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Journal of Clinical Oncology, Vol 23, No 7 (March 1), 2005: pp. 1530-1537 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.123 High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and RadiationFrom the Departments of Radiation Oncology and Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center; Hematology-Oncology Unit, Department of Medicine, Massachusetts General Hospital; Division of Thoracic Surgery, Brigham and Women's Hospital; and Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA Address reprint requests to Raphael Bueno, MD, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; e-mail: rbueno{at}partners.org
PURPOSE: Lung cancer is the leading cause of cancer mortality in the United States. We sought to review our experience with surgically staged IIIA (N2) non–small-cell lung cancer (NSCLC), focusing on the patterns of failure in consecutively treated patients from 1988 to 2000. PATIENTS AND METHODS: The records of 177 patients were reviewed. Collected data included stage, histology, use of chemotherapy and radiation, initial and subsequent sites of failure, and survival. One hundred twenty-four patients have died; follow-up time is 35 months among the remaining patients. RESULTS: The median survival from the time of surgery was 21.0 months, with a 3-year overall survival (OS) of 34%. Nodal downstaging to N0 disease correlated with OS and progression-free survival (PFS; P < .001). The most common site of recurrence was the brain. Thirty-four percent of patients recurred in the brain as their first site of failure, and 40% of patients developed brain metastases at some point in their course. In patients with nonsquamous histology and residual nodal involvement after neoadjuvant therapy, the risk of brain metastases was 53% at 3 years. CONCLUSION: Patients treated with neoadjuvant therapy for N2-positive stage IIIA NSCLC enjoy an advantage in both OS and PFS if their lymph node status is downstaged to N0. Because brain metastases constitute the most common site of failure in these patients, future studies focusing on prophylaxis of brain metastases may improve the outcome in patients with stage IIIA NSCLC.
Lung cancer remains the leading cause of cancer mortality in both women and men in the United States. For 2004, the estimated incidence of lung cancer in the United States is 173,770 cases and 160,440 deaths.1 Approximately 80% of these cancers are non–small-cell lung cancer (NSCLC). The best current standard therapy for early-stage NSCLC is complete surgical resection of the involved lobe or lung. The 5-year survival rate after surgical resection is approximately 65% to 70% for stage I and 50% for stage II NSCLC.2,3 The International Adjuvant Lung Trial demonstrated a statistically significant survival benefit for adjuvant platinum-based chemotherapy in patients with stages I through III NSCLC.4 More recent prospective randomized trials from the Cancer and Leukemia Group B5 and the National Cancer Institute of Canada6 have demonstrated significant survival advantages to adjuvant chemotherapy for early-stage lung cancer. Cancer and Leukemia Group B trial 9633 demonstrated a benefit to carboplatin and paclitaxel in stage IB patients, and the National Cancer Institute of Canada trial JBR.10 obtained a similar result using vinorelbine and cisplatin in patients with stage IB to II disease. Approximately 40,000 patients per year present with locally advanced, nonmetastatic NSCLC (ie, stage III lung cancer). Stage IIIA has been defined since 1997 to include patients with potentially resectable primary tumors (T1-T3) and positive ipsilateral mediastinal (N2) lymph nodes, as well as patients with locally invasive T3 tumors with hilar or bronchopulmonary (N1) nodal involvement. Patients diagnosed with stage IIIA NSCLC fall into a fairly wide variety of subgroups; some subgroups have more favorable outcomes, as anticipated in patients with T3 N1 or microscopic N2 disease, and others have less favorable expected outcomes, such as those patients who present with bulky mediastinal adenopathy at multiple nodal stations.7 Stage IIIB NSCLC is defined by the presence of cancer in the contralateral mediastinal and/or supraclavicular lymph nodes (N3) or by the presence of an unresectable primary tumor (T4), regardless of the lymph node status. The recommended treatment for most patients with stage IIIB disease is chemotherapy combined with radiation therapy.8 The preferred treatment for patients with stage IIIA NSCLC is currently controversial and, to a great extent, depends on the experience of the care providers and the performance and cardiorespiratory status of the patients. Some centers advocate chemotherapy combined with full-dose radiation therapy without surgery, whereas other centers recommend surgery, alone or after neoadjuvant chemotherapy with or without concurrent radiation therapy. Surgery alone is curative in 10% to 40% of patients with stage IIIA NSCLC, depending on patient selection and the degree of lymph node involvement. Most9-11 but not all trials12 have suggested that preoperative induction chemotherapy can improve the survival compared with surgery alone. A large randomized intergroup trial failed to demonstrate a survival advantage when adjuvant cisplatin and etoposide were added to radiation compared with radiation alone for resected stage II and IIIA disease.13 Most studies of NSCLC demonstrate a stage-related incremental risk of distant metastases, particularly brain metastases. Robnett et al14 reported on the clinical outcomes of 150 patients treated from 1992 through 1998 with chemoradiation for NSCLC. This group included a small number of patients with stage II disease, with most patients diagnosed with stage IIIA or IIIB NSCLC. Forty-three percent of these patients (ie, those with stage II and nonbulky N2 IIIA disease) also underwent pulmonary resection. The crude and 2-year actuarial rates of brain metastases in this population were 19% and 30%, respectively, with the highest rate (42%) seen in patients with IIIB disease and nonsquamous histology. Similarly, Andre et al15 reported a high rate of brain metastases among a large cohort of patients diagnosed with stage IIIA (N2) NSCLC. Eighty-one patients treated with preoperative platinum-based combination chemotherapy were compared with a group of 186 patients treated with primary surgery during the same period. Some of these patients received postoperative radiation, but none received preoperative radiation. Chemotherapy was always cisplatin based and was administered in combination with vinblastine, vinorelbine, mitomycin, or etoposide; none of these patients received taxanes as a component of their chemotherapy. The crude rate of isolated brain metastases with a median follow-up of 52 months was 28% in patients with adenocarcinoma and 11% in patients with squamous cell carcinoma. Overall, 39% of patients developed brain metastases at some point during the follow-up interval. We recently reported our experience with 103 surgically staged and treated patients with biopsy-proven N2, stage IIIA NSCLC.16 In these patients, downstaging to N0 disease after neoadjuvant therapy was highly associated with improved cancer-free survival. We now extend these observations to a larger cohort of patients with a longer follow-up interval, and we conducted a more detailed analysis of the patterns of failure, with an emphasis on factors that correlate with the risk of brain metastases.
A retrospective chart review was conducted on surgically staged IIIA NSCLC patients who underwent anatomic lung resection by members of the Brigham and Women's Hospital Thoracic Surgery Division. From November 1988 through December 2000, 177 patients were identified who had N2 disease confirmed by mediastinoscopy or at thoracotomy and for whom a minimum of 6 months of follow-up data were available. Initially, 183 consecutively treated patients were identified; six were excluded from the analysis because of insufficient follow-up data. All but three patients were staged with mediastinoscopy before definitive surgery. The remaining three patients were found to have N2 disease at the time of surgery. All patients had negative pretreatment head computed tomography (CT) scans as part of their initial staging. Some of the patients were enrolled onto institutional or cooperative group trials. The majority of the patients received neoadjuvant treatment with chemotherapy, radiation, or both modalities. All of the patients who received preoperative therapy were restaged with a chest CT scan before thoracotomy to rule out disease progression or development of metastases. Many patients had adjuvant treatment as well (Table 1).
Long-term outcome was determined from hospital records and correspondence with referring physicians. Both the initial sites of recurrence and the subsequent sites of recurrence were documented. Because this study includes both patients who had pulmonary resection as initial therapy and those who had preoperative therapy after staging mediastinoscopy, follow-up was defined from the time of pulmonary resection. Outcome data are presented from the time of definitive surgery to avoid lead-time bias as a result of the guaranteed preoperative duration in favor of the neoadjuvant group. Patients with symptoms concerning for brain metastases were typically evaluated with a CT scan of the head; although in some cases, a magnetic resonance imaging scan was obtained in addition to or instead of a CT scan. In many cases, the identification of brain metastases was followed by CT scans of the chest and abdomen to evaluate for other sites of metastatic disease. Overall survival (OS), progression-free survival (PFS), and incidence of brain metastases were estimated by the Kaplan-Meier method. Patients who died without evidence of brain metastases were censored at their time of death in the analysis of brain recurrence. The log-rank test was used in the univariate analysis of potential prognostic factors. The variables considered were age, sex, histology, tumor size, nodal status, timing of radiation, and type of chemotherapy. The proportional hazards regression model was used for multivariate analysis to identify the factors with independent prognostic significance. The development of brain metastases was modeled as a time-varying covariate for estimating the associated risk of death. Fisher's exact test was used to determine the association of preoperative therapy with postoperative nodal status. In general, the P values are based on a two-sided hypothesis, except when indicated otherwise. The institutional review boards of the Brigham and Women's Hospital and Dana-Farber Cancer Institute approved this study.
There were 85 men and 92 women enrolled onto the study, with a median age of 60 years. For the 53 surviving patients, the median follow-up from the time of surgery was 34.8 months. For the purposes of analysis, the squamous cell carcinoma patients were considered as one group, and the remainder of patients (70%), who predominantly had adenocarcinomas, was considered nonsquamous (Table 1). The majority of surgical resections consisted of lobectomies (68%) or pneumonectomies (23%). The postoperative mortality rate was 3%, which was defined as death within 30 days of surgery. All but five patients had preoperative and/or postoperative chemotherapy, radiation, or both. One patient chose observation rather than the recommended postoperative chemotherapy, and the four other patients were not considered candidates for adjuvant chemotherapy or radiation because of poor performance status after surgery. Eighty-seven percent of patients received chemotherapy, and virtually all chemotherapy regimens included platinum. Roughly half of the patients who received chemotherapy were treated with a taxane (in most cases paclitaxel) in addition to platinum (Table 1). In summary, 69% of patients received preoperative chemotherapy (with or without radiation), 5% received postoperative chemotherapy, and 14% received both. Twenty-nine percent of patients received preoperative radiation, 46% received postoperative radiation, and 10% received both. Seventy-five percent of patients received both chemotherapy and chest/mediastinal radiation therapy at some point in the initial management of their disease.
Univariate Analysis
The factors that predicted for PFS by univariate analysis were similar to those that predicted for OS (ie, downstaging of tumor and nodal stage to N0 and use of taxane-platinum combination chemotherapy regimens; data not shown). The use of preoperative radiation showed a trend toward improved PFS (P = .096). Although age less than 70 years correlated with improved OS, there was not a statistically significant association between younger age and improved PFS. The local control rate in this cohort of stage IIIA patients predominantly receiving trimodality therapy was 86%. Despite excellent local control, most patients in our series developed distant metastatic disease. The most common site of recurrence was the brain, with 34% of patients developing brain metastases as the initial site of recurrence and 40% of patients developing brain metastases at some point during their follow-up (Fig 2, Tables 3 and 4). Development of brain metastases was associated with a four-fold increase in the risk of death (P < .001). The median survival time after development of brain metastases was 7.0 months.
Univariate analysis showed more patients with brain metastases among patients with nonsquamous than squamous histology (44% v 32%, respectively, at 3 years; P = .037; Fig 3). Treatment with a taxane-platinum–containing regimen was associated with a lower risk of brain metastases than other platinum-based chemotherapy regimens (25% v 52%, respectively, at 3 years; P = .044). Preoperative chest and mediastinal radiation, with or without a postoperative boost, showed a trend toward a lower risk of brain metastases than postoperative radiation (27% v 46%, respectively; P = .062). Although T0–1 at resection correlated with improved survival, T stage did not correlate with the risk of developing brain metastases. Downstaging to N0 status by neoadjuvant treatment was, however, highly correlated with a decreased rate of brain metastases (27% for N0 patients at 3 years v 49% in patients with persistent nodal disease; P = .025). Patients with residual nodal disease and nonsquamous histology had a 53% incidence of brain metastases at 3 years (Table 5 and Fig 4).
Univariate analysis of factors associated with brain metastases as the first site of recurrence revealed that nodal downstaging and use of a taxane remained statistically significant favorable factors (Table 4). In patients with nonsquamous histology compared with patients with squamous histology, there was a trend toward increased risk of brain metastases as the first site of failure (38% v 26%, respectively, at 3 years; P = .076) and a trend toward a reduced risk for brain metastases with preoperative radiation (25% v 39%, respectively, at 3 years; P = .080).
Multivariate Analysis The incidence of any recurrence in the brain is increased independently by the presence of residual nodal disease (P = .058) and the diagnosis of nonsquamous histology (P = .026). The respective estimates of 1.84 and 2.14 for the hazard ratio suggest that each of these adverse prognostic factors confers patients with about twice the risk of developing brain metastases. The same factors also apply to the risk of brain metastases as the first site of first recurrence, namely nodal status (P = .033) and histology (P = .057). The risk of initial recurrence in the brain is also approximately doubled by either persistent nodal disease or nonsquamous histology based on the estimated hazard ratios of 2.17 and 1.99, respectively. Similarly, multivariate analysis identifies nodal status (P = .002) as a significant prognostic factor for PFS but not the use of radiation or taxanes (again with about twice the risk associated with residual nodal disease indicated by a hazard ratio estimate of 1.92). Although histology (P = .020) and tumor size (P = .032) are also independently significant by statistical criteria, the respective estimates of 1.57 and 1.52 for the hazard ratio suggest that a nonsquamous histology and a larger tumor size (T2–4) do not increase the risk of progression-free failure by as much as residual nodal disease.
This retrospective review describes one of the largest reported series of patients with stage IIIA (N2) NSCLC treated with multimodality therapy, including resection of the primary lesion and lymph node dissection. All patients in this study were surgically staged, and the overwhelming majority of these patients were staged with mediastinoscopy and biopsy of multiple nodal stations before thoracotomy. Although this study is limited by factors inherent to all retrospective studies, such as the potential for selection bias, the high follow-up rate of 177 of 183 consecutively treated patients should help assure that the patients studied are highly representative of the stage IIIA NSCLC patients treated surgically at our institution during the years of the study. The use of chemotherapy has evolved during the time period reviewed in this study. Most chemotherapy regimens introduced after 1980 included cisplatin and, more recently, carboplatin. We have found a 46% 3-year survival rate in patients receiving a taxane plus platinum compared with 28% in patients who received platinum-based chemotherapy without a taxane (P = .007). Although this difference is statistically significant, we cannot draw any conclusions about the superiority of taxanes to other types of chemotherapy because of the retrospective, nonrandomized nature of this study and because the more recently treated patients were more likely to have received a taxane. Thus, the improved results may be related to improved surgical or postoperative care, improved staging techniques, improved radiation techniques, such as CT planning, or other unknown variables that may have led to improved patient outcome during the 12 years reviewed in this study. The aggressive management of the primary pulmonary disease with trimodality therapy resulted in a low rate of locoregional recurrence of 14%. Although this result is better than the rate achieved with chemotherapy and radiation therapy alone, most trials of definitive chemotherapy and radiation are limited to patients with unresectable disease and often combine patients with stage IIIA and IIIB disease.8,17,18 Nevertheless, the 3-year survival rate in our study was only 34% because of the high rate of distant metastases, particularly in the brain. Forty percent of the patients in this study had developed brain metastases by 3 years of follow-up (34% as the first site of failure). This finding is comparable to other studies.15,19-23 Also consistent with prior reports, we have shown that there is an increased risk of brain metastases with nonsquamous histology.14,15,24 In univariate analysis, both nodal downstaging after induction therapy and the addition of a taxane to platinum-based chemotherapy are associated with a decreased rate of brain metastases. However, multivariable analysis indicates that the effect of taxanes on reducing the risk of brain metastases is mediated by nodal downstaging. Robnett et al14 reported that delay of radiation, either by surgery as the initial treatment or by induction chemotherapy preceding chemoradiotherapy, was associated with a higher incidence of brain metastases. Our data are consistent with this finding, in that preoperative radiation is associated with a trend toward a lower risk of brain metastases than postoperative radiation (Table 3). In small-cell lung cancer, where the incidence of brain metastases is higher than in NSCLC, a meta-analysis of seven randomized trials of prophylactic cranial irradiation (PCI) suggested an improvement in both the rate of brain metastases and in OS.25 Several trials of PCI in NSCLC have shown a decrease in development of brain metastases but not a survival advantage.26-28 The hypothesis that PCI may be of benefit in NSCLC remains worth testing, particularly because several studies have suggested that at least half of patients who develop brain metastases die of symptomatic intracranial tumor progression.29-31 Although these are relatively old studies, brain metastases remain a major cause of morbidity and mortality in patients with NSCLC. The Radiation Therapy Oncology Group is currently leading a phase III randomized trial of PCI for stage III NSCLC. In our study, we identified a subset of patients with NSCLC (ie, patients with residual nodal disease after neoadjuvant therapy and nonsquamous histology) who are at particularly high risk for the development of brain metastases. Our data lend support to prior studies that suggest that brain metastases are a sufficiently common and serious clinical problem to warrant a large randomized trial of PCI in resected stage IIIA patients. Our results confirm other reports that metastatic disease, particularly brain metastases, is a much more significant problem than local failure in patients who are treated with surgical resection. Therefore, improving survival will require improved systemic therapies, of which PCI may be a component, because, at present, systemic chemotherapy has been shown to decrease the risk of extracranial metastases but to have little effect on brain metastases.24 In summary, we demonstrate that patients who are treated with neoadjuvant therapy for N2-positive stage IIIA NSCLC enjoy a survival benefit if their lymph node status is downstaged to N0. Furthermore, brain metastases constitute the most common site of failure in these patients and, in particular, in the nonresponders with nonsquamous histology.
The authors have indicated no potential conflicts of interest.
Supported in part by a grant from the Lowe Thoracic Oncology Program at the Dana-Farber Cancer Institute (R.B.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
