Ann Thorac Surg 2006;82:1027-1032
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Lung Cancer Surgery in Patients With Liver Cirrhosis
Akinori Iwasaki, MD, PhD*,
Takayuki Shirakusa, MD, PhD,
Kan Okabayashi, MD,
Koji Inutsuka, MD,
Satoshi Yoneda, MD, PhD,
Satosi Yamamoto, MD,
Takeshi Shiraisi, MD
Second Department of Surgery, School of Medicine, Fukuoka University, Fukuoka, Japan
Accepted for publication April 24, 2006.
* Address correspondence to Dr Iwasaki, Second Department of Surgery, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan (Email: akinori{at}fukuoka-u.ac.jp).
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Abstract
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BACKGROUND: Few reports have described surgery for lung cancer in patients with liver cirrhosis. The objective of this study was to clarify the efficacy of surgical treatment and evaluate its postoperative outcome.
METHODS: We retrospectively reviewed the medical charts of 17 patients between 1985 and 2005 who were found to have nonsmall cell lung cancer (NSCLC) with liver cirrhosis. The grading of the severity of liver cirrhosis was made according to the Child-Pugh classification.
RESULTS: Four patients were classified as Child-Pugh class A, whereas another 13 patients were classified as Child-Pugh class B. Of these 17 patients, 11 underwent lobectomies, 3 underwent pneumonectomies, and 3 underwent wedge resections. The only patient who experienced hospital death (5.9%) was a male patient with Child-Pugh class B cirrhosis. There were five respiratory-associated postoperative complications including pneumonia, bleeding from the staple line, and prolonged air leak. The morbidity rate was 29.5%. Median duration of chest tube insertion was 6.8 days, and mean volume of pleural effusion was 1,015.0 mL at 3 days total postoperatively. A total of 9 deaths occurred during follow-up (3 from cancer, 4 from hepatic failure, 1 from cardiac causes, and 1 unknown). The overall survival was 87.8%, 57.0%, and 45.6% at 1, 3, and 5 years, respectively. None of the patients experienced morbidity or mortality in Child-Pugh class A, but class B had 30.8% morbidity and 7.6% mortality.
CONCLUSIONS: Surgical treatment may be an acceptable and valuable approach for NSCLC patients who also have low severity liver cirrhosis.
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Introduction
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Liver cirrhosis in patients has been regarded as a contraindication to major surgery, because of frequent hemostatic abnormalities and malnutrition, which lead to increasing postoperative morbidity or mortality. Patients with cirrhosis have been reported to die due to postoperative complications from hepatorenal failure with intractable ascites [1]. However, advancements in perioperative management along with nutritional support or pharmacological therapy may prevent postoperative complications. In addition, a less invasive operative technique such as endoscopic surgery is advantageous for the these compromised patients. A randomized controlled trial by Ji and colleagues [2] showed the benefits of laparoscopic surgery in patients with cirrhotic portal hypertension. Recently, an increasing number of reports have described patients with mild to moderate cirrhosis safely undergoing cardiac surgery [3–4]. Lung cancer remains the most common cancer, and surgery remains its foundation therapy worldwide. We believe that few reports to date have described patients with liver cirrhosis who have undergone lung cancer surgery. In the present study we evaluate the clinical outcome after thoracotomy of patients with coexisting nonsmall cell lung cancer (NSCLC) and liver cirrhosis.
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Patients and Methods
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A total of 1,650 patients undergoing NSCLC resection in our department between January 1985 and December 2005 were found to also have liver cirrhosis. There were 7 patients with liver cirrhosis who did not have surgery, 4 patients who were denied surgery due to impaired liver condition, and 3 patients who were denied surgery due to advanced stage of lung cancer. The remaining 17 patients with liver cirrhosis who under curative resection were included in this study. The Fukuoka University Institutional Review Board of Clinical Research approved this study, and individuals gave their informed consent to take part in this retrospective study. Our inclusion criteria for the resection of these patients were as follows: control of the liver condition and other organs, possibility for complete resection, and patients who had sufficient surgical tolerance. Systemic node dissection was routinely performed for curative operation and accurate staging. A diagnosis of liver cirrhosis was based on the patients' clinical histories and findings of typical morphologic change of the liver and spleen. This diagnosis regarding the liver was confirmed by liver biopsy or abdominal ultrasound, computed tomography, or magnetic resonance imaging. The severity of liver cirrhosis was graded according to the Child-Pugh classification, which is based on the following 5 factors graded from 1 to 3: degree of encephalopathy, ascites, prothrombin time, level of albumin, and total bilirubin. The liver status was classified according to the sum of each grade (class A, from 5 to 6; class B, from 7 to 9; class C, from 10 to 15) [5]. The NSCLC was staged postoperatively according to the classification system of the International Union Against Cancer. Details of demographic data extracted from a review of the patients' records, including the results of many function results and preoperative medical problems such as cardiorespiratory disease and performance status. After extubation in the operating room, patients were routinely transferred to the intensive care unit for overnight observation. Postoperatively, chest tubes were inserted with –8 cm H2O water suction, with the level of suction gradually decreased to zero. The chest tube was removed when the effusion was less than 150 mL per day. Antibiotics were administered intravenously for 3 days before and after surgery, respectively. All patients were treated with early intake of balanced food, which preserved nutrition status and frequent monitoring for liver function testing. In addition, patients were prohibited a postoperative hydration. We reviewed the postoperative results of NSCLC patients with cirrhosis who had undergone pulmonary resection. All patients underwent standard pulmonary function tests and arterial blood-gas tests. As part of the postoperative clinical assessment of each patient, the presence of each of the following was recorded: prolonged air leak (> 7 days) or chest tube placement for control of pleural effusion, atelectasis confirmed by chest roentgenogram, pneumonia, mechanical ventilation after surgery, or tracheotomy or mini-tracheotomy for sputum support. Other postoperative complications were determined as follows: liver (deterioration of liver function), renal (dialysis or acute renal failure), cardiac (arrhythmia need with medication, ischemic change with therapy), bleeding (need for re-thoracotomy, need for transfusion), neurological (stroke, encephalopathy). Mortality was defined as death occurring during hospitalization after surgery. Survival rates were calculated using the Kaplan-Meier method.
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Results
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Characteristics Associated With Lung Cancer
A summary of the 17 patients is shown in Table 1. There were 3 female and 14 male patients; their mean age was 67.2 ± 7.3 years (range, 54 to 79 years). Histologic distribution of tumor types included eight adenocarcinomas, eight squamous cell carcinomas, and one carcinosarcoma. Low pulmonary function (forced expiratory volume in 1 second of less than 60%) was observed in 3 patients. Of the 17 thoracotomies, 14 were lobectomies, 3 were pneumonectomies, and 3 were wedge resections. Of these patients, 11 were in pathologic stage I, 3 in pathologic stage III, and 3 in clinical stage I. Three patients underwent video-assisted thoracic surgery. All patients were considered to be potentially cured by the surgical approach. All patients were administered a planned course of postoperative adjuvant chemotherapy consisting of tegaful and uracil. Another induction of postoperative adjuvant chemotherapy in combination with platinum was not administered. Ten of 17 patients had comorbid disease, which included diabetes mellitus in 4, chronic obstructive pulmonary disease in 3, hepatocellular carcinoma in 2, hypertension in 3, arrhythmia in 1, and old myocardial infarction in 1.
Characteristics of the Preoperative Liver Condition
The cause of liver cirrhosis was alcohol related in 4 patients and viral related in 13 (ie, hepatitis C virus in 11 patients and hepatitis B virus in 2). Profile of the liver condition is shown in Table 2. The severity of liver cirrhosis indicated that 4 patients were classified as Child-Pugh class A and the remaining 13 patients were classified as Child-Pugh class B. No class C patients were present.
Operative Information and Clinical Outcome
The mean operative time was 246.1 ± 97.8 minutes (range, 90 to 360 minutes). Estimated blood loss averaged 425.1 ± 484.2 mL (range, 20 to 1,700 mL). The only patient (case No. 3) who experienced hospital death was a 69-year-old man with Child-Pugh class B-associated virus infection. The overall in-hospital mortality rate was 5.9 % (1 of 17). This patient underwent a left upper lobectomy with node dissection for stage I NSCLC. He had pneumonia followed by the development of hepatorenal syndrome, and finally died of multiple organ failure on postoperative day 11. The comorbid disease of this case included hepatocellular carcinoma with a history of transatrial embolization in the previous 2 months. There were three respiratory-associated postoperative complications, including pneumonia in 2 patients and prolonged air leakage in 1. Incidence of bleeding from the staple line was seen in 2 patients. Two of 17 patients required mechanical ventilation. The morbidity rate was 29.5%. Median duration of chest tube drainage was 6.8 days (range, 3 to 16 days). Mean volume of pleural effusion was 1015.0 ± 888.4 mL at 3 days total. In addition, the daily volume of pleural effusion reached its maximum on postoperative day 1, reaching nearly 400 mL. In 1 patient (case No. 10), the pleural effusion was greater than 1,000 cc up to 3 days, after which it showed a steady decrease. One patient (case No. 13) received pleurodesis and parenteral nutrition. Nine of the patients were given fresh frozen plasma at operation or postoperatively. The mean postoperative hospital stay was 16.2 ± 8.0 days. A total of 9 deaths occurred during follow-up as follows: 3 from cancer progression, 4 from hepatic failure, 1 from cardiac causes, and 1 from unknown causes (Table 3). The overall survival was 87.8%, 57.0%, and 45.6% at 1, 3, and 5 years, respectively (Fig 1).
The association between factors and clinical course are summarized in Table 4. None of the patients experienced major morbidity and mortality in Child-Pugh class A, and many of these cases are alive, whereas the 30.8% (4 of 13) of those patients with Child-Pugh class B had morbidity and 1 mortality (7.6%) occurred. The mode of surgery and TNM stage did not affect morbidity.
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Comment
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Surgical procedures have a high risk of hemorrhage, liver failure, infection, and metabolic imbalance, and are sometimes withheld regarding cirrhotic patients for fear of complications. Abdominal operation in patients with liver cirrhosis is well known to cause massive ascites and be difficult to manage postoperatively [6–7].
However, recent studies have demonstrated that major surgery in patients with liver cirrhosis has acceptable clinical outcomes [8–9]. In the field of cardiothoracic surgery, a small number of articles have described cardiac surgery in patients with cirrhosis. Previously, we described the course of thoracotomy in 11 patients with both lung disease and cirrhosis [10]. However, in the field of surgery for lung cancer, surgery regarding patients with liver cirrhosis has rarely been reported. Lung cancer is one of the most common malignancies throughout the world as well as in Japan. Surgical resection remains the only therapeutic modality with a curative potential for patients with NSCLC. Surgical resection may continue to offer the best chance of long-term survival in patients with NSCLC who also have liver cirrhosis. We utilized the widely used Child-Pugh classification for evaluating the severity of cirrhosis. In our study, 4 patients (23.5%) were classified as Child-Pugh class A, whereas the remaining 13 (76.5%) were classified as class B. The only in-hospital death occurred in a patient having Child-Pugh class B cirrhosis, with a mortality rate of 5.9%. Another 7.7% were from the Child-Pugh class B group. Garrison and colleagues [11] reported that the postoperative mortality of abdominal operations in patients with liver cirrhosis was 10% in patients who had a Child-Pugh class A cirrhosis and 30% in those with a Child-Pugh class B. Another author showed that colorectal carcinoma in cirrhotic patients was 13% [12]. Our data indicate that patients having NSCLC with liver cirrhosis have a lower probability of mortality than those undergoing abdominal surgery. As shown in Table 4, no morbidity and mortality were recorded in patients with Child-Pugh class A cirrhosis. However, Foreman and colleagues [13] reported that, based on his national database of the hospital discharges of 1.7 million patients, a diagnosis of cirrhosis is strongly associated with an increased risk of sepsis, acute respiratory failure, sepsis-related mortality, and acute respiratory failure-related mortality. This data indicated that NSCLC with liver cirrhosis requires careful postoperative respiratory care. A recent report by Hayashi and colleagues [14] showed a mortality rate of 50% in Child-Pugh class B patients undergoing cardiopulmonary bypass, whereas none of the patients with Child-Pugh class B undergoing off-pump coronary artery in his study died. This data suggested that a surgical approach involving cardiopulmonary bypass may be negatively indicated for NSCLC patients with Child-Pugh class B liver cirrhosis.
In the field of cardiothoracic surgery, it is well known that systemic inflammatory response syndrome often occurs after cardiac surgery. The mechanisms that lead to systemic inflammatory response syndrome in patients who are operated on under cardiopulmonary bypass are considered to involve several factors, including ischemia, hypothermia, reperfusion injury, blood contact with foreign material, and excess shear stress. Systemic inflammatory response syndrome and organ failure develop in many patients hospitalized for hepatic cirrhosis, with these factors associated with increased mortality [15]. Recently, we showed that systemic inflammatory response syndrome is associated with postoperative complications and survival in NSCLC [16]. Our data also suggested that patients with NSCLC and liver cirrhosis should be carefully chosen for surgery for fear of systemic inflammatory response syndrome. In our series, the morbidity rate was 29.5%; these patients included 2 with pneumonia requiring respiratory support, 1 with prolonged air leakage, and 2 with lung hemorrhage. Five cases required postoperative transfusion for improving hemostasis. Other types of management were not indicated in the remaining patients. In general, one of the most common postoperative complications was the development of ascites in abdominal surgery. Otherwise, hepatic hydrothorax is defined as a pleural effusion in a patient with cirrhosis of the liver and no cardiopulmonary disease. The estimated prevalence of this often debilitating complication in patients with liver cirrhosis is 4% to 10% [17]. In our study, massive pleural effusion (ie, a 3-day total volume of more than 1,000 mL) was present in 4 patients (23.5%). One patient had pleurodesis, which required the injection of tetracycline through the drain to avoid massive effusion after postoperative day 7. Assouad and colleagues [18] reported that the assuage of ascites through diaphragmatic defects seems to be the main cause of pleural effusion complicating cirrhosis. However, none of our patients who underwent thoracotomy showed diaphragmatic defect. Although pleural effusion is a rare complication of advanced liver cirrhosis in nonthoracic surgery, thoracotomy for patients with lung cancer may pose a different problem. All but 3 of our patients underwent a lobectomy or pneumonectomy with lymph node dissection. A large amount of lymph fluid tends to be produced in these cases. Although it remains controversial, complete surgical resection with lymph node dissection is believe to be the most reliable treatment for NSCLC, and this treatment has been reported to improve the survival rate [19–20]. Avoiding node dissection may decrease the massive pleural effusion or related complications, but it also may lead to an incomplete cure. Large pleural effusion was not present in our 3 patients who underwent wedge resection without node dissection. The surgical criteria for malignancy are controversial, because liver cirrhosis itself is considered to be a terminal stage of liver disease. Of the 14 patients identified with node dissection, 4 cases were stage IA, 6 were stage IB, and 4 were stage IIIA. During the follow-up of all patients, 9 patients died, 4 experienced related hepatic failure, and 3 experienced recurrent related lung cancer. Otherwise, 1 patient died from cardiac event and another death was due to unknown causes. In general, patients with T1N0 and T2N0 tumors have early lung cancer, and most are curable by resection, with 5-year survival rates in the range of 75% to 80% for patients with stage IA [21]. However, from the patients in our study with early stage IA with liver cirrhosis, half (ie, 2 of 4) died of liver failure. Our data may indicate that cirrhosis as well as tumor factors are important prognostic indicators. Similar to our findings, Gervaz and colleagues [12] showed that the TNM stage of colorectal carcinoma in cirrhotic patients provided no prognostic information [12]. Minimal-access surgery (such as laparoscopic or thoracoscopic surgery) may have safety and feasibility for the patients with liver cirrhosis. Martinez and colleagues [22] reported that laparoscopic-assisted colorectal surgery can be performed in compensated cirrhotic patients with low morbidity and mortality. However, few reports have described surgical thoracoscopy for the management of cirrhotic patients [23], and few reports to date have described patients with lung cancer and liver cirrhosis who have undergone video-assisted thoracic surgery.
Two of the present patients classified as Child-Pugh class B underwent video-assisted thoracic surgery lobectomy, but 1 patient died during the early postoperative days. The operative time was 150 minutes and blood loss was 245 mL in this case. Our result may suggest that video-assisted thoracic surgery should not be performed in NSCLC patients with liver cirrhosis.
Some available evidence has been proposed regarding the survival benefits of adjuvant chemotherapy as the standard care for resected NSCLC patients [24–25]. However, adjuvant chemotherapy, which may cause liver damage, is impossible for the NSCLC patient with liver cirrhosis.
In our series we used an oral fluoropyrimidine that has been shown to be beneficial by several Japanese trials confirmed by meta-analysis [26]. Our retrospective study was limited by its small case number. However, our study has confirmed that surgery for NSCLC with liver cirrhosis is feasible with careful management.
In conclusion, the postoperative mortality rate for patients with both NSCLC and liver cirrhosis was in a lower range than that of cardiac or noncardiac patients with liver cirrhosis. Although long-term survival may still be disappointing with a survival rate lower than that of patients without liver cirrhosis, our findings suggests that patients with liver cirrhosis and lung cancer have a favorable chance of postoperative recovery after thoracotomy access with complete resection.
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Abstract
Introduction
