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Ann Thorac Surg 2004;78:234-237
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

Twelve-year experience with left atrial resection in the treatment of non–small cell lung cancer

^a Department of Thoracic Surgery, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
^b Istituto Scientifico Tumori, Genoa, Italy

Accepted for publication January 22, 2004.

^* Address reprint requests to Dr Ratto, Azienda Ospedaliera Santa Croce e Carle, Via Michele Coppino 26, 12100 Cuneo, Italy
e-mail: ratto.gb{at}scroce.sanitacn.it

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: We retrospectively reviewed our 12-year experience in the surgical treatment of non–small cell lung cancer invading the left atrium. End points of the study were overall survival and factors potentially affecting survival.

METHODS: Nineteen consecutive patients with lung cancer invading the left atrium underwent surgery. Three patients with N2 disease underwent induction chemotherapy. Patients with either incomplete resections or pN2 disease received postoperative chemoradiotherapy.

RESULTS: Five-year survival was 14%, and the median survival time was 25 months. These figures refer to a very homogeneous group of patients with respect to the extent of atrial infiltration. Patients with N2 disease tended to have a worse outcome than patients with N0 or N1 disease (p = 0.06). The 3 patients with N2 disease who underwent induction chemotherapy were alive and disease-free at 30, 15, and 11 months from surgery. Survival was not affected by histology, type of surgery, or completeness of resection. Three patients with residual cancer in the atrial resection margin underwent postoperative chemoradiotherapy and are alive at 25, 17, and 15 months after surgery.

CONCLUSIONS: In spite of the poor survival rates we report, the present experience suggests that more-favorable results could be expected by the routine preoperative use of positron emission tomographic scan staging, a more-extensive assessment of atrial invasion, the application of induction chemotherapy in patients with N2 disease, and postoperative chemoradiotherapy in patients with tumors abutting the atrial resection margin.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Non–small cell lung cancer (NSCLC) invading the left atrium or the intrapericardial portion of the pulmonary veins is classified as T4, independent of the degree of infiltration. Reports of atrial resections for NSCLC are limited and include patients with differing extents of atrial wall infiltration. In the present study only patients with tumor invading the left atrial wall are included. According to tumor extension, different techniques of atrial resection, involving either the use of vascular clamps or total cardiopulmonary bypass, have been adopted [1, 2]. Although it is well recognized that atrial resection for NSCLC is technically feasible, survival after these extensive operations remains poor. Prognostic factors (ie, lymph node metastases, completeness of resection, postoperative bleeding, and tumor localization) for identifying patients who would more likely benefit from atrial resection have been described [1, 3, 4]. In this study we retrospectively reviewed our 12-year experience in the surgical treatment of patients with NSCLC invading the left atrium. End points of the study were overall survival and factors potentially affecting survival.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
From January 1991 to December 2002, 19 consecutive patients with NSCLC invading the left atrium underwent surgery. Excluded from the study were patients in whom pathologic examination of the removed specimen demonstrated cancer infiltration limited to the intrapericardial portion of the pulmonary veins, without any involvement of the atrial wall. Our policy was to offer surgical resection only to patients with low operative risk. Preoperative pulmonary function evaluation included blood gas analysis, spirometry, and quantitative lung ventilation–perfusion scans. Determination of maximum oxygen consumption during exercise was used when calculated postoperative values of either forced expiratory volume in 1 second or diffusing capacity for carbon monoxide were lower than 50% of predicted. Cardiac risk was assessed by stress echocardiography in patients with a history of heart complaints or abnormal electrocardiogram.

Preoperative evaluation of local extension of the tumor included computed tomographic (CT) scan, magnetic resonance imaging, echocardiography, and bronchoscopy. Preoperative angiography was not used. Whenever preoperative evaluation suggested the need for cardiopulmonary bypass because of the extent of atrial wall invasion, chemoradiotherapy without subsequent surgery was applied. Cardiopulmonary bypass was never used because (1) its benefits and detrimental effects remain undefined, (2) it was not readily available when a more-extensive-than-expected atrial infiltration was discovered at operation, and (3) we tried to develop a uniform and simple therapeutic approach.

Cervical mediastinoscopy was performed in all patients with accessible mediastinal nodes larger than 1 cm (smaller axis) on CT scan, and in those with left-sided primary tumor and enlarged subaortic or paraaortic nodes (independent of the diameter of accessible nodes by cervical mediastinoscopy). In patients with left-sided tumors, mediastinotomy or thoracoscopy were not used to preoperatively demonstrate metastases in the subaortic or paraaortic nodes. Before induction chemotherapy became a standard, the literature reported reasonably acceptable 5-year survival rates in patients with metastases in the aortopulmonary window nodes, provided that paratracheal nodes were negative [5]. At present, with the routine use of both positron emission tomographic scan and preoperative chemotherapy in N2 patients, every positron emission tomographic–positive mediastinal node is biopsied before surgery. In our hospital, positron emission tomographic scan was available for staging of lung cancer since March 2002.

Three patients with mediastinoscopically proved N2 disease underwent induction chemotherapy: three cycles of cisplatin (75 mg/m², day 1) and gemcitabine (1,200 mg/m², days 1 and 8).

The inclusion criteria were (1) histologic diagnosis of NSCLC, (2) partial pressure of carbon dioxide less than 45 mm Hg, (3) calculated postoperative forced expiratory volume in 1 second and carbon monoxide diffusing capacity greater than 50% of predicted or maximum oxygen consumption during exercise greater than 15 mL · kg^–1 · min^–1, (4) negative stress echocardiography, (5) predicted complete resection of the primary tumor, (6) no N2 disease at more than two mediastinal levels and no N3 disease, (7) no extra nodal tumor spread in the mediastinal tissues, (8) absence of distant metastases as documented by CT scan of brain, chest, and upper abdomen and bone scanning, and (9) no cancer cell–positive pleural or pericardial effusion.

The median age was 59 years, ranging from 46 to 72 years. All the patients were male. The tumor cell type, nodal status, surgical procedure performed, and completeness of resection are reported in Table 1.

In 2 patients partial esophageal muscle removal was needed. Postoperatively, patients with either pathologically incomplete resections (R1 or R2) or pN2 disease underwent radiotherapy to the residual disease site (60 Gy) or the mediastinum (45 to 50 Gy), respectively.

The adoption of a uniform follow-up protocol was not feasible; however, information from the clinicians to whom the patients were referred was obtained in all cases. Computed tomographic scan was performed yearly in 11 patients, whereas the remaining 8 patients had CT scan at irregular follow-up periods (range, 8 to 24 months).

Patients' characteristics in the various subgroups were compared by means of the ² test. Survival in each subgroup was described with the Kaplan-Meier product limit estimator. Comparison of survival was based on the log-rank test. All tests are two-sided, with a significance level of 0.05. However, because of the limited number of patients, the study had very low power to detect any significant association between patients' characteristics and prognosis. As a consequence, survival comparisons are to be considered as merely descriptive.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
The mean follow-up was 26 months. The in-hospital and 30-day mortality was 0%. Six patients experienced postoperative arrhythmia, and 1 patient had a cerebrovascular attack.

Eleven patients died during the follow-up period. The cause of death was documented in 8 patients: distant metastases in 4 cases, local recurrence in 2 cases, and both local and distant disease relapse in 1 case. One patient died of a myocardial infarction. Overall survival is reported in Figure 1. The 5-year survival was 14%, and the median survival time was 25 months. The only long-term survivor (7 years) was a patient with N0 disease and R0 resection.

View larger version (20K): [in this window] [in a new window]   Fig 1. Survival curve (Kaplan-Meier method).

Survival was not affected by histology (squamous cell carcinoma versus adenocarcinoma), type of surgical procedure (pneumonectomy versus lesser resections), and completeness of resection (R0 versus R1 and R2).

No significant difference in survival was found between patients who received adjuvant treatments and those who had no postoperative therapy. Three patients with microscopic infiltration of the atrial resection margin underwent postoperative chemoradiotherapy with radical intent (60 Gy plus cisplatin 75 mg/m²). No CT evidence of relapsing disease was present in these patients 25, 17, and 15 months after surgery, respectively. Another patient with histologically negative atrial resection margin but with macroscopic tumor abutting the limit of resection did not have any adjuvant treatment. This patient developed recurrence in the atrial resection area 13 months after resection.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
The results of surgery in patients with NSCLC invading the left atrium are deceiving because of the substantial operative mortality and low long-term survival rates. Operative mortality after resection for T4 NSCLC is reported between 5% and 18% [7]. The present study showed that operative mortality may be kept to very low rates by adopting rigorous functional selection criteria and using the clamping or direct suture technique for partial atrial removal. Whether the use of cardiopulmonary bypass increases operative mortality rates remains unclear. Instead, in our series considerable postoperative cardiac morbidity occurred. Arrhythmias occurred in approximately one third of patients, suggesting that prophylactic treatment would be reasonable when atrial resection is anticipated.

In this study the 5-year-survival after atrial resection for NSCLC was 14%, and the median survival, 25 months. Nakagawa and colleagues [8] reported 13 patients who underwent atrial resection for NSCLC using a vascular clamping technique. Four patients were alive at 24 months. Shirakusa and Kimura [9] described 12 patients with NSCLC invading the atrium; 8 patients had atrial resection using a clamping technique, whereas 4 patients underwent atrial resection with total cardiopulmonary bypass. Six of 12 patients were alive and apparently disease-free 12 months after surgery. In the series by Burt and coworkers [10] there was no long-term survivor among 3 patients with NSCLC involving the left atrium. Tsuchiya and colleagues [1] reported 22% 5-year survival after left atrium resection for NSCLC. Both the 3-year and the 5-year survival rates published by Bernard and coworkers [3] in 19 patients with NSCLC requiring atrial resection were 8%. Fukuse and associates [7] recorded a median survival of 10 months in 14 patients after surgery for NSCLC invading the left atrium. The authors suggested that the poor results in these patients were related to the degree of infiltration of the atrial wall, favoring the development of distant metastases. If we accept this concept, the 25-month median survival time of our series gives a more precise figure of the results of surgery in a relatively homogeneous group of patients with respect to the degree of atrium infiltration. Excluded from our study were both patients in whom preoperative CT and magnetic resonance imaging showed extensive atrial infiltration (dictating the need of total cardiopulmonary bypass) and those with limited involvement of the intrapericardial portion of the pulmonary veins. In our series, 3 patients could have undergone a complete resection if cardiopulmonary bypass had been used. In fact, the extent of left atrium and septum involvement cannot be defined without atriotomy. These 3 patients with residual disease in the atrial resection margin underwent a full course of adjuvant chemoradiotherapy. Inasmuch as they are alive and apparently disease-free after 15 to 25 months from surgery, the question of whether a more-extensive atrial resection allowed by cardiopulmonary bypass would have improved survival can be raised. Previous studies [7, 11] have shown early recurrence after atrial resection with cardiopulmonary bypass.

Risk factors for identifying patients with T4 NSCLC who could benefit from surgery have been repeatedly investigated [1, 3, 4]. The influence of the N status on survival is well recognized [3]. Martini and colleagues [12] reported no long-term survivor in patients with T4 N2 NSCLC. Tsuchiya and coworkers [1] found N status to be a significant prognostic factor. Fukuse and associates [7] reported a median survival time of 29 months in patients with T4 N0 NSCLC and 9 months in T4 N2 NSCLC. The median survival time of patients with N2 disease was two times lower than that of N0 or N1 patients in the series by Doddoli and coworkers [4]. Although our experience is in keeping with those previously reported, it also suggests that the results of surgery may be improved by induction treatments. This confirms previous studies reporting that preoperative chemotherapy improves survival in patients with T4 NSCLC [13, 14].

It is generally accepted that the completeness of resection significantly affects survival [7, 12, 15–17]. The high percentage of incomplete resections in the present series depends on several factors: (1) the definition of incomplete resection we have adopted (a resection was classified as R1 either when there was microscopic residual disease at the resection margins or when the last node removed in one major lymphatic drainage pathway was metastatic), (2) the number of patients treated before induction therapy became routinely used, and (3) the lack of immediate availability of total cardiopulmonary bypass when frozen-section examination of the atrial resection margin showed microscopic cancer infiltration.

In this study, adjuvant radiotherapy was given to patients with incomplete resection or involved mediastinal nodes. Survival in patients who had postoperative radiotherapy, either when coupled with chemotherapy or not, was similar to that of patients not receiving postoperative treatments.

In conclusion, the present study shows that long-term survival remains poor in patients operated on for NSCLC infiltrating the left atrium. However, we may assume that the results we obtained can be improved by means of a more-accurate staging and definition of the extent of atrial infiltration. More-favorable results might be expected in the near future by adopting the following approach:

1. Positron emission tomographic scan should be routinely used for staging patients with atrial involvement as the risk of occult metastases is particularly high. It is conceivable that at least 2 patients who had early metastases and 2 other patients with pathologic N2 disease in spite of normal size mediastinal nodes on CT scan images could be preoperatively identified.
   
2. In 3 patients surgical exploration showed an atrial infiltration more extensive than expected preoperatively. Transesophageal cardiac sonography and breath-hold gadolinium-enhanced three-dimensional magnetic resonance imaging angiography have been proposed as useful tools to improve preoperative evaluation of the extent of atrial involvement [1, 17]. In patients with more-extensive atrial infiltration, cardiopulmonary bypass and atriotomy could allow a better assessment of tumor invasion.
   
3. Surgery proved to be inadequate when used as primary treatment in patients with N2 NSCLC invading the atrium. Every positron emission tomographic–positive mediastinal node should be biopsied by cervical mediastinoscopy, mediastinotomy, or thoracoscopy to offer induction chemotherapy to this subset of patients.
   
4. Postoperative chemoradiotherapy allowed local disease control in patients with microscopic residual cancer in the atrial wall. Its use could be considered in selected cases. We are now trying to address the potential role of intraoperative radiotherapy in this subset of patients.
   

In spite of these expectations, we must recognize that the question of the role of surgery in the treatment of NSCLC invading the left atrium (and whether surgery may improve the results of definitive chemoradiotherapy with radical intent) remains unanswered.

	References

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6. Keller S.M. Mediastinal lymph node dissection. In: Pearson F.G., Cooper J.D., Deslauriers J., et al. , eds. Thoracic surgery, 2nd ed. Philadelphia: Churchill Livingston, 2002:1061-1072.
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