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Ann Thorac Surg 2007;84:1810-1817. doi:10.1016/j.athoracsur.2007.07.030
© 2007 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Long-Term Outcome of Surgical Treatment for Non-Small Cell Lung Cancer With Comorbid Liver Cirrhosis
Takashi Iwata, MDa,*,
Kiyotoshi Inoue, MDa,
Noritoshi Nishiyama, MDa,
Koshi Nagano, MDa,
Nobuhiro Izumi, MDa,
Shinjiro Mizuguchi, MDa,
Ryuhei Morita, MDa,
Takuma Tsukioka, MDa,
Shigefumi Suehiro, MDb
a Department of Thoracic, Osaka City University Graduate School of Medicine, Osaka, Japan
b Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
Accepted for publication July 9, 2007.
* Address correspondence to Dr Iwata, Department of Thoracic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan (Email: taiwata{at}med.osaka-cu.ac.jp).
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Abstract
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Background: Long-term outcome of surgery for non-small cell lung cancer with comorbid liver cirrhosis is not well known. We aimed to establish the factors influencing survival in such cases.
Methods: We retrospectively reviewed 33 patients who had undergone surgery for non-small cell lung cancer with comorbid liver cirrhosis. Clinical features, early outcome, survival time, and cause of death were investigated. Factors influencing survival were estimated by univariate and multivariate analyses.
Results: There were 2 in-hospital deaths (6.5%). Five-year survival rate for lung cancer death (n = 9) was 59.7%, whereas for hepatic death (n = 6), it was 62.9%. Factors influencing lung cancer death were nodal stage and limited resection (p < 0.05 for each). Factors influencing hepatic death were serum total bilirubin (p < 0.0001) and cholinesterase (p < 0.05), platelet count (p < 0.05), and alpha-fetoprotein (p < 0.05). Lung disease factors such as local extensiveness of the tumor and pathologic stage, and surgical factors such as performance of mediastinal dissection and limited surgery, also influenced survival from hepatic death (p < 0.05 for each).
Conclusions: Although pulmonary resection invasiveness may have some impact on long-term liver function, the life expectancy of patients with cirrhosis does not seem to be severely affected by pulmonary resection itself. Curative surgery should be performed if possible, even in patients with cirrhosis.
Liver cirrhosis is an advanced stage of chronic inflammation in the liver, with repeated destruction and proliferation of the liver cells, that gradually progresses to severe fibrosis. This chronic inflammation of the liver can have various causes, such as habitual alcohol consumption or immunologic or hereditary liver diseases. However, continuous infection with hepatitis viruses, such as hepatitis B virus and hepatitis C virus (HCV), is considered to be a major cause of the pathogenesis of liver cirrhosis in Japan [1].
Hepatitis C virus infection is spreading in many countries, with Japan being one of the most endemic areas [1–3]. More than 60% of cases of liver cirrhosis in Japan are related to HCV infection [1]. The prevalence of HCV infection has also been increasing in Europe and North America in recent decades, and the number of patients with liver cirrhosis has increased in these countries [4]. Furthermore, recent advances in antiviral therapy have prolonged life expectancy of patients with cirrhosis [5–7]. Although the number of cases of primary lung cancer incidentally detected in patients with comorbid liver cirrhosis is predicted to increase world wide, we have little knowledge about lung cancer surgery in such patients [8, 9]. Regarding lung cancer and liver cirrhosis, which are both severe life-threatening conditions, we sometimes face serious problems in determining the best surgical strategy for lung cancer in patients with cirrhosis. Pulmonary resection may exacerbate liver dysfunction and increase the risk of cirrhotic death, both in the long term as well as during the perioperative period. In this study, we aimed to establish the long-term outcome and its influencing factors, according to the results of surgical treatment for patients with primary non-small cell lung cancer (NSCLC) with comorbid liver cirrhosis.
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Material and Methods
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Patients
Informed consent for the use of clinical data in later retrospective studies had been obtained at the time of lung cancer surgery from all the patients involved in this study. The Institutional Review Board of Osaka City Medical School Hospital, Japan, also approved this study. We retrospectively reviewed the medical records of 876 patients who underwent curative surgery for primary lung cancer at our institute from 1 January 1990 to 30 September 2006. We found 33 cases of NSCLC with comorbid liver cirrhosis. Liver cirrhosis was diagnosed according to clinical features, laboratory data, and findings of ultrasonography and computed tomography. Two or more hepatologists diagnosed each patient as having liver cirrhosis. Observation or treatment of liver disease had been performed by these hepatologists before lung surgery in each patient. The extent of liver fibrosis had not been confirmed histopathologically by liver biopsy in all the cases.
Clinical features were investigated, including evaluation of liver function, such as Child-Pugh and liver damage classes. Child-Pugh classification is a simplified evaluation method of liver disease severity according to physical and clinical examination, and until October 2000 in our institute, it was determined by using prothrombin time. International normalized ratio of prothrombin time has been used instead since November 2000. Details of grading Child-Pugh class are shown in Table 1
[10, 11]. Liver damage class, according to the Liver Cancer Study Group of Japan, is another useful and more accurate classification for severely impaired liver function, compared with Child-Pugh classification (Table 2). In Japan, this liver damage grading is widely used in diagnosis and treatment in patients with hepatocellular carcinoma (HCC) complicated with liver cirrhosis, and is considered to be more closely correlated with clinical outcome than is the Child-Pugh class [12, 13]. Concurrent appearance of HCC at the time of lung surgery was investigated, because liver malignancy often arises in cirrhotic liver and may shorten life expectancy [4, 14–16]. Preoperative laboratory data and pulmonary function were also investigated. Profiles of the lung disease and the operation performed were also investigated in detail. Survival time was defined as the difference between the date of pulmonary resection and the time of last follow-up. Cirrhotic death included mortality from liver failure or acute bleeding due to rupture of esophagogastric varices or gastroduodenal ulcers. Hepatic death was defined to include both HCC and cirrhosis mortality.
Statistics
Five-year survival rates were calculated for lung cancer death and hepatic death by the Kaplan-Meier method. Lung cancer survival censors hepatic death and patients who are still alive or missing at the end of the study. Survival from hepatic death censors lung cancer death and patients who are still alive or missing at the end of the study. Survival from both causes censors patients who are still alive or missing at the end of study. The log-rank test was used to compare the difference in survival between the groups. The Cox regression hazard model was used for multivariate analysis of factors influencing survival. Multiple logistic regression analysis was used for multivariate analysis of risk factors. All p values less than 0.05 were considered statistically significant.
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Results
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Patient Characteristics
Detailed characteristics of all 33 patients are shown in Table 3. Diabetes mellitus was complicated in 8 patients. Mean Brinkmann index was 603. Performance status was graded as 1 in 20 patients, 2 in 12, and 3 in 1. Laboratory data on admission are shown in Table 4. Indocyanine green retention rate at 15 min (ICGR15) was measured in 24 patients, with values ranging from 6.9% to 57.4%. Other data shown in Table 4 were measured in all 33 patients. Perioperative liver-function–preserving therapy such as blood transfusion, including fresh frozen plasma, administration of branched-chain amino acids, diuretics, and various other drugs, was performed according to the severity of the liver dysfunction in each individual patient.
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Table 4 Preoperative Laboratory Data on 33 Patients Who Underwent Pulmonary Resection for NSCLC With Comorbid Liver Cirrhosis
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Surgical Treatment and Lung Cancer Characteristics
Table 5
shows details of pulmonary resection and the clinical profile of the lung disease. Thirty-two patients had unilateral disease, and 1 had bilateral disease. Posterolateral thoracotomy, axillary thoracotomy, and video-assisted thoracoscopic surgery were performed in 19, 10, and 4 cases, respectively. Mean operating time was 277 minutes (range, 60 to 505). Mean operative bleeding was 311 g (range, 5 to 1,200). Limited surgery was performed in 5 cases. The reason for limited surgery was severely diminished pulmonary function in 3 cases, multiple advanced HCC in 1, and both low pulmonary function and multiple HCC in 1 case. There was no patient in whom a limited operation for lung cancer was undertaken on the grounds of impaired liver function. Mean duration of chest tube placement was 9.9 days (range, 2 to 36). Mean volume of chest drainage on day 1 was 383 mL/day (range, 110 to 1,000), and mean total drained volume was 2,297 mL (range, 210 to 8,767). Histopathologically, adenocarcinoma was diagnosed in 22 cases, squamous cell carcinoma in 10, and large cell carcinoma in 1. Mean tumor size was 41 mm (range, 17 to 95).
Early Clinical Outcome and Perioperative Complications Related to Liver Cirrhosis
There were 2 operation-related deaths (6.5%); 1 case of operative mortality (3.2%) was a patient who died of acute respiratory distress syndrome after sepsis on day 6, and 1 case of in-hospital mortality (3.2%), a patient who died of acute sepsis followed by hepatic failure on day 46. The direct cause of death in both cases was considered to be a complication of postoperative bacterial infection. Postoperative acute liver failure directly induced by pulmonary resection, accompanying flapping tremor, jaundice, and ascites collection arose in 2 patients (6.5%) on days 6 and 7, respectively. Both of these were successfully treated with usual liver-function–preserving therapy, and were discharged without hepatic coma. Postoperative bleeding from the chest tube in patients who required blood transfusion occurred in 3 cases (9.7%). One of these was associated with postoperative hepatic coma due to acute liver failure, and another was accompanied by upper gastrointestinal bleeding, in addition to intrathoracic bleeding. All 3 patients with postoperative bleeding were also successfully treated conservatively. In another case, a chylothorax suddenly occurred 2 weeks after surgery (0.3%). This patient was also successfully treated conservatively. Two deaths occurred because of infectious disease; however, none of the patients died of acute liver failure in the early postoperative period.
Long-Term Outcome After Lung Cancer Surgery
Survival curves for all 33 patients for death from lung cancer, hepatic death, and death from both causes after lung cancer surgery are shown in Figure 1. Lung cancer death occurred in 9 patients. One-, 3-, and 5-year survival rate from lung cancer death after lung cancer surgery was 84.0%, 65.1%, and 59.7%, respectively. Mean survival time was 33.5 ± 2.5 months. Hepatic death was observed in 6 patients. One-, 3- and 5-year survival rate from hepatic death after lung cancer surgery was 92.1%, 92.1%, and 62.9%, respectively. Mean survival time was 60.1 ± 4.8 months. One-, 3-, and 5-year survival rate from both lung cancer death and hepatic death was 77.3%, 59.9%, and 37.6%, respectively, and mean survival time was 44.8 ± 5.2 months.
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Fig 1. Survival rates after lung cancer surgery in 33 patients with comorbid liver cirrhosis for lung cancer death (black solid line), hepatic death (gray solid line), and deaths from both causes (broken line).
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Factors Influencing Long-Term Survival From Lung Cancer Death
The results of univariate analysis of factors influencing long-term survival from lung cancer death are shown in Table 6. Nodal stage and limited surgery showed significant differences. The patients with N0 disease survived significantly longer than those with N1 or more advanced disease (p < 0.05). The patients who underwent limited surgery for lung cancer showed worse prognosis than patients who did not (p < 0.05). Complications of diabetes mellitus, habitual alcohol consumption, and serum carcinoembryonic antigen level were not correlated with the prognosis of lung disease in patients with cirrhosis. Table 7
shows the results of multivariate analysis of factors influencing long-term survival from lung cancer death. The same nodal stage (p < 0.05) and limited surgery (p < 0.05) also demonstrated significant differences.
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Table 6 Factors Influencing Survival From Lung Cancer Death After Pulmonary Resection for NSCLC With Comorbid Liver Cirrhosis
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Table 7 Multivariate Analysis of Factors Influencing Survival From Lung Cancer Death After Pulmonary Resection for NSCLC With Comorbid Liver Cirrhosis
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Factors Influencing Long-Term Survival From Hepatic Death
The results of univariate analysis of factors influencing long-term survival from hepatic death are shown in Table 8. Serum values of total bilirubin (p < 0.0001) and cholinesterase (p < 0.05), ICGR15 (p < 0.0005, n = 24), platelet count (p < 0.05), and alpha-fetoprotein (p < 0.05) were correlated with survival. Lung disease factors, such as local extensiveness of the tumor (p < 0.05) and pathologic stage (p < 0.05), and surgical factors, such as a performance of mediastinal dissection (p < 0.05) and limited surgery (p < 0.05), were also associated with survival from hepatic death. The patients who experienced early postoperative liver failure survived significantly shorter than those who did not (p < 0.0001). Sex, age, complication of diabetes mellitus, habitual alcohol consumption, presence of serum hepatitis B virus surface antigen or HCV antibody were not correlated with the prognosis of liver disease after pulmonary resection. Multivariate analysis was used to estimate the adjusted odds ratio for possible risk factors (Table 9). Platelet count was the only independent risk factor influencing survival from hepatic death after lung cancer surgery (p < 0.05).
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Table 8 Factors Influencing Survival From Hepatic Death After Pulmonary Resection for NSCLC With Comorbid Liver Cirrhosis
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Table 9 Multivariate Analysis of Factors Influencing Survival From Hepatic Death After Pulmonary Resection for NSCLC With Comorbid Liver Cirrhosis
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Risk Factors for Long-Term Hepatic Death After Lung Cancer Surgery
Table 10
shows risk factors for long-term hepatic death after lung cancer surgery, calculated by multivariate analysis. Only comorbid HCC was an independent risk factor for long-term hepatic death after lung cancer surgery. Its odds ratio was about 65.
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Table 10 Risk Factors for Long-Term Hepatic Death After Lung Cancer Surgery in Patients With Liver Cirrhosis by Multivariate Analysis
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Comment
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Surgery for cirrhosis patients is problematic, and several reports of abdominal surgery have been found in the literature [17–23]. Generally, abdominal surgery in patients with severely damaged liver function is usually followed by a serious postoperative course.
Even without surgical stress, the clinical course of patients with liver cirrhosis can involve various complications, such as acute exacerbation of liver dysfunction or acute bleeding from the upper gastrointestinal tract. Furthermore, in patients with liver cirrhosis, HCC frequently arises during their clinical course, and 50% to 90% of patients die of such cirrhosis-related events [14, 24]. Thus, liver cirrhosis is a critical condition, and the life expectancy of patients is approximately 40% of that of the general population in the same age group [24].
According to recent advances in antiviral treatment for viral hepatitis and local control methods for HCC, however, life expectancy in patients with liver cirrhosis, with or without liver malignancy, is improving [5–7, 25, 26]. During such a prolonged course of liver cirrhosis, the incidence of associated NSCLC is also predicted to be increasing. To establish the surgical strategy for NSCLC in patients with liver cirrhosis, there are two problems related to impaired liver function.
The first problem is an increased risk of early postoperative complications, according to the extent of liver dysfunction. In patients with liver cirrhosis, tolerance to various surgical stresses is reduced. The excessive invasiveness of such surgical procedures may easily induce acute liver failure in the early perioperative period after pulmonary resection. Furthermore, abnormal coagulability associated with cirrhosis may increase the risk of perioperative bleeding. Compromised systemic status due to abnormal metabolism increases susceptibility to infection. Postoperative prolonged lymphorrhea is another important factor that can exacerbate systemic status [17–19]. Therefore, in patients with severely damaged liver function, the surgical procedures for lung cancer must be carefully selected.
The second problem is difficulty in predicting long-term prognosis of patients with NSCLC and comorbid liver disease. In patients with severely damaged liver function, standard surgical treatment for NSCLC may induce progression of the liver dysfunction, and result in decreased life expectancy. On the other hand, in patients with limited liver damage, or with HCC well controlled by successful repeated treatment, limited surgery for NSCLC may not be curative. Assessment of life expectancy according to liver function is very difficult, especially with concerns over comorbid lung disease, and it is problematic to determine the best surgical treatment for NSCLC.
There are several reports in the literature about cardiac surgery in patients with liver cirrhosis [27–30]. However, to the best of our knowledge, there are still only two reports concerning thoracotomy or lung cancer surgery in patients with cirrhosis [8, 9]. In a series of 11 patients with liver cirrhosis, including 4 of Child-Pugh class C, 2 died of liver failure at 2 and 4 months after thoracotomy [8]. It has also been reported that control of postoperative pleural effusion is a major problem. The same group has also reported a series of 17 patients with liver cirrhosis who underwent lung cancer surgery [9]. They found 1 in-hospital death among 13 patients graded Child-Pugh class B. As in our study, they did not include Child-Pugh class C patients. The mortality rates in our study and in this previous study were similar. A problem with a large amount of postoperative pleural effusion has also been reported. This increased effusion is probably due to the same mechanism that leads to an increase in ascites after abdominal surgery in patients with liver cirrhosis [17–19]. We also found an increase in postoperative pleural effusion, and it was controllable by classic conservative therapy, consisting of diuretics and restriction of water and salt intake during lung cancer surgery.
In our study, factors influencing long-term survival from lung cancer death were nodal stage and performance of limited surgery, by both univariate and multivariate analyses (Tables 6 and 7). Nodal involvement in lung cancer is an advanced stage of disease and is considered to have a poor prognosis. In addition, patients who underwent limited surgery may be considered to have had a poorer systemic status than those who did not, and this might have resulted in a shorter survival time. On the other hand, factors influencing long-term survival from hepatic death included various laboratory data related to liver function, and interestingly, factors reflecting lung disease, such as local extensiveness of the tumor and pathologic stage, and factors reflecting the surgical method, such as mediastinal dissection and limited surgery, were also associated with survival in patients with liver cirrhosis (Table 8). These nonhepatic factors have an impact on long-term hepatic death, and probably reflect the invasiveness of pulmonary resection, especially in advanced lung disease; and they may cause further and irreversible damage to the cirrhotic liver, and influence long-term hepatic hypofunction.
It is difficult to determine surgical strategy in patients with liver cirrhosis, especially when it is complicated with HCC. In our study, comorbid HCC at the time of lung cancer surgery was the only independent risk factor for postoperative hepatic death, but this result was related to the small number of cases in our study. In a larger study from Japan, including patients with HCC, median survival of patients with liver cirrhosis was 7.9 years and 5-year survival rate was 62% [24]. In another study from Europe, 10-year survival in patients with alcoholic and nonspecific cirrhosis was 34% and 32%, respectively. Five-year survival rate in both groups was less than 60% [14]. Our data shown in Figure 1 were not substantially different from these results. From these data on patients who underwent curative surgery for NSCLC, long-term outcome of liver cirrhosis did not seem to be greatly modified by pulmonary resection. From our current data, however, we cannot exclude the possibility that pulmonary resection itself might increase the risk of hepatic death in the long-term and lower life expectancy in patients with liver cirrhosis. Advances in less invasive procedures such as video-assisted thoracoscopic surgery may improve both the early perioperative and long-term outcomes.
In conclusion, in surgical treatment for NSCLC in patients with liver cirrhosis, although the invasiveness of pulmonary resection may have influenced the long-term outcome of liver function, life expectancy did not seem to be severely affected. The strongest factor predicting long-term hepatic death was the presence of comorbid HCC. Therefore, we should make an effort to overcome perioperative cirrhosis-related complications, and perform curative surgery for NSCLC, even in patients with liver cirrhosis. Our knowledge about lung cancer surgery in patients with cirrhosis is still limited, however. Further studies are required to establish the detailed effects of lung cancer surgery in patients with liver cirrhosis.
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Acknowledgments
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We thank Yukiko Wakita for her help in preparation of this manuscript. Funding was provided by the Osaka City University Graduate School of Medicine.
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Abstract
Introduction
