Eur J Cardiothorac Surg 2001;20:344-349
© 2001 Elsevier Science NL
Risk analysis and long-term survival in patients undergoing resection of T4 lung cancer
Alain Bernard,
Olivier Bouchot,
Olivier Hagry,
Jean Pierre Favre
Service de Chirurgie Thoracique, Hôpital Universitaire, Dijon, France
Received 30 November 2000;
received in revised form 1 May 2001;
accepted 3 May 2001.
Corresponding author. Service de Chirurgie Thoracique, Hôpital du Bocage, Boulevard de Lattre de Tassigny, 21034 Dijon Cedex, France. Tel.: +33-3-8029-3747; fax: +33-3-8029-3591
e-mail: alain.bernard{at}chu-dijon.fr
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Abstract
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Objective: The aim of this study is to identify the risk group of patients with T4 lung cancer who could more likely benefit from surgical resection. Methods: Between January 1, 1990, and December 31, 1998, 77 patients underwent pulmonary resection for T4 lung cancer: lobectomy (n=20), bilobectomy (n=4) and pneumonectomy (n=53). The T4 sites of mediastinal involvement were: Intrapericardiac portions of the pulmonary artery (n=30), left atrium (n=19), aorta (n=8), superior vena cava (n=8), carina (n=7), the esophagus (n=8) and the vertebral body (n=6). Ten patients had multiple neoplastic nodules in the same lobe of the lung. Results: Overall survival rates at 1, 2 and 3 years were 46, 31 and 21%, respectively. Factors adversely affecting survival with univariate analysis included the localization of tumours in the lower lobe (P=0.04) and both the involvement of superior and inferior mediastinal lymph nodes (P=0.03). Multivariate analysis included two factors adversely affecting survival: the location of the primary tumour and the nodal stations involved. Regression tree analysis classified the patients into low-risk group (primary tumour in upper lobe or in main stem bronchus and pN0 or pN1 or superior or inferior mediastinal nodes involved), intermediate-risk group (primary tumour in upper lobe or in main stem bronchus and both superior and inferior mediastinal nodes involved, primary tumour in inferior lobe and pN0 or pN1 or inferior mediastinal nodes involved) and high-risk group (primary tumour in inferior lobe and both superior and inferior nodes involved). The 3-year survival rates were 36% for the low-risk group, 4% for the intermediate-risk group and 0% for the high-risk group (P=0.006). Conclusions: In patients with T4 lung cancer, the surgery can justify itself for tumours in the upper lobe or in the main stem bronchus and with pN0 or pN1.
Key Words: T4 lung cancer • Surgery • Long-term survival
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1. Introduction
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Primary tumours invading adjacent organs (T4) are often considered unresectable by most surgeons, this is due to the fact that patients with tumours invading the mediastinum generally do poorly in response to surgical resection as shown by Naruke et al. [1] who reported a 5.6% survival among resected patients with postoperative stage IIIb tumours. This stage of disease included patients with N3, for whom no long-term resected survivor has been reported [2]. Complete surgical resection is not always possible because these T4 tumours invade major mediastinal structures. However, these extended resections are associated with high mortality and morbidity rate [2]. These observations explain the existing differences in opinion regarding resection as the primary treatment for patients with T4 tumours.
Conversely, certain T4 tumours may be curable by complete surgical resection, which could improve the survival rate of patients in relation to chemotherapy and radiotherapy. For most pulmonary physicians and oncologists, the association of chemotherapy and radiotherapy constitutes reference treatment for lung cancer invading the mediastinal structure.
In the current review, we analyzed the results of surgical treatment in patients with non-small cell lung cancer invading the mediastinum by direct extension (T4) or multiple neoplastic nodules in the same lobe of the lung (T4). The aim of this study is to identify the risk group of patients with T4 lung cancer who would more likely benefit from surgical resection.
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2. Patients and methods
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Between January 1, 1990, and December 31, 1998, 77 patients who underwent pulmonary resection, had advanced non-small cell lung cancer classified as stage T4 tumour. The mean age of patients was 60 years (range 32–78 years). There were 68 men and nine women. The type of pulmonary resection was lobectomy in 20 patients, bilobectomy in four patients and pneumonectomy in 53 patients. The cell type was squamous cell carcinoma in 46 patients, adenocarcinoma in 16 patients, and large cell carcinoma in 15 patients (Table 1).
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Table 1. Patient, tumour and treatment characteristics in patients with lung resection of T4 non-small cell lung carcinoma
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The primary tumour was in the right upper lobe in 19 patients, in the right lower or middle lobe in 18 patients, in the left upper lobe in 26 patients, in the left lower lobe in seven patients and in the main stem bronchus in seven patients (Table 1). The T4 sites of mediastinal involvement were the large vessels (intrapericardiac portions of the right or left pulmonary arteries (n=30), left atrium (n=19), aorta (n=8) and superior vena cava (n=8)). The primary tumour invaded the carina in seven patients, the esophagus in eight patients, and the vertebral body in six patients. Ten patients were classified as T4 because multiple neoplasic nodules existed in the same lobe of the lung (Table 1). In three patients, cardiopulmonary bypass was needed in the resect ostium of the left pulmonary artery and the defect of the main pulmonary trunk was covered with a pericardial patch. In 19 patients who underwent left atrium resection, the defect of the left atrium was sutured directly using vascular clamps, without cardiopulmonary bypass. In eight patients with the primary tumour invading the thoracic aorta, only the adventitia was resected. Four of these eight patients underwent a partial resection of the superior vena cava with a side clamp and direct suture of the defect. In two patients, the superior vena cava was replaced with a polytetrafluoroethylene (PTFE) bypass graft (W.L. Gore & Associates) between the brachiocephalic vein and the right atrium. In two patients, partial resection of superior vena cava was performed, and the defect was covered with a PTFE patch (W.L. Gore & Associates). The resection of the oesophagus was limited to muscle wall in eight patients. In six patients, resection of the vertebral body was limited to fascia. In 17 patients (22%), the resection was judged incomplete because the pathological margin was positive with microscopic residual tumour (Table 1).
In general complete mediastinal lymph node dissection was performed, with complete removal of the high paratracheal, mid–low paratracheal, subcarinal, paraoesophageal and inferior pulmonary ligament lymph nodes. Aortic and subaortic lymph nodes were dissected completely for left-sided tumours. N1 nodes were also dissected completely, as appropriate for the primary surgical procedure performed. After the operative procedure and pathological examination, lymph nodes were also assigned to one of 14 lymph node stations from Montain and associates [3] (Table 1).
Systematically, the radiation therapy was performed when the pathological margin was positive. Other indications of irradiation were performed in patients that had invasions of major mediastinal structure as superior vena cava or pulmonary artery or oesophagus or vertebral body. The postoperative radiation was also indicated at the patient's having several mediastinal nodal stations involved. The dose of radiotherapy delivered on the mediastinal structure was of 60 Gy.
End points in this analysis were survival and cause of death. Times to death were measured from the date of surgical resection. Survival distributions were estimated by the method of Kaplan and Meier including postoperative mortality [4]. Comparisons between actuarial curves were made with the log rank test or adjusted log rank test [4]. Mutivariate analyses were performed by the methods of Cox [4]. The risk groups were definite by using the method of classification and regression tree from variable selected by Cox's model [5].
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3. Results
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The mean follow-up for all patients in this analysis, including those who died, was 20 months. Overall survival rates at 1, 2 and 3 years were 46, 31 and 21%, respectively. The absolute number of patients who died, were 61. At time of death, distant metastasis was localized to single site in 18 patients (bone in seven patients, brain in five patients, surrenals in four patients, liver in one patient and skin in one patient). In 11 patients, distant metastasis were localized in multiple anatomic sites. Finally, local recurrence was the cause for death in 11 patients.
Univariate analysis showed that the patients with a tumour localized in the upper lobe or in the main stem bronchus had in 3 years a rate of survival of 29 vs. 5% for tumours in the lower lobe (P=0.04) (Fig. 1)
. Patients with a tumour invading the left atrium or the vertebral fascia or the oesophagus had a survival rate lower than the other T4 sites of mediastinal but this difference was not significant (Table 2). The classified patient pN0 or pN1 or superior mediastinal nodes involved or inferior mediastinal nodes involved had, respectively, a 2-year survival rate and a 3-year survival rate of 35 and 25%, vs. 0% for the patients with both superior and inferior mediastinal involved (P=0.03) (Fig. 2)
. Finally, surgical procedure, tumour histological type and pathological margin status did not affect significantly the survival of the patients.
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Fig. 1. Survival curves of patients with a tumour localized in the upper lobe or in the main stem bronchus and patients with a tumour localized in the lower lobe. The comparison by log rank test was significant (P=0.04).
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Table 2. Univariate analyses, survival rates according to various T4 sites of mediastinal involvement or satellite tumour nodules
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Fig. 2. Survival curves of classified patients pN0 or pN1 or superior mediastinal nodes involved or inferior mediastinal nodes involved and patients with both superior and inferior mediastinal involved. The comparison by log rank test was significant (P=0.03).
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Multivariate analysis included two factors adversely affecting survival: the location of the tumour and the nodal stations involved. Classification and regression tree analysis were used to classify the patients into low-, intermediate- and high-risk groups for survival. The following factors were considered: the tumour localized in the upper lobe or in the main stem bronchus, the tumour localized in the lower lobe, pN0 or pN1 or superior mediastinal nodes or inferior mediastinal nodes involved, both superior and inferior mediastinal nodes involved. Table 3 shows the results of the regression tree analysis. The 3-year survival rates were 36% for the low-risk group, 4% for the intermediate-risk group and 0% for the high-risk group (P=0.006) (Fig. 3)
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Fig. 3. Survival curves of patients in low-risk group, intermediate-risk group or high-risk group. The comparison by log rank test was significant (P=0.006).
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Adjuvant postoperative radiation was performed in 40 patients. The 3-year survival of 30% for radiation versus 16% for patients who did not receive radiation (P=0.05). After adjustment on the risk groups, adjuvant radiation improved the survival significantly (P=0.04). The 3-year actuarial survival rate for the low-risk group who received adjuvant postoperative radiation, was 36 vs. 33% for those patients who did not receive adjuvant postoperative radiation. The benefit from adjuvant radiation was for the patients in the intermediate-risk group. The 3-year survival rate for patients in the intermediate-risk group who received adjuvant postoperative radiation was 12 vs. 0% for those patients who did not receive thoracic radiation therapy (Fig. 4)
. For the patients in the high-risk group, the size of the sample was too small to be able to compare survival curves. All patients in the high-risk group died within 13 months.
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Fig. 4. Survival curves of patients in intermediate-risk group who received adjuvant postoperative radiation and patients who did not receive adjuvant postoperative radiation.
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4. Discussion
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The patients with T4 non-small cell lung cancer, are too few to be able to benefit from a lung resection. The patients reported in the literature, are selected [6–17]. The superior vena cava, the carina and the left atrium [6,8,12,13,17] are some of the major mediastinal structures the most easily accessible to a radical surgery. The surgery of the right or left pulmonary artery is used most often in a resection of the intrapericardiac portion [7,9]. The resection of the trunk of the pulmonary artery needing cardiopulmonary bypass is rarely used [13]. Most of the time, only the adventitia of the thoracic aorta is resected, only three studies including few patients [13,16,17] reported resections of the wall.
The rates of 3-year survival of the patients undergoing surgery for a T4 lung cancer go from 17 to 40% according to the authors [7,8,10,12,13] (Table 4). These differences of survival can explain themselves by the selection of the patients. The study of Spagiarri et al. [8] reports a rate of 3-year survival of 40% and 5-years survival of 29%, excluding all the patients having mediastinal lymph nodes 
15 mm measured on the preoperative computed tomography scan. On the other hand, this study [8] is limited because the 95% confidence interval of the rate of 5-year survival goes from 7 to 51%. The patients having preoperative chemotherapy have a better rate of survival, as reported in the study of Macchiarini et al. [11] with a rate of 3-year survival of 54% and that of Stamatis et al. [9] 35% in 4 years.
The patients with T4 lung cancer localized at level the aorta, the oesophagus, the left atrium or the vertebral fascia have a more unfavourable prognosis [12]. On the contrary, the patients of our study having an extension of the lung cancer in the superior vena cava, in the carina or in the intrapericardiac pulmonary artery seem to benefit from the surgery with 3-year survival of 20%, as reported in the study of Spaggiari et al. [8].
Any incomplete resection on either the gross residual tumour or the microscopic residual tumour is responsible for a significant decrease of the survival of the patients [6,7,9,12,13]. The local recurrences are more frequent and constitute the main cause of long-term death [6,7,9,13]. Our study did not allow to factor in this evidence.
The patients with a tumour localized in the lower lobe have a worse survival rate than the patients with a tumour localized in the upper lobe or in the main stem bronchus. The tumours localized in the lower lobe invade preferentially the left atrium, the esophageal muscle or the thoracic aortic adventitia. For these tumours, a possibly incomplete resection risks leaving a microscopic residual tumour.
In our study, it is the importance of the invasion of the mediastinal nodal station which constitutes a factor adversely affecting survival of the patients. Tumours which colonized both the superior and lower mediastinal nodes are responsible for a significant decrease in the survival of the patients [6,7].
The classification in three risk groups allows to better isolate the patients being able to benefit from a surgical operation. The patients with a tumour localized in the upper lobe, or the main stem bronchus invading the carina, the superior vena cava, or the intrapericardiac portions of the pulmonary artery with pN0 lymph nodes or pN1 lymph nodes or superior mediastinal nodes or inferior mediastinal nodes involved, have a 3-year survival rate of 33%. This rate can be improved by the association of surgery with chemotherapy and radiotherapy. We showed more especially for the patients with intermediate risk that radiotherapy improved the survival in a in significant way. Postoperative radiation could improve the local control of the tumour by treating the possible microscopic residual tumour, especially at the level of the vertebral body or of the esophagus. In contrast, radiotherapy used in patients for whom mediastinal lymph nodes are involved has no effect on the survival rate as shown the meta-analysis [18]. The preoperative chemotherapy would seem to improve the survival of the patients with T4 lung cancer [9,11]. On the other hand, for unresectable, locally advanced tumours, the association of radiotherapy and chemotherapy allows to improve the survival of the patients [19]. The benefit of adjuvant therapy in patients undergoing resection can only be confirmed by a randomized controlled trial.
In conclusion, the patients with T4 lung cancer who can benefit from a surgical operation are few. The physiological state of the patient must be compatible with an extended resection.
The results of the present study suggest that the patients with T4 lung cancer most likely to benefit from resection that effectively improve the survival are those with a tumour localized in the upper lobe or in the main stem bronchus who have had lymph nodes status N0 or N1.
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Top
Abstract
1. Introduction
