Ann Thorac Surg 2003;75:1745-1751
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Survival and prognostic factors of surgically resected T4 non-small cell lung cancer
Toshihiro Osaki, MDa*,
Kenji Sugio, MDa,
Takeshi Hanagiri, MDa,
Mitsuhiro Takenoyama, MDa,
Toshihiro Yamashita, MDa,
Masakazu Sugaya, MDa,
Manabu Yasuda, MDa,
Kosei Yasumoto, MDa
a Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan
Accepted for publication December 31, 2002.
* Address reprint requests to Dr Osaki, Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
e-mail: t-osaki{at}med.uoeh-u.ac.jp
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Abstract
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BACKGROUND: Category T4 nonsmall cell lung cancer (NSCLC) encompasses heterogenous subgroups. We retrospectively analyzed the survival of patients with surgically resected T4 NSCLC to evaluate the evidence for prognostic implications according to the subgroups of T4 category, nodal status, and resection completeness.
METHODS: Seventy-six patients with T4N0-2M0 NSCLC were divided into three subgroups within the T4 category: 24 patients with the tumor invading the mediastinal organs (mediastinal group), 16 with a malignant pleural effusion or dissemination (pleural group), and 36 with satellite tumor nodules within the ipsilateral primary tumor lobe (satellite group). Complete resection was possible in 47 patients (61.8%). The pathologic N statuses were N0 in 28, N1 in 13, and N2 in 35 patients.
RESULTS: The overall survival of the 76 patients was 19.1% at 5 years. The overall 5-year survivals according to the three subgroups of the T4 category were as follows: mediastinal group, 18.2%; pleural group, 0%; and satellite group, 26.7% (mediastinal/satellite versus pleural, p = 0.037). Factors significantly influencing the overall 5-year survival were the pathologic N status (N2 versus N0-1, p = 0.022) and the completeness of resection (complete versus incomplete, p = 0.0001). A multivariate survival analysis demonstrated that the pathologic N status and the completeness of resection were significant independent predictors of a poorer prognosis even after adjusting for the subgroup of the T4 category.
CONCLUSIONS: Resectable T4N0-1 NSCLC that is not due to pleural disease deserves consideration of aggressive surgical resection with expected 5-year survival of about 20%.
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Introduction
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Lung cancer is the leading cause of cancer death in North America and it became the most common cause of cancer death among Japanese in 1998. Lung cancer is also an aggressive carcinoma with a poor outcome. In 1997 Mountain [1] refined the TNM staging system of lung cancer and it is widely used as a guide for estimating prognosis and selecting treatment modality. In this staging system the T4 category includes a tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or a tumor with a malignant pleural or pericardial effusion, or with satellite tumor nodules within the ipsilateral primary tumor lobe. Thus patients with T4 nonsmall cell lung cancer (NSCLC) belong to a heterogenous subgroup of the T4 category. Against this background the staging and treatment modalities, including the indications for surgery for T4 NSCLC, remain somewhat ambiguous. Considerable differences of opinion exist regarding surgery versus other treatment modalities for these patients. In addition it is suggested that T4 tumors are biologically very different from N3 tumors among stage IIIB disease and some of the local T4 diseases are suitable for aggressive surgical resection. Selectivity is therefore very important whenever surgical resection is offered to these patients.
In this study we retrospectively analyzed the survival of patients with resected T4 NSCLC according to subgroups of the T4 category: patients with tumor invading the mediastinal organs, those with a malignant pleural effusion or dissemination, and those with satellite tumor nodules within the ipsilateral primary tumor lobe. We also analyzed the prognostic impact of the nodal status and the completeness of resection. The main objective of this study was to propose subgroups of T4 NSCLC as a guide for selecting patients who may benefit from surgical resection.
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Patients and methods
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Patients
Between September 1979 and December 1999, 772 consecutive patients with N0-2M0 NSCLC underwent surgical resections at the Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Japan. Among them 76 patients were T4N0-2M0 NSCLC. The patients were divided into three subgroupswithin the T4 category: 24 patients with tumor invading the mediastinal organs (mediastinal group), 16 with a malignant pleural effusion or dissemination (pleural group), and 36 with satellite tumor nodules within the ipsilateral primary tumor lobe (satellite group). Intrapulmonary metastasis was defined as a parenchymatous satellite lesion that was histologically identical to the main tumor and lacked microscopic features suggesting a primary tumor. Patients with synchronous multiple primary lung cancers were excluded, according to the criteria proposed by Martini and Melamed [2]. However patients without lymph node involvement were included in the pulmonary metastasis category. Fifteen of the 16 patients within the pleural group were found at thoracotomy to have a malignant pleural effusion or dissemination. The histopathologic features of the surgical specimens were classified according to the World Health Organization criteria [3] and the tumor-node-metastasis (TNM) staging system [1]. Before surgery, all patients underwent various diagnostic procedures, including brain computed tomography (CT) scan, body CT scan, and a bone scintigram without mediastinoscopy. The characteristics of the 76 patients are summarized in Table 1. The patients ranged in age from 37 to 82 years (median, 65.1 yrs) and comprised 59 men and 17 women. The histological types were 45 adenocarcinomas, 27 squamous cell carcinomas, 3 large cell carcinomas, and 1 adenosquamous carcinoma. Postoperative pathologic N factors were N0 in 28 patients, N1 in 13 patients, and N2 in 35 patients.
Recurrence, survival, and statistical analysis
We defined a locoregional recurrence as disease in the hilum and mediastinum, the supraclavicular node, the surgical margin, or a malignant pleural or pericardial effusion; and a distant recurrence as disease in the ipsilateral lung or outside the ipsilateral thorax. The associations between the clinicopathologic characteristics and the three subgroups within the T4 category were analyzed by the use of a contingency table. Statistical significance was evaluated using the 
2 test. A univariate survival analysis for each prognostic variable on overall survival was estimated according to the Kaplan-Meier method [4]. The terminal event was death attributable to cancer or noncancer causes. The statistical significance of the differences in survival distribution among the prognostic groups was evaluated by the log-rank test [5]. The Cox proportional hazards model was applied to the multivariate survival analysis [6]. The statistical difference was considered to be significant if the p value was below 0.05. Data were analyzed with the use of the Abacus Concepts, Survival Tools for StatView program (Abacus Concepts, Berkeley, CA).
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Results
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Distribution of patients
There were no significant differences in sex, age, or pathologic N status among the three groups. With respect to the histologic type the ratio of patients with squamous cell carcinoma showed a significant increase in the mediastinal group as compared with the pleural group (p = 0.025; Table 1).
Preoperative therapy
Of the 24 patients in the mediastinal group 10 patients were offered bronchial arterial infusion (BAI) consisting of cis-diamminedichloroplatinum ([CDDP] 50 to 100 mg/m2) as an induction chemotherapy before surgery (induction BAI). One patient received radiotherapy in addition to BAI. One patient received radiotherapy and 1 patient received systemic chemotherapy. One patient of the satellite group received systemic chemotherapy because his preoperative histologic diagnosis of the biopsy specimen was small cell lung cancer. No patients in the pleural group received preoperative therapies.
Surgery
Surgical procedures and resectability are listed in Table 2.
Of the 24 patients in the mediastinal group the complete resection of all of the primary site and the lymph nodes with the combined resection of the adjacent organs was possible in 14 patients. Of the 16 patients in the pleural group simple standard pulmonary resection without systematic mediastinal lymphadenectomy was performed in 12 patients, extrapleural pneumonectomy was achieved in 1 patient who was found preoperatively to have a malignant pleural effusion, and pulmonary resection with partial resection of the disseminated pleura was carried out in 3 patients. Of the 36 patients in the satellite group 3 patients underwent incomplete resections because of surgically unresectable remnant tumors of the chest wall. As a result among the 76 patients with T4 NSCLC, complete resection was possible in 47 (61.8%).
Postoperative therapy
Among the 24 patients of the mediastinal group 6 patients did not receive postoperative adjuvant therapy. Eleven patients received thoracic radiotherapy, 4 patients received systemic chemotherapy, and 3 patients received both therapies. Among the 16 patients of the pleural group 4 patients did not receive postoperative adjuvant therapy. Ten patients received intrapleural chemotherapy; among them 6 also received systemic chemotherapy and 1 also received radiotherapy. Two patients received systemic chemotherapy alone. Among the 36 patients of the satellite group 21 patients did not receive postoperative adjuvant therapy. Thirteen patients received systemic chemotherapy, 1 patient received thoracic radiotherapy, and 1 patient received both therapies.
Recurrence and survival
The mean observation period after the operation was 27.4 months (range, 0.3 to 164 ms). Two deaths occurred within 30 days after operation in 76 patients, with a 30-day operative mortality of 2.6%. Eighteen of 47 patients with complete resection had recurrences: 16 patients had a distant recurrence and 2 had a locoregional recurrence. In 4 patients detailed data for recurrences was not available. The overall survival of the 76 patients with T4 disease was 29.3% at 3 years and 19.1% at 5 years, with 14.6 months of median survival time (Fig 1).
The overall 5-year survivals according to the three subgroups within the T4 category were as follows: the mediastinal group, 18.2%; the pleural group, 0%; and the satellite group, 26.7%. There was a borderline significance among the three groups (p = 0.056); especially between two subgroups, the mediastinal/satellite group versus the pleural group, the survival difference was significant (p = 0.037; Fig 2).
Among the 16 patients of the pleural group 12 patients died within 2 years after the operation and the median survival time was 8.5 months. To estimate the contribution of the invaded organs to the prognosis we compared the survivals of the patients within the mediastinal group according to the invaded organ (Table 3). Patients with different invaded organs had different prognoses. Among patients with the tumors invading the esophagus, vertebral body, and superior vena cava, there were no 1-year survivors.
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Fig 1. Survival curve of the 76 patients with resected T4 non-small cell lung cancer. Three-year survival was 29.3%; 5-year survival was 19.1%; median survival time was 14.6 months. Number of patients at risk was 45 at 1 year after operation, 24 at 2 years, 15 at 3 years, 14 at 4 years, and 9 at 5 years.
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Fig 2. Survival curves of patients with resected T4 nonsmall cell lung cancer according to T4 subgroup. Among the three groups, p = 0.056; between the mediastinal/satellite group versus the pleural group, p = 0.037. Five-year survivals for the satellite group (heavy line; n = 36), the mediastinal group (light line; n = 24), and the pleural group (dashed line; n = 16) were 26.7%, 18.2%, and 0%, respectively. Median survival times for the three groups, respectively, were 17.3 months, 11.4 months, and 8.5 months. Number of satellite group patients at risk was 25 at 1 year after operation, 14 at 2 years, 10 at 3 years, 9 at 4 years, and 6 at 5 years. Number of mediastinal group patients at risk was 12 at 1 year after operation, 8 at 2 years, 4 at 3 years, 4 at 4 years, and 3 at 5 years. Number of pleural group patients at risk was 8 at 1 year after operation, 2 at 2 years, 1 at 3 years, 1 at 4 years, and 0 at 5 years.
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We also analyzed the survivals of patients with T4 disease according to the pathologic N status (N0-1 versus N2) and the completeness of resection (complete versus incomplete). The prognosis of patients with N2 disease (5-year survival, 10.9%) was poorer than that for those with N0-1 disease (5-year survival, 26.6%; p = 0.022; Fig 3).
The prognosis of patients with incompletely resected T4 disease (5-year survival, 0%) was poorer than that for those with completely resected T4 disease (5-year survival, 29.8%; p = 0.0001; Fig 4).
A Cox multivariate survival analysis demonstrated that the N status and the completeness of resection were significant independent predictors of a poorer prognosis even after adjusting for the subgroup of the T4 category (p = 0.024 and relative risk = 1.85 for N status, 0.0002 and 3.91 for the completeness of resection, respectively; Table 4).
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Fig 3. Survival curves of patients with pathologic N0-1 (heavy line; n = 41) and N2 (light line; n = 35) status (p = 0.022). Five-year survival was 26.6% for N0-1 patients and 10.9% for N2 patients; median survival time was 26.3 months for N0-1 patients and 13.7 months for N2 patients. Number of N0-1 patients at risk was 26 at 1 year after operation, 17 at 2 years, 12 at 3 years, 11 at 4 years, and 7 at 5 years. Number of N2 patients at risk was 19 at 1 year after operation, 7 at 2 years, 3 at 3 years, 3 at 4 years, and 2 at 5 years.
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Fig 4. Survival curves of patients with complete (heavy line; n = 47) and incomplete (light line; n = 29) resection (p = 0.0001). Five-year survival was 29.8% for complete resection and 0% for incomplete resection; median survival time was 27.3 months for complete and 8.9 months for incomplete resection. Number of complete resection patients at risk was 33 at 1 year after operation, 21 at 2 years, 14 at 3 years, 13 at 4 years, and 9 at 5 years. Number of incomplete resection patients at risk was 12 at 1 year after operation, 3 at 2 years, 1 at 3 years, 1 at 4 years, and 0 at 5 years.
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Table 4. Multivariate Cox Regression Analysis of Overall Survival Including T4 Subgroup, Pathologic N Status, and Completeness of Resection
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Comment
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Stage IIIB NSCLC is usually defined as an unresectable disease; however there may be a different biologic behavior in patients with local T4 disease and in those with N2 or N3 nodal disease within the stage classification as IIIB. In this study the patients with resected T4 NSCLC belonged to some heterogenous subgroups according to their survival analyses. The factors that were found to possibly affect survival were the completeness of resection and the lymph node status.
Variations exist in the surgical results for patients with tumor invading the adjacent organs [7]. The role of extended resection for the invaded adjacent organs in the T4 groups is not as clearly established as in the T3 group of patients with NSCLC. The largest surgical experience with T4 NSCLC contains tumors involving the carina. Various reports [8–10] have described tracheal sleeve pneumonectomy and pulmonary resection with carinal resection and reconstruction. In our experience the T4 patients with different invaded organs had different prognoses. Among the patients with tumors invading the superior vena cava, esophagus, and vertebral body there were no 1-year survivors. In contrast among the patients with tumors invading the trachea and pulmonary vein/artery in the inside of pericardium, some were alive in the long term. In T4 disease with the primary tumor invading the mediastinal organs, selected patients may benefit from extended surgery with long-term survival.
Induction chemotherapy for patients with locally advanced NSCLC offers several potential advantages including (1) early control of micrometastasis, (2) reduction in primary tumor size, and (3) patient acceptance and compliance (versus postoperative adjuvant chemotherapy). Some prospective randomized trials have compared primary surgery with induction cisplatin-based chemotherapy and surgery in N2 stage IIIA NSCLC, indicating a survival advantage for the chemotherapy-treated patients [11, 12]. However different biologic behaviors may exist in patients with local T4 disease and in those with N2 or N3 nodal disease. We performed induction BAI chemotherapy before surgery for the 10 patients with tumors invading the mediastinal organs. Bronchial arterial infusion is not a relatively new therapy [13,14]; however Watanabe and associates [15] reported that BAI therapy should be reappraised as a preoperative adjuvant therapy for advanced lung cancer especially in central type stages IIIA and IIIB because its histopathologic effect was observed to have a high response (57.7% to 92.2%). Induction BAI and surgery for patients with T4 NSCLC are well tolerated. Neither treatment-related serious complications nor postoperative death occurred during hospitalization. As presented previously [16], induction BAI is timesaving, safe, and produces successful locoregional control; however a larger number of patients with a longer follow-up period are still needed to truly assess its clinical usefulness.
All in all the prognosis of patients with pleural dissemination and malignant effusion is dismal and at the present time the appropriate treatment has not been found. The role of surgery, including pleuropneumonectomy, in the management of lung cancer with pleural dissemination and malignant effusion is controversial. Shimizu and coworkers[17] reported that the 5-year survival rate for the 14 patients who underwent resection of the primary tumor plus parietal pleurectomy of disseminated pleura was 35.5%, a significantly better outcome as compared with those who underwent pleuropneumonectomy, indicating that local excision plus pleurectomy for patients with pleural dissemination is justified. However a study with a larger number of patients is still needed to truly assess the role of surgery for patients within this category. In our experience 12 of 16 patients in this group died within 2 years after the operation. Three patients who underwent partial resection of the disseminated pleura and 1 patient who received an extrapleural pneumonectomy also died within 2 years after the operation. We have tried the pulmonary resection of the primary tumor lobe as a palliative treatment for patients who were found at thoracotomy to have a malignant pleural effusion or dissemination; however the palliative surgery for patients in this category is not justified according to our results. Many intrapleural therapeutic approaches for carcinomatous pleuritis found at thoracotomy have been developed. Intrapleural perfusion hyperthermochemotherapy [18] and hypotonic cisplatin treatment [19] seem to have considerable value as adjuvant therapies for patients with pleural dissemination and effusion after the resection of the primary tumor.
Under the new staging system if the lobe contains two or more satellite tumor nodules within the same lung, this disease (PM1) is categorized as a T4 disease. The staging of satellite lesions within the same lobe of the primary tumor as T4 disease is controversial. Yano and associates [20] reported that if all PM1 cases were included in T4 disease according to the new staging system, then it may elevate the survival rate of T4 higher than that of T4 by the former staging system. The most arguable point of the T4 staging system is whether a satellite lesion in the primary tumor lobe is an intrapulmonary metastasis from the primary cancer or represents double primary lung cancers. It is difficult to determine whether satellite lesions are either metastases from the primary tumor or synchronous primary lung cancers. To assess whether a satellite lesion in the primary tumor lobe is an intrapulmonary metastasis from the primary cancer (PM1) or represents double primary lung cancers we examined and recently reported the p53 genetic differentiation between a satellite lesion and a primary lesion [21]. We examined 16 of 37 patients with PM1 for mutations of the p53 gene occurring in exons 5 through 8 by the fluorescence-based polymerase chain reaction single-strand conformation polymorphism. Seven of the 16 patients analyzed had at least one p53 mutation in their tumors. The mutational status of the p53 gene was discordant in 5 patients, suggesting that they had double primary lung cancers. The mutational status including DNA sequencing of the p53 gene was concordant in 2 patients, suggesting that the lesions were intrapulmonary metastases.
Martini and colleagues [22] reported that complete resection was possible in only 18% (8 of 44) of T4 tumors with mediastinal invasion that were selected for operation. Incomplete resection of NSCLC with rare exceptions does not result in long-term survival. Among our patients the survival of those with incomplete resections was significantly poorer than that of patients with complete resections. The accurate assessment of whether a complete resection is possible by preoperative clinical examinations or intraoperative findings is important to yield the survival benefits from surgery for T4 NSCLC. The prognostic and diagnostic implications of intraoperative pleural lavage cytology for the patients with no pleural effusion are still controversial; however Okada and associates [23] reported that the prognosis of the patients with positive lavage findings was as poor as that of patients with stage IIIB disease and that of patients with malignant effusion. This method may provide an advantage in the intraoperative assessment of occult pleural dissemination.
Considerable controversy exists regarding surgical treatment for patients with N2 disease. N2 disease, as in the cases of incomplete resection, is the most powerful negative prognostic factor. Among the patients with T4 NSCLC, N2 disease had an adverse impact on the overall survival. Vansteenkiste and coworkers [24] reported that mediastinoscopy-negative N2 cases had a significantly better prognosis than mediastinoscopy-positive N2 cases. Given the poor results of patients resected for T4N2 NSCLC, mediastinoscopy is a critical preoperative assessment in order to exclude patients with occult N2 disease who have negligible benefit from aggressive surgical therapy.
In conclusion patients with T4 NSCLC belong to a heterogenous subgroup according to their survival analyses, suggesting different therapeutic approaches according to the subgroup profile. Resectable T4N0-1 NSCLC that is not due to pleural disease deserves consideration of aggressive surgical resection with expected 5-year survival of about 20%.
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References
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Abstract
Introduction
