2-N3 (60 vs. 24%, respectively; RR, 0.03; p =0.038) (40%) had stable disease, nine patients (30%) achieved [Figure 2]. In a univariate analysis using the Log Rank partial response, and nine (30%) presented complete test, there was no statistically significant difference in response. Median number of chemotherapy cycles was survival according to age (p = 0.07), KPS (p =0.5), glo- six. Five patients did not receive the planned cycles bal response (p = 0.7), history of smoking (p = 0.4), and (17%). When primary tumor response was assessed, 18 histology (p = 0.17). patients (60%) achieved a partial response and 12 patients (40%) had stable disease. Discussion A considerable proportion of patients with NSCLC Outcome develop brain metastases at some point during their dis- Median follow-up was 10.2 ± 2 months. Median PFS ease course and this generally leads to a poor prognosis. and OS were 8.43 ± 1.5 months and 31.8 ± 15.8 months, However, in some cases, long-term survival has been respectively [Figures 1A and 1B]. PFS was 39.5% at 1 achieved after aggressive therapy of cerebral lesions, year and 24.7% at 2 years. Fifteen patients (50%) had Arrieta et al. Radiation Oncology 2011, 6:166 Page 4 of 7 http://www.ro-journal.com/content/6/1/166 definitive chemoradiotherapy as an alternative to a more aggressive surgical approach. To our knowledge, five different studies have reported their results in patients with NSCLC with synchronous brain metastatic disease treated with radiotherapy [13,16-18,26] and/or chemoradiotherapy [17,18] to the primary tumor, but the majority of these studies also included patients treated with other modalities, such as surgical resection of the thoracic lesion [13,16,18] or solely chemotherapy [17]. Brain management differed significantly among these series, and included surgical resection of brain metastases, WBRT, stereotactic sur- gery, or a combination of the former. Median OS times varied between 5.2 and 18 months, with 1- and 2-year survival rates that ranged between 22-71.3% and 10- Figure 2 Overall survival (OS) for patients with NSCLC treated 34.1%, respectively. For patients treated with definitive with WBRT and concurrent chemoradiotherapy. thoracic therapy after brain metastases management with gammaknife stereotactic radiosurgery, Flannery et al. reported significantly better survival than those that did not receive definitive treatment (median OS, 26.4 vs. with a median survival of 10-12 months and 5-year sur- vival rates ranging from 10-25% [7,8,20,21]. 13.1 months). In our series, we reached a median survi- As improvements are made in the management of val of 31.8 months, the longest survival reported to date patients with brain metastases without extracranial dis- in patients with synchronous brain metastatic disease ease, the question arises of how to treat the primary treated with definitive chemoradiation to the primary. lung cancer. This is due to the fact that the main cause Unlike other studies, in our report, treatment delivered of death in patients with lung carcinoma treated aggres- to the brain, as well as systemic and local therapy, was sively for brain metastases is progression of the primary homogeneous among all patients included. cancer [13,22]. By applying American Joint Committee on Cancer In a recent review of the literature, Modi et al. identi- (AJCC) staging only to the primary site, Hu et al. reported that patients with thoracic stage I had a more fied 11 papers that addressed the issue of surgical resec- favorable outcome, with a median survival time of 25.6 tion of the primary tumor within the context of months (compared with 9.5 and 9.9 months for stages II metastatic brain lesions [23]. They found that median and III, respectively), and concluded that aggressive survival for curative intent groups (combined therapy treatment to the lung may be justified for newly diag- with or withoutadjuvanttreatment)rangedfrom19-27 nosedthoracicstageINSCLC with asolitarybrain months (mean, 23.12 ± 3.3 months) and 1-, 2-, and 5- metastasis [17]. Also, Louie et al. reported longer overall year OS reached 56-69%, 28-54%, and 11-24%, respec- survival for stage I/II disease of 14.7 months compared tively. The authors concluded that in the absence of with 7 months for patients with stage III NSCLC with mediastinal lymph node involvement, surgical resection synchronous solitary brain metastasis treated with cra- of NSCLC with complete resection of the brain metasta- niotomy and WBRT [16]. In our study, according to the sis improves prognosis. Furthermore, they described that univariate analysis, we found that patients with N0-N1 some features such as adenocarcinoma histology, low disease had a significantly better 3-year survival rate carcinoembryonic antigen (CEA) levels at presentation, response to preoperative chemotherapy before local compared with those with N2-N3 disease. Similar find- treatment, and high KPS score may have a positive ings have been reported in previous studies where the prognostic value. absence of mediastinal lymph node involvement (N2) is The benefit of surgical resection after induction ther- one of the most important survival determinants apy compared with definitive radiotherapy remains [15,27,28]. Accordingly, in patients with controlled brain uncertain and appears to be associated with an increase diseaseand earlylungdisease (N0-N1)amenableto in early surgery-associated mortality. The Intergroup resection, a conservative surgery of the primary tumor 0139 [24] and the EORTC 08941 [25] did not confirm a may be the best treatment alternative (segmentectomy or lobectomy). For patients who are not candidate for significant survival advantage for surgery following surgical resection, chemoradiatiation to the primary either neoadjuvant concurrent chemoradiotherapy or tumor should be considered. In Table 2, we condensed induction chemotherapy. Thus, we opted to treat our the studies that assessed radiation therapy or patients with NSCLC with brain metastases with Arrieta et al. Radiation Oncology 2011, 6:166 Page 5 of 7 http://www.ro-journal.com/content/6/1/166 Table 2 Series evaluating radiation therapy or chemoradiotherapy of lung cancer in NSCLC with brain metastasis Study Year Number of Number of Brain Median 1-year 2-year 5-year Prognostic factors patients brain treatment survival, survival survival survival metastases months rate (%) rate (%) rate (%) Chidel et al. 1999 Sx = 2 1Sx Overall: 6.9 12 (3-year) WBRT [13] Sx + RT = 3 WBRT Definitive tx: Aggressive thoracic RT = 8 STS 20.1 treatment Palliative = and No definitive 15 combination tx: 3.5 Moazami et 2002 Chemo/RT 42 pts: 1 Sx 5.2 22 10 - Younger age al.[31] =29 49 pts: > 1 WBRT Stage IIIA Sx = 59 Metachronous STS Lung resection brain lesions and ECOG combinations No extracranial mets Sx of brain mets STS Hu et al.[17] 2006 RT = 44 1Sx Overall: ~15 49.8 16.3 7.6 Thoracic stage I Chemo = STS Stage I: 25.6 23 Stage II: 9.5 Chemo/RT Stage III: 9.9 =13 Ampil et al. 2007 > 65 year 1 WBRT RT = 5 RT = 14 - - Sx of brain mets [26] RT = 22 STS No RT = 3 No RT = 11 No RT = 50 Sx p = 0.28 p= 0.28 and combinations Flannery et al. 2008 RT = 26 1 STS Overall: 18 Overall: 71.3 Overall: 34.1 Overall: 21 Definitive thoracic [18] Chemo/RT Definitive tx: RT: 34.6 therapy =9 26.4 No RT: 0 KPS Sx = 12 No definitive p < 0.0001 Preop tx: 13.1 Chemo + p < 0.0001 Sx = 5 Louie et al. 2009 Sx = 8 1 Sx + WBRT 7.8 - - - Lung surgery [16] Chemo = Stage I/II: Primary lung 24 14.7 treatment RT = 14 Stage III: 7 > 8 weeks after brain Sx Stage I/II disease Arrieta et al. 2010 Chemo- > 1 WBRT 31.8 71.1 60.2 3-year OS for N0-1 (present Chemo/RT was 60 vs. 24% for series) =30 N2-3 NSCLC: Non-small-cell lung cancer; Sx: Surgery; RT: Radiotherapy; WBRT: Whole-brain radiotherapy; STS: Stereotactic surgery; Comb: Combination; Mets: Metastasis/Metastases; Chemo: Chemotherapy; Chemo/RT: Chemo-radiotherapy; Preop: Pre-operative. a) Univariate analysis. chemoradiotherapy of the primary lung tumor in [18,30-32,34], adenocarcinoma subtype [14,28,32,35], patients with central nervous metastatic disease. location of primary tumor, site of brain metastases, and To our knowledge, this is the first time that patients low CEA levels [28,36]. with multiple synchronous brain metastases treated with Median survival in patients treated in this series is WBRT have been managed with aggressive therapy for remarkably long. One of the reasons might be that we primary tumor in chest with concurrent chemora- selected patients who presented with synchronous brain diotherapy, showing a very long OS. Among series that tumors and did not include those with metachronous evaluated surgery as local treatment for the thoracic dis- lesions, which may represent a better prognostic group. ease, several included patients with multiple brain In addition, we selected patients who did not progress metastases [12,28-32]. In none of these studies was the after induction chemotherapy to proceed with further number of brain lesions described as a factor that con- thoracic management, in order to ensure that patients ferred poor prognosis. with rapid progressive metastatic disease would not be Other prognostic factors associated with better out- submitted to a more aggressive management instead of comes with this definitive strategy after treatment to the a palliative approach. 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Fischer B, Lassen U, Mortensen J, Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, Ravn J, Clementsen P, Høgholm A, Larsen K, Rasmussen T, Keiding S, Dirksen A, Gerke O, Skov B, Steffensen I, Hansen H, Vilmann P, Jacobsen G, Backer V, Maltbaek N, Pedersen J, Madsen H, Nielsen H, Højgaard L: Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009, 361(1):32-9. doi:10.1186/1748-717X-6-166 Cite this article as: Arrieta et al.: Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiation Oncology 2011 6:166. 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Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation

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Springer Journals
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Copyright © 2011 by Arrieta et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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10.1186/1748-717X-6-166
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Abstract

Background: Brain metastases occur in 30-50% of Non-small cell lung cancer (NSCLC) patients and confer a worse prognosis and quality of life. These patients are usually treated with Whole-brain radiotherapy (WBRT) followed by systemic therapy. Few studies have evaluated the role of chemoradiotherapy to the primary tumor after WBRT as definitive treatment in the management of these patients. Methods: We reviewed the outcome of 30 patients with primary NSCLC and brain metastasis at diagnosis without evidence of other metastatic sites. Patients were treated with WBRT and after induction chemotherapy with paclitaxel and cisplatin for two cycles. In the absence of progression, concurrent chemoradiotherapy for the primary tumor with weekly paclitaxel and carboplatin was indicated, with a total effective dose of 60 Gy. If disease progression was ruled out, four chemotherapy cycles followed. Results: Median Progression-free survival (PFS) and Overall survival (OS) were 8.43 ± 1.5 and 31.8 ± 15.8 months, respectively. PFS was 39.5% at 1 year and 24.7% at 2 years. The 1- and 2-year OS rates were 71.1 and 60.2%, respectively. Three-year OS was significantly superior for patients with N0-N1 stage disease vs. N2-N3 (60 vs. 24%, respectively; Response rate [RR], 0.03; p= 0.038). Conclusions: Patients with NSCLC and brain metastasis might benefit from treatment with WBRT and concurrent thoracic chemoradiotherapy. The subgroup of N0-N1 patients appears to achieve the greatest benefit. The result of this study warrants a prospective trial to confirm the benefit of this treatment. Keywords: NSCLC, brain metastases, chemoradiotherapy, survival Introduction combination, which have achieved a median survival Brain metastases occur in 30-50% of patients with Non- time that ranges from 6.5-10 months [7-11]. small-cell lung cancer (NSCLC) and confer upon the As improvements are made in the management of patient a worse prognosis and quality of life [1-6]. Med- brain metastases, the question arises on how to manage ian survival of patients who receive supportive care and patients with NSCLC who have solely stable brain meta- are treated only with corticosteroids is approximately 1- static disease and on whether treatment should be con- 2 months [2]. Primary approaches to the treatment of sidered for the primary lung lesion. Long-term survival brain metastases include Whole-brain radiation therapy has been achieved in some patients who have undergone (WBRT), surgery, stereotactic radiosurgery, or a either cranial surgery or radiotherapy and aggressive thoracic management with lung tumor resection, with studies reporting 5-year survival rates between 10 and * Correspondence: ogar@servidor.unam.mx Clinic of Thoracic Oncology, Instituto Nacional de Cancerología (INCan), 20% [12-16]. Few studies have evaluated the role of Mexico City, Mexico thoracic radiation or chemoradiotherapy as definitive Full list of author information is available at the end of the article © 2011 Arrieta et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Arrieta et al. Radiation Oncology 2011, 6:166 Page 2 of 7 http://www.ro-journal.com/content/6/1/166 treatment in the management of patients with NCSLC Systemic and thoracic treatment and synchronous solitary brain metastasis, and some of Initially, two cycles of systemic chemotherapy were these have shown promising results [17,18]. Despite administered with paclitaxel 175 mg/m Intravenously (IV) > 3 h and cisplatin 75 mg/m IV on day 1 every 21 these findings, the majority of patients are only offered days. Following response assessment after the first two chemotherapy or radiation therapy in a palliative man- cycles of chemotherapy and in the absence of progres- ner [18]. sion either at the primary lung tumor or Central ner- In an effort to clarify such conflicting data and in vous system (CNS), chemoradiotherapy was indicated. order to identify patients who may benefit from Thoracic radiotherapy was administered with a linear aggressive management, we reviewed the outcome of 30 patients with either unresectable single or multiple accelerator (energy 6 and/or 15 MV), and the treatment brain metastases treated with WBRT, who were volume for the primary tumor was based on initial diag- managed subsequently with definitive thoracic nosis volume. The ipsilateral hilum was treated for N0- chemoradiotherapy. N2 disease, while for N3, the contralateral hilum was also included. Clinical target volume (CTV) included Methods gross tumor volume plus 2-cm margin and the dose to In a retrospective review of patients treated at the Insti- the primary tumor was 60 Gy (BED). tuto Nacional de Cancerología (INCan) in Mexico City Concurrently with radiotherapy, weekly paclitaxel 60- from May 2005 to March 2009, we identified 30 patients 80 mg/m and carboplatin at a dose of AUC 2, accord- with histologically proven NSCLC and synchronous ing to Calvert, were administered. If disease progression brain metastases. All patients selected for this analysis was ruled out, four chemotherapy cycles followed, using had the following characteristics: (1) synchronous diag- the same schedule as that of the induction regimen. nosis of NSCLC and brain metastasis (within 2 months Response assessment of the lung primary diagnosis); (2) absence of neoplastic Follow-up for primary disease was performed with CT, spread elsewhere in the body at the time of NSCLC and generally every 2 months. Follow-up for brain metas- brain metastases detection, and (3) patients with either tases was conducted by MRI, usually every 2 months. All patients were evaluated according to Response Eva- one unresectable lesion or multiple brain metastases, luation Criteria in Solid Tumors (RECIST) criteria every who were not candidates for surgery or stereotactic two cycles: Complete response was defined as resolution radiosurgery treated with WBRT. of all disease, partial response constituted a 30% Patients ’ hospital records and office charts were decrease in the sum of the longest diameter of target reviewed. Variables collected for analysis included age, gender, Karnofsky performance status (KPS), Radiation lesions, progressive disease was defined as 20% increase Therapy Oncology Group Recursive partitioning analysis in the sum of the longest diameter of target lesions, and (RPA) class, primary Tumor-node-metastasis staging stable disease comprised neither sufficient shrinkage to (TNM, according to the American Joint Committee on qualify for partial response nor sufficient increase to Cancer Staging Manual, sixth edition [19]), primary his- qualify for progressive disease. Response assessment was tology, and number of brain metastases. performed before chemoradiotherapy was indicated. Diagnosis of brain metastases was made based on Statistical analysis brain imaging using either Computed tomography (CT) For descriptive purposes, continuous variables were sum- or Magnetic resonance imaging (MRI). These studies marized as arithmetic means and Standard deviation (SD), were obtained as a routine staging procedure or in the and categorical variables as relative frequencies and propor- evaluation of suspicious symptomatology. Thoracic stage tions. Progression-free survival (PFS) was calculated from and nodal status were determined by means of chest date of diagnosis of NSCLS until progression. Overall survi- Computed tomography (CT) with or without Positron val(OS)wasdefinedastimefromdiagnosisof NSCLS emission tomography (PET) imaging. until death or until the patient was censored at time of last follow-up. Median time to progression, median probability Treatment plan of survival, and 1- and 2-year survival rates were estimated Whole-brain radiotherapy by the Kaplan-Meier method. Significance value was set at p < 0.05. SPSS software package version 17 (SPSS, Inc., Conventional megavoltage external beam radiotherapy Chicago, IL, USA) was employed to analyze the data. was administered with a linear accelerator (energy 6 MV) or with a cobalt bomb (1.25 MV). For WBRT, two Results lateral opposed fields were used, covering up to C2 ver- Patient Characteristics tebral body. Dose administered was 30 Gy/10 fractions. Patient characteristics are summarized in Table 1. Med- Once patients received WBRT, systemic chemotherapy ian patient age at time of diagnosis was 57 years, and was started. Arrieta et al. Radiation Oncology 2011, 6:166 Page 3 of 7 http://www.ro-journal.com/content/6/1/166 Table 1 Baseline characteristics of patients and disease Median age (years) 57 ± 11.1 Gender (Female) 17 (56.7%) ECOG 0 8 (26.7%) 1 19 (63.3%) 2 3 (10%) Comorbidities EPOC 4 (13.3%) Diabetes 3 (10%) Hypertension 3 (10%) Histology Adenocarcinoma 24 (80%) Squamous 4 (13.3%) Other 2 (6.7%) Smoking history Yes 23 (76.7%) No 7 (23.3%) Nodal status N 0-1 (n) 16 (53.3%) N 2-3 (n) 14 (46.7%) RPA class 2 30 (100%) Median brain metastatic lesions 3±2 ECOG: Eastern Cooperative of Gynecologists; RPA: Radiation Therapy Oncology Group Recursive partitioning analysis (RPA). 56.7% of patients were females. Smoking history was documented in 76.7% of patients. The majority of patients had an Eastern Cooperative of Gynecologists (ECOG) performance status of 0 or 1 (90%). The most Figure 1 A) Kaplan-Meier Progression-free survival (PFS) curve common histology was adenocarcinoma (80%), and all for patients with NSCLC treated with WBRT and concurrent patients were RPA 2 class. Twenty patients (66.7%) were chemoradiotherapy (n = 30). B) Kaplan-Meier Overall survival (OS) evaluated with PET CT to rule out other sites of meta- curve for patients with NSCLC treated with WBRT and concurrent static disease. The number of brain metastatic lesions chemoradiotherapy (n = 30). varied between 1 and 5, with a median of three CNS metastases. local progression, whereas 10 (33%) developed distant sites of metastases. The 1- and 2-year OS rates were Response 71.1 and 60.2%, respectively. Three-year OS was signifi- With regard to response after WBRT, all patients cantly superior for patients with N0-N1 stage disease vs. received the planned radiotherapy dose. Twelve patients N2-N3 (60 vs. 24%, respectively; RR, 0.03; p =0.038) (40%) had stable disease, nine patients (30%) achieved [Figure 2]. In a univariate analysis using the Log Rank partial response, and nine (30%) presented complete test, there was no statistically significant difference in response. Median number of chemotherapy cycles was survival according to age (p = 0.07), KPS (p =0.5), glo- six. Five patients did not receive the planned cycles bal response (p = 0.7), history of smoking (p = 0.4), and (17%). When primary tumor response was assessed, 18 histology (p = 0.17). patients (60%) achieved a partial response and 12 patients (40%) had stable disease. Discussion A considerable proportion of patients with NSCLC Outcome develop brain metastases at some point during their dis- Median follow-up was 10.2 ± 2 months. Median PFS ease course and this generally leads to a poor prognosis. and OS were 8.43 ± 1.5 months and 31.8 ± 15.8 months, However, in some cases, long-term survival has been respectively [Figures 1A and 1B]. PFS was 39.5% at 1 achieved after aggressive therapy of cerebral lesions, year and 24.7% at 2 years. Fifteen patients (50%) had Arrieta et al. Radiation Oncology 2011, 6:166 Page 4 of 7 http://www.ro-journal.com/content/6/1/166 definitive chemoradiotherapy as an alternative to a more aggressive surgical approach. To our knowledge, five different studies have reported their results in patients with NSCLC with synchronous brain metastatic disease treated with radiotherapy [13,16-18,26] and/or chemoradiotherapy [17,18] to the primary tumor, but the majority of these studies also included patients treated with other modalities, such as surgical resection of the thoracic lesion [13,16,18] or solely chemotherapy [17]. Brain management differed significantly among these series, and included surgical resection of brain metastases, WBRT, stereotactic sur- gery, or a combination of the former. Median OS times varied between 5.2 and 18 months, with 1- and 2-year survival rates that ranged between 22-71.3% and 10- Figure 2 Overall survival (OS) for patients with NSCLC treated 34.1%, respectively. For patients treated with definitive with WBRT and concurrent chemoradiotherapy. thoracic therapy after brain metastases management with gammaknife stereotactic radiosurgery, Flannery et al. reported significantly better survival than those that did not receive definitive treatment (median OS, 26.4 vs. with a median survival of 10-12 months and 5-year sur- vival rates ranging from 10-25% [7,8,20,21]. 13.1 months). In our series, we reached a median survi- As improvements are made in the management of val of 31.8 months, the longest survival reported to date patients with brain metastases without extracranial dis- in patients with synchronous brain metastatic disease ease, the question arises of how to treat the primary treated with definitive chemoradiation to the primary. lung cancer. This is due to the fact that the main cause Unlike other studies, in our report, treatment delivered of death in patients with lung carcinoma treated aggres- to the brain, as well as systemic and local therapy, was sively for brain metastases is progression of the primary homogeneous among all patients included. cancer [13,22]. By applying American Joint Committee on Cancer In a recent review of the literature, Modi et al. identi- (AJCC) staging only to the primary site, Hu et al. reported that patients with thoracic stage I had a more fied 11 papers that addressed the issue of surgical resec- favorable outcome, with a median survival time of 25.6 tion of the primary tumor within the context of months (compared with 9.5 and 9.9 months for stages II metastatic brain lesions [23]. They found that median and III, respectively), and concluded that aggressive survival for curative intent groups (combined therapy treatment to the lung may be justified for newly diag- with or withoutadjuvanttreatment)rangedfrom19-27 nosedthoracicstageINSCLC with asolitarybrain months (mean, 23.12 ± 3.3 months) and 1-, 2-, and 5- metastasis [17]. Also, Louie et al. reported longer overall year OS reached 56-69%, 28-54%, and 11-24%, respec- survival for stage I/II disease of 14.7 months compared tively. The authors concluded that in the absence of with 7 months for patients with stage III NSCLC with mediastinal lymph node involvement, surgical resection synchronous solitary brain metastasis treated with cra- of NSCLC with complete resection of the brain metasta- niotomy and WBRT [16]. In our study, according to the sis improves prognosis. Furthermore, they described that univariate analysis, we found that patients with N0-N1 some features such as adenocarcinoma histology, low disease had a significantly better 3-year survival rate carcinoembryonic antigen (CEA) levels at presentation, response to preoperative chemotherapy before local compared with those with N2-N3 disease. Similar find- treatment, and high KPS score may have a positive ings have been reported in previous studies where the prognostic value. absence of mediastinal lymph node involvement (N2) is The benefit of surgical resection after induction ther- one of the most important survival determinants apy compared with definitive radiotherapy remains [15,27,28]. Accordingly, in patients with controlled brain uncertain and appears to be associated with an increase diseaseand earlylungdisease (N0-N1)amenableto in early surgery-associated mortality. The Intergroup resection, a conservative surgery of the primary tumor 0139 [24] and the EORTC 08941 [25] did not confirm a may be the best treatment alternative (segmentectomy or lobectomy). For patients who are not candidate for significant survival advantage for surgery following surgical resection, chemoradiatiation to the primary either neoadjuvant concurrent chemoradiotherapy or tumor should be considered. In Table 2, we condensed induction chemotherapy. Thus, we opted to treat our the studies that assessed radiation therapy or patients with NSCLC with brain metastases with Arrieta et al. Radiation Oncology 2011, 6:166 Page 5 of 7 http://www.ro-journal.com/content/6/1/166 Table 2 Series evaluating radiation therapy or chemoradiotherapy of lung cancer in NSCLC with brain metastasis Study Year Number of Number of Brain Median 1-year 2-year 5-year Prognostic factors patients brain treatment survival, survival survival survival metastases months rate (%) rate (%) rate (%) Chidel et al. 1999 Sx = 2 1Sx Overall: 6.9 12 (3-year) WBRT [13] Sx + RT = 3 WBRT Definitive tx: Aggressive thoracic RT = 8 STS 20.1 treatment Palliative = and No definitive 15 combination tx: 3.5 Moazami et 2002 Chemo/RT 42 pts: 1 Sx 5.2 22 10 - Younger age al.[31] =29 49 pts: > 1 WBRT Stage IIIA Sx = 59 Metachronous STS Lung resection brain lesions and ECOG combinations No extracranial mets Sx of brain mets STS Hu et al.[17] 2006 RT = 44 1Sx Overall: ~15 49.8 16.3 7.6 Thoracic stage I Chemo = STS Stage I: 25.6 23 Stage II: 9.5 Chemo/RT Stage III: 9.9 =13 Ampil et al. 2007 > 65 year 1 WBRT RT = 5 RT = 14 - - Sx of brain mets [26] RT = 22 STS No RT = 3 No RT = 11 No RT = 50 Sx p = 0.28 p= 0.28 and combinations Flannery et al. 2008 RT = 26 1 STS Overall: 18 Overall: 71.3 Overall: 34.1 Overall: 21 Definitive thoracic [18] Chemo/RT Definitive tx: RT: 34.6 therapy =9 26.4 No RT: 0 KPS Sx = 12 No definitive p < 0.0001 Preop tx: 13.1 Chemo + p < 0.0001 Sx = 5 Louie et al. 2009 Sx = 8 1 Sx + WBRT 7.8 - - - Lung surgery [16] Chemo = Stage I/II: Primary lung 24 14.7 treatment RT = 14 Stage III: 7 > 8 weeks after brain Sx Stage I/II disease Arrieta et al. 2010 Chemo- > 1 WBRT 31.8 71.1 60.2 3-year OS for N0-1 (present Chemo/RT was 60 vs. 24% for series) =30 N2-3 NSCLC: Non-small-cell lung cancer; Sx: Surgery; RT: Radiotherapy; WBRT: Whole-brain radiotherapy; STS: Stereotactic surgery; Comb: Combination; Mets: Metastasis/Metastases; Chemo: Chemotherapy; Chemo/RT: Chemo-radiotherapy; Preop: Pre-operative. a) Univariate analysis. chemoradiotherapy of the primary lung tumor in [18,30-32,34], adenocarcinoma subtype [14,28,32,35], patients with central nervous metastatic disease. location of primary tumor, site of brain metastases, and To our knowledge, this is the first time that patients low CEA levels [28,36]. with multiple synchronous brain metastases treated with Median survival in patients treated in this series is WBRT have been managed with aggressive therapy for remarkably long. One of the reasons might be that we primary tumor in chest with concurrent chemora- selected patients who presented with synchronous brain diotherapy, showing a very long OS. Among series that tumors and did not include those with metachronous evaluated surgery as local treatment for the thoracic dis- lesions, which may represent a better prognostic group. ease, several included patients with multiple brain In addition, we selected patients who did not progress metastases [12,28-32]. In none of these studies was the after induction chemotherapy to proceed with further number of brain lesions described as a factor that con- thoracic management, in order to ensure that patients ferred poor prognosis. with rapid progressive metastatic disease would not be Other prognostic factors associated with better out- submitted to a more aggressive management instead of comes with this definitive strategy after treatment to the a palliative approach. 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Fischer B, Lassen U, Mortensen J, Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, Ravn J, Clementsen P, Høgholm A, Larsen K, Rasmussen T, Keiding S, Dirksen A, Gerke O, Skov B, Steffensen I, Hansen H, Vilmann P, Jacobsen G, Backer V, Maltbaek N, Pedersen J, Madsen H, Nielsen H, Højgaard L: Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009, 361(1):32-9. doi:10.1186/1748-717X-6-166 Cite this article as: Arrieta et al.: Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiation Oncology 2011 6:166. 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Radiation Oncology – Springer Journals

Published: Nov 25, 2011

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