Eur J Cardiothorac Surg 2004;25:515-519
© 2004 Elsevier Science NL
Causes of death within 1 year of resection for lung cancer. Early mortality after resection
Alper Tokera,
Sukru Dilegea,
Sedat Ziyadea,
Osman Eroglua,
Serhan Tanjua*,
Dilek Yilmazbayhanb,
Zeki Kilicarslanc,
Goksel Kalaycia
a Department of Thoracic Surgery, Istanbul Medical School, Istanbul University, Istanbul, Turkey
b Department of Pathology, Istanbul Medical School, Istanbul University, Istanbul, Turkey
c Department of Chest Diseases, Istanbul Medical School, Istanbul University, Istanbul, Turkey
Received 23 October 2003;
received in revised form 7 January 2004;
accepted 12 January 2004.
* Corresponding author. Address: Tasmektep sok. Cinarli apt. 34/5, Goztepe, Kadikoy, 81060 Istanbul, Turkey. Tel.: +90-216-3602301; fax: +90-216-478-1309
e-mail: drstanju{at}hotmail.com
 |
Abstract
|
|---|
Objectives: Some of the lung cancer patients who are treated surgically with curative intent ultimately die in the early postoperative period. The aim of this study is to analyze the causes of death within 1 year of resection for lung cancer in our patients. Methods: Six hundred and twenty patients, who underwent resection for lung cancer with a curative intent were reviewed retrospectively. Eighteen patients (2.9%) died due to postoperative complications or within the first month and 51 (8.4%) patients (group 1) died within the first year after operation. Fifty-one patients (group 1) were compared with the survivors (group 2) in terms of age, gender, preoperative FEV 1, pathological tumor node metastasis (TNM), histopathological subtypes, type of resection, completeness of the resection, preoperative Karnofsky performance status and application of postoperative radiotherapy. Results: Pathological TNM (P<0.001), type of resection (P<0.01), histopathological subtype (P<0.001), completeness of the resection (P<0.05) and postoperative radiotherapy (P<0.001) were determined to be significant factors in mortality within 1 year after resection for lung cancer. Conclusions: The patients with pathological stage 3 disease, with large cell histology or who had undergone pneumonectomy have a higher risk of mortality within 1 year. These patients require detailed preoperative work up in terms of metastatic disease and cardiopulmonary physiological status.
Key Words: Mortality • Lung cancer • Surgery
|
1. Introduction
|
|---|
The most important predictors of survival in non-small cell lung cancer (NSCLC) are the tumor node metastasis (TNM) stage at diagnosis, completeness of the resection and the histopathological subtype. Patients who have undergone resection with a curative intent for clinical stage 1 disease (pathological stages 1, 2, and 3a) have an estimated 50% recurrence and cancer death rate at 5 years [1,2]. However, some patients who are treated surgically ultimately die within several months following surgery. The reasons for early mortality are operative mortality, postoperative complications, physiological problems associated with resection, cerebral metastatic disease or cerebro-cardiovascular events. By understanding the tumor virulence or postoperative physiological status prediction may identify subsets of early stage patients with dismal prognosis. Proper selection of the surgical procedure and effective use of systemic therapies depend upon the elucidation of prognostic factors. The aim of this study is to (a) document 1-year mortality in our patients and try to determine the reasons of mortality, (b) identify the patients who are not candidates for surgery, and (c) draw attention to this subject for further researches.
|
2. Materials and methods
|
|---|
All lung cancer patients who underwent resection with curative intent from January 1990 to January 2002 were reviewed retrospectively. Sixty-five (10.4%) female and 555 (89.5%) male patients with a mean age of 59.5±14.3 (22–84) years, were analyzed. No intraoperative death occurred. In-hospital and 1-month mortality consisted of 18 (2.9%) patients who were excluded from the study. Fifty-one (8.4%) patients (group 1) died within the first year. Group 2 included 551 patients (91.4%) who were alive for 1 year after operation. The groups were analyzed and compared in terms of age, gender, preoperative FEV 1, pathological TNM status, histopathological subtypes, type of resection, preoperative Karnofsky performance status, postoperative radiotherapy and completeness of the resection. Histopathological subtypes were grouped as squamous cell, adenocarcinoma, adenosquamous, large cell and other types including carcinoid tumor, mucoepidermoid carcinoma, adenoid cystic carcinoma, bronchoalveolar carcinoma, pulmonary carcinosarcoma, pulmonary blastoma and unclassified primary pulmonary tumors.
|
3. Preoperative work up
|
|---|
Routine evaluation included biochemical profile with blood cell count, chest X-ray, computed tomography (CT) of the chest and upper abdomen, abdominal ultrasonography, fiber-optic bronchoscopy with cytological specimens. Magnetic resonance imaging (MRI) of the chest was performed in case of central or apical location of the tumor. Bone scintigraphy and brain CT were performed to all patients except T1 epidermoid lung cancer unless the patient is symptomatic.
|
4. Mediastinal evaluation
|
|---|
Between 1990 and 2001, preoperative mediastinal staging by means of mediastinoscopy or anterior mediastinotomy was performed selectively in case of enlarged (>1 cm in the shorter axis) mediastinal lymph nodes at CT scan. Standard cervical mediastinoscopy was the procedure of evaluation of both paratracheal and subcarinal lymph nodes (five stations 2R, 2L, 4R, 4L and 7 according to American Thoracic Society Guidelines) [3]. Patients who did not have N2 disease underwent thoracotomy. From February 2001, mediastinoscopy indications were redefined in our department as: radiologically enlarged lymph nodes (>1 cm), clinical T4 tumor, high operative risk in terms of cardiac and pulmonary functions (cardiopulmonary risk index score over 4 according to Goldman [4]), and radiologically identified lymph nodes of any size with adeno or large cell carcinoma histology.
|
5. Surgical approach
|
|---|
All patients underwent lung resection with a standard posterolateral thoracotomy by the same surgical team. The standard resection procedure in case of complete regional verification of tumor negative lymph nodes was lobectomy. Pneumonectomy was performed in case of technical and oncological clearance necessity. Sleeve lobar resection (52 patients, 8.6%) was the preferred approach when appropriate for oncological principles. In our department segmentectomy is not accepted as an approved approach in the treatment of primary lung cancer and was only utilized in cases of strict pulmonary deteriorations such as compromised resection, like second and third primary lung cancer or as an adjunct to lobectomy when a second mass was found in another lobe. Intraoperative frozen section analyses of the resected bronchus and regional and mediastinal lymph nodes were routinely used in all the operations.
A resection was defined as complete if the margins of the resected specimens (bronchus–pulmonary artery–vein and associating organ in T4 or T3 tumor) and the dissected most distant lymph nodes were negative. Most distant lymph node was defined as the excised mediastinal lymph node at the superior, contralateral or inferior mediastinal region [5].
Routine systematic sampling of the mediastinal lymph nodes was the standard procedure with evaluation of at least four mediastinal stations according to the drainage pattern of the primary tumor lobe even if the lymph nodes are not palpable. This procedure was performed in order to decide the type of pulmonary resection and mediastinal lymph node dissection. If a metastatic lymph node was noticed at thoracotomy with the aforementioned sampling system with frozen section analysis, complete mediastinal lymph node dissection was the procedure of choice in right-sided resections. In patients who were operated in 1996 and 1997, complete mediastinal dissection was the routine procedure in right-sided operations.
|
6. Postoperative radiotherapy
|
|---|
Patients who have undergone complete resection and have been found, on histopathological examination, to have involvement of regional lymph nodes (N1 or N2) received postoperative radiotherapy (RT). Patients with incomplete resection were also accepted as candidates for adjuvant therapy, either chemotherapy or radiotherapy. Chemotherapy was employed to patients with incomplete resection with ECOG 0–1 and to patients who developed disseminated disease during follow up. Chemotherapy was mainly employed with cysplatine-based regimen with combination of RT. RT was delivered in patients with positive hiler or mediastinal nodes and in patients with positive surgical margins approximately 4–6 weeks after the operation. The median RT dose was 50 Gy for positive nodes and 60 Gy for residual disease at 1.8–2.0 Gy/fraction, 5 days a week. The initial treatment volume included the mediastinum, ipsilateral hilum, residual tumor and bronchial stump with a margin of 2 cm. The inferior border was 5 cm below the carina or 2 cm below the residual tumor. The inferior border was extended to the diaphragm if lower mediastinal nodes contained tumor. A reduced volume included the residual tumor. The initial volumes were treated with AP–PA portals, followed by off-cord oblique portals. The spinal cord dose was limited to 45–46 Gy. Treatment was given using megavoltage irradiation and doses were not corrected for lung transmission and were specified to isocenter.
|
7. Data collection and statistical analysis
|
|---|
Perioperative patient variables were collected in the surgical database. The pathological results and TNM status were reorganized according to the last revisions in the international staging system for lung cancer in 1999 [6]. Groups 1 and 2 were compared in terms of mean age, mean Karnofsky performance status and mean FEV 1 with Independent Samples Test. Pathological stage, histopathological subtype, type of resection, gender, completeness of the resection and application of postoperative radiotherapy were compared in both groups in terms of Fisher's Exact test and Pearson 
2 tests. Also the aforementioned risk factors which were found to be significant, were reanalyzed with one of the multivariance analysis tests (logistic regression analysis).
|
8. Results
|
|---|
The difference in preoperative data: age, gender, absolute value and percent of predicted FEV 1, and preoperative Karnofsky performance status were not statistically significant (Table 1). In postoperative data, stage, type of resection, histological subtype, completeness of the resection and postoperative radiotherapy were significant factors in terms of mortality within 1 year (consecutively P<0.001, 0.01, 0.001, 0.05 and 0.001; Table 2). With logistic regression analysis, mortality within 1 year after operation could be predicted as 91.5%. With the analysis of logistic regression, the type of resection (P=0.047) and histological subtype (P=0.017) were noticed to be significant risk factors in mortality within 1 year after operation.
The documented reasons for 1-year mortality are presented in Table 3.
|
9. Discussion
|
|---|
The factors affecting early mortality after curative lung cancer resection are (1) completeness of the resection, (2) undetected metastatic disease, (3) physiological alterations after resection, (4) associated undetected pathologies like cardio-cerebrovascular diseases and (5) late surgical complications. In this study, the reasons for mortality were determined in 73.9% of the patients (Table 3). The most common causes were surgical mortality (including postoperative deaths and late surgical mortality) and cancer-related mortality. Disseminated metastatic disease was the most common cause (14.5%) in cancer-related mortality. Sudden death at home could be attributed to the cerebro-cardiovascular events. Unfortunately, the only way to document the reasons for mortality in these patients was to perform autopsies. The other way to be a guide for assessing the reasons for sudden death could be reevaluation of the cardiological data of the patients in the preoperative period. Seven of the sudden death patients had received cardiology consultation, with five having echocardiographic examination. The patients had been referred to the surgery with acceptable risk and without any compromise of cardiac event during perioperative period.
In a recent study which addresses the fate of lung cancer patients after surgery it was shown that 16 (12.2%) patients out of 139 patients were dead (excluding the operative mortality) at the 6th month, the most common reason being cancer progression [7]. Our series show similarity with this study in terms of most common death month. Nine patients (17.6%) died in the sixth month and 25 (49%) patients died within the sixth month, the most common cause being cancer-related mortality.
Despite the advances in the management of NSCLC, recurrence rates after ‘curative’ surgical procedures remain high [6,8,9]. Patients who have undetected disseminated disease at the time of thoracotomy would be expected to have treatment failure and ultimate death. Imaging modalities may reveal metastatic disease in up to 50% of patients with abnormalities in history, physical examination or laboratory tests [10], therefore these patients could be saved from an unnecessary surgical procedure. On the other hand, in patients with negative history, negative physical examination and negative laboratory screening the incidence of metastatic disease is lower [11]. Some researchers suggest evaluation of brain, bones, adrenal glands, and liver or combination of these procedures extensively, as it is performed in our institution. While being able to lower the morbidity and mortality rates with this aggressive approach, it has not been possible to completely identify the patients with metastatic disease. Even with this extensive preoperative evaluation, metastatic disease was the reason for early mortality in 31% of our patients, with metastatic disseminated disease (14.5%) being the most common form. It is apparent that the algorithm of preoperative metastatic disease evaluation requires further discussion. A theory could be created as follows: postoperative radiotherapy or chemotherapy could be applied to the patients with complete resection to prevent disseminated disease if one of the most common reasons for mortality within 1 year is metastatic disease. But this theory was destructed by the conclusion of chemotherapy or radiotherapy in the postoperative period after a complete resection did not prolong survival [12]. In patients with N2 disease application of postoperative radiotherapy is debatable. We preferred to employ postoperative radiotherapy in such patients but the data do not show a prolonged survival in patients with N2 disease after radiotherapy [12]. Neoadjuvant chemotherapy applications to prevent dissemination of the lung cancer in clinical stage 1 and 2 diseases are under investigation. But the toxicity of chemotherapy should be considered although it is reported to be the reason for mortality as 0.8% [13].
From a second point of view, depending on the fact that 26.1% of our patients were lost by sudden death at home, cardiovascular events compromise another mortal issue. When this group was analyzed it was seen that 55.5% of these patients had undergone pneumonectomy. This can be explained with the physiological complications, such as postpneumonectomy syndrome and late respiratory failure although performing the routine preoperative assessment tests [14]. The occurrence of respiratory failure several months after a pneumonectomy can be explained with overdistention and emphysematous changes of contralateral lung showing evidence of histological hyperplasia and loss of elasticity could cause an increase in the airway resistance, resulting in alveolar gas mixing, arterial desaturation and late pulmonary failure.
The surgical literature is replete with studies examining patient demographics, cardiopulmonary physiology, and comorbidities that try to determine predictors of undesirable perioperative outcomes [14–18].
Postoperative cardiopulmonary function and exercise capacity have been examined after pulmonary resection and demonstrated to be persistently decreased only by pneumonectomy [19,20]. This could explain the mortality in the pneumonectomy patients within the first year after operation. Especially the functional status could be worse when respiratory system infections complicate the scene.
Large cell carcinoma is known to be an aggressive tumor with a prognosis approaching the dismal outlook for small cell carcinoma. Fifty percent of large cell carcinoma patients died at 1.2 years, and the 5- and 10-year survival are 23 and 11%, respectively [21]. Some of these patients especially those with stage 1 and 2 tumors may do well. However, almost 25% of our large cell carcinoma patients died in 1 year. Almost all of these patients were at stage 3a, their clinical staging being at lower stages. The optimal therapy remains to be defined because these tumors are rare and few institutions have accumulated enough patients to make therapeutic recommendations. According to our results, large cell carcinoma has the worst prognosis within histopathological subtypes. We recommend the usage of more detailed preoperative work up to detect dissemination of the disease in this specific subtype.
The absence of stratification by stage and that of multivariable analyses to determine independent factors of early mortality are the limitations of this study. Further analyses considering these major points can be more helpful to define these factors.
As a result, our study defined a specific subtype of lung cancer with poorer prognosis after resection. Most of these prognostic factors have been presented but none of them was shown to be effective in 1-year survival after resection for lung cancer. Patients who are candidates of pneumonectomy, who have large cell carcinoma, and who have higher stage should be evaluated carefully for metastatic disease and physiological status. Incomplete resection and postoperative radiotherapy seemed to affect the prognosis even worse.
As physicians or surgeons who deal with a disease which is 100% mortal if not treated, we must be aware of the dismal results of the ongoing therapeutic regimens. The high early-death rates after resection can be lowered with the assessment of prognostic factors that have already been defined and remains to be determined.
|
References
|
|---|
- Strauss G.M., Kwiatowski D.J., Harpole D.H., Lynch T.J., Skarin A.T., Sugarbaker D.J. Molecular and pathological markers in stage 1 non small cell carcinoma of the lung. J Clin Oncol 1995;13:1265-1271.[Abstract]
- Harpole D.H., Jr., Herndon J.E., II, Young W.G., Jr., Wolf W.G., Sabiston D.C., Jr. Stage I nonsmall cell lung cancer: a multivariate analysis of treatment methods and patterns of recurrence. Cancer 1995;76:787.[CrossRef][Medline]
- Tisi G., Friedmann P., Peters R., Pearso G., Carr D., Lee R., Selawry O., The American Thoracic Society Clinical staging of primary lung cancer. Am Rev Respir Dis 1983;127:659-664.[Medline]
- Goldman L. Cardiac risks and complications of non cardiac surgery. Ann Surg 1983;198:780-888.
- LoCicero J., III, Ponn R.B., Daly B.D.T. Surgical treatment of nonsmall cell lung cancer. In: Shields T.W., LoCicero J., III, Ponn R.B., eds. General thoracic surgery. Philadelphia, PA: Lippincott Williams and Wilkins, 2000:1311-1342.
- Mountain J.F. Revisions in the international staging system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
- Handy J.R., Asaph J.W., Skokan L., Reed C.E., Koh S., Brooks G., Douville E.C., Tsen A.C., Ott G.Y., Silvestri G.A. What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest 2002;122:21-30.[Abstract/Free Full Text]
- Naruke T., Goya T., Tsuchiya R., Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1998;96:440-447.
- Conill C., Astudillo J., Verger E. Prognostic significance of metastases to mediastinal lymph node levels in resected non small cell lung carcinoma. Cancer 1993;72:1199-1202.[CrossRef][Medline]
- Silvestri G.A., Littenberg B., Colice G.L. The clinical evaluation for detecting metastatic lung cancer. A meta-analysis. Am J Respir Crit Care 1995;152:225-230.[Abstract]
- Hillers T.K., Sauve M.D., Guyatt G.H. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax 1994;49:14-19.[Abstract/Free Full Text]
- Port Meta-Analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 1998;352:257.[CrossRef][Medline]
- Le Chevalier T. Results of the Randomized International Adjuvant Lung Cancer Trial (IALT): cisplatin-based chemotherapy (CT) vs no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003;22:2.
- Deslauriers J., Ferraro P. Late complications. In: Pearson F.G., Cooper J.D., Deslauriers J., Ginsberg R.J., Hiebert C.A., Patterson G.A., Urschel H.C., eds. Thoracic surgery. Philadelphia, PA: Churchill Livingstone, 2000:189-207.
- Kearney D.J., Lee T.H., Reilly J.J., DeCamp M.M., Sugarbaker D.J. Assessment of operative risk in patients undergoing lung resection: importance of predicted of pulmonary functions. Chest 1994;105:753-759.[Abstract/Free Full Text]
- Wang J., Olak J., Ferguson M.K. Diffusing capacity predicys operative mortality but not long term survival after resection of lung cancer. Thorac Cardiovasc Surg 1999;117:581-587.
- Whittle J., Steinberg E.P., Anderson G.F., Herbert R. Use of medicare claims data to evaluate outcomes in elderly patients undergoing lung resection for lung cancer. Chest 1991;102:729-734.
- Romano P.S., Mark D.H. Patient and hospital characteristics related to in-hospital mortality after lung cancer resection. Chest 1992;101:1332-1337.[Abstract/Free Full Text]
- Nugent A.M., Steele I.C., Carragher A.M., McManus K., MacGuigan J.A., Gibbons J.R., Riley M.S., Nicholls D.P. Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer. Thorax 1999;54:334-338.[Abstract/Free Full Text]
- Larsen K.R., Swendsen U.G., Milman N., Brenoe J., Petersen B.N. Cardiopulmonary function at rest and during exercise after resection for bronchial carcinoma. Ann Thorac Surg 1997;64:960-964.[Abstract/Free Full Text]
- Travis W.D., Linder J., Mackay B. Classification, histology, cytology, and electron microscopy. In: Pass H.I., Mitchell J.B., Johnson D.H., Turrisi A.T., Minna J.D., eds. Lung cancer principles and practice, 2nd ed Philadelphia, PA: Lippincot Williams and Wilkins, 2000:453-495.
Top
Abstract
1. Introduction
