High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and Radiatio
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《临床肿瘤学》
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
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
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.
RESULTS
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
Fifty-three of 177 patients were alive at last follow-up. The median survival time from resection for all patients in this study was 21.0 months, and the 1-, 2-, and 3-year survival rates from resection were 71%, 49%, and 34%, respectively (Fig 1). Factors correlated with improved survival on univariate analysis were younger age, lower tumor stage at resection, nodal downstaging, and chemotherapy with a platinum-taxane combination (Table 2). Patients younger than 70 years of age had a 24.4-month median survival compared with 10.6 months for patients over 70 years old (P = .010). Tumor stage of T0 or T1 was associated with a 42% 3-year survival, compared with 28% in patients with T2–4 disease at resection (P < .001). Nodal downstaging was a highly significant predictor of survival in univariate analysis (P < .001). Patients with no residual tumor in any of the resected lymph node stations (N0) had a median survival of 39.9 months compared with 18.6 months for patients with residual nodal cancer. The use of a taxane in addition to platinum also correlated with favorable survival. Those patients who received a taxane-platinum combination had a median survival of 31.2 months compared with 18.0 months for patients who received platinum without a taxane (P = .007). Survival did not differ by squamous versus nonsquamous histology or by whether radiation was administered preoperatively, postoperatively, or both.
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
Because nodal downstaging was associated with improved OS, PFS, and decreased brain metastases, we sought to determine what factors were associated with nodal downstaging. The use of preoperative chemotherapy and radiation was strongly correlated with nodal downstaging compared with preoperative chemotherapy alone (P < .001). Thus, it is not surprising that the apparent effect of preoperative radiation on the rates of brain metastases and PFS does not remain significant in a multivariate model that adjusts simultaneously for the impacts of nodal status and histology.
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.
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
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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9. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673-680, 1994
10. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330:153-158, 1994
11. Rosell R, Gomez-Codina J, Camps C, et al: Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: A 7-year assessment of a randomized controlled trial. Lung Cancer 26:7-14, 1999
12. Depierre A, Milleron B, Moro-Sibilot D, et al: Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 20:247-253, 2002
13. Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer: Eastern Cooperative Oncology Group. N Engl J Med 343:1217-1222, 2000
14. Robnett TJ, Machtay M, Stevenson JP, et al: Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 19:1344-1349, 2001
15. Andre F, Grunenwald D, Pujol JL, et al: Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: Should prophylactic cranial irradiation be reconsidered Cancer 91:2394-2400, 2001
16. Bueno R, Richards WG, Swanson SJ, et al: Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 70:1826-1831, 2000
17. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530, 1992
18. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996
19. Machtay M, Seiferheld W, Komaki R, et al: Is prolonged survival possible for patients with supraclavicular node metastases in non-small cell lung cancer treated with chemoradiotherapy: Analysis of the Radiation Therapy Oncology Group experience. Int J Radiat Oncol Biol Phys 44:847-853, 1999
20. Komaki R, Scott C, Ettinger D, et al: Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92–04. Int J Radiat Oncol Biol Phys 38:149-155, 1997
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27. Russell AH, Pajak TE, Selim HM, et al: Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: Results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21:637-643, 1991
28. Umsawasdi T, Valdivieso M, Chen TT, et al: Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol 2:253-259, 1984
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Hematology-Oncology Unit, Department of Medicine, Massachusetts General Hospital
Division of Thoracic Surgery, Brigham and Women's Hospital
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
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.
RESULTS
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
Fifty-three of 177 patients were alive at last follow-up. The median survival time from resection for all patients in this study was 21.0 months, and the 1-, 2-, and 3-year survival rates from resection were 71%, 49%, and 34%, respectively (Fig 1). Factors correlated with improved survival on univariate analysis were younger age, lower tumor stage at resection, nodal downstaging, and chemotherapy with a platinum-taxane combination (Table 2). Patients younger than 70 years of age had a 24.4-month median survival compared with 10.6 months for patients over 70 years old (P = .010). Tumor stage of T0 or T1 was associated with a 42% 3-year survival, compared with 28% in patients with T2–4 disease at resection (P < .001). Nodal downstaging was a highly significant predictor of survival in univariate analysis (P < .001). Patients with no residual tumor in any of the resected lymph node stations (N0) had a median survival of 39.9 months compared with 18.6 months for patients with residual nodal cancer. The use of a taxane in addition to platinum also correlated with favorable survival. Those patients who received a taxane-platinum combination had a median survival of 31.2 months compared with 18.0 months for patients who received platinum without a taxane (P = .007). Survival did not differ by squamous versus nonsquamous histology or by whether radiation was administered preoperatively, postoperatively, or both.
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
Because nodal downstaging was associated with improved OS, PFS, and decreased brain metastases, we sought to determine what factors were associated with nodal downstaging. The use of preoperative chemotherapy and radiation was strongly correlated with nodal downstaging compared with preoperative chemotherapy alone (P < .001). Thus, it is not surprising that the apparent effect of preoperative radiation on the rates of brain metastases and PFS does not remain significant in a multivariate model that adjusts simultaneously for the impacts of nodal status and histology.
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.
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
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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