|Year : 2013 | Volume
| Issue : 5 | Page : 92-97
Pleuropneumonectomy for diffuse pleural metastasis in primary lung cancer
Wen-Bo Jin1, Chao-Yang Liang2, Yang-Hong Peng3, Nai-Kang Zhou1
1 Department of Thoracic Surgery, Chinese People's Liberation Army Medical School, Beijing 100853, China
2 Department of Thoracic Surgery, People's Liberation Army General Hospital, Beijing 100853, China
3 Department of Thoracic Surgery, People's Liberation Army 309th Hospital, Beijing 100091, China
|Date of Web Publication||30-Sep-2013|
Department of Thoracic Surgery, People's Liberation Army General Hospital, Beijing 100853
Source of Support: None, Conflict of Interest: None
Objective: The purpose of this study is to analyze a single institution experience with pleuropneumonectomy for pleural metastasis and malignant pleural effusion in primary lung cancer.
Materials and Methods: From August 1978 to August 2011, 66 consecutive patients with lung cancer underwent pleuropneumonectomy. Patients were followed-up after the operation. The quality-of-life and the survival time were recorded.
Results: All the 66 patients were successfully operated on, including 38 patients in early years (1978-1993) and 28 patients in recent years (1994-2011). Two patients in early years died after the operation. Post-operative complications occurred including heart arrhythmia, respiratory insufficiency and bacterial infection of residual lung, chylothoraxin and mental disorder. A total of 61 patients have been successfully followed-up and three patients in early years were lost in 1 year after the operation. Local recurrence was found in seven cases (4 in early years, 3 in recent years) and distant metastasis was found in 48 cases (29 in early years, 19 in recent years). A total of 54 patients died from tumors, seven patients survived. The actuarial 1, 2 and 3-year survival rates are 72.7%, 27.2% and 6.1% of 36 in patients of early years and 85.7%, 46.4% and 21.4% in 28 patients of recent years. The mean survival and the median survival of the total 64 patients were 20.0 ± 10.9 months and 17 months respectively. Further analysis showed that the mean survival and the median survival of the 36 patients in early years were 17.2 ± 9.7 months and 15 months, in contrast to 23.4 ± 11.3 months and 18 months of the 28 patients in recent years.
Conclusion: Pleuropneumonectomy is an option of patients with advanced-stage lung cancer associated with uncontrolled malignant pleural fluid by conservative therapies. Strict selection of patient to be operated, careful procedures to eradicate obvious tumors and metastasis and enhanced post-operative combined therapy are beneficial to patients' long-term survival.
Keywords: Long-term survival, lung cancer, operative risk, pleuropneumonectomy, pneumonectomy
|How to cite this article:|
Jin WB, Liang CY, Peng YH, Zhou NK. Pleuropneumonectomy for diffuse pleural metastasis in primary lung cancer. J Can Res Ther 2013;9, Suppl S1:92-7
| > Introduction|| |
According to the latest tumor node metastases (TNM)/International Union Against Cancer (UICC) classification, lung cancer with diffuse pleural metastasis and malignant pleural effusion is classified as stage IV.  These patients are usually not indicated for surgery due to the impossibility of complete resection of lung cancer with pleural dissemination. Hence, they have to be treated conservatively with the purpose of control of pleural effusion.  Thus, their prognoses are usually poor. At present, the optimal therapy for these patients is still in dispute. Many questions need to be answered, such as whether they should be operated and what is the optimal operative procedure. , The purpose of this study is to analyze 66 consecutive pleuropneumonectomies performed on cancer patients aimed at identifying factors that affect morbidity, immediate results and long-term survival.
| > Materials and Methods|| |
From August 1978 to August 2011, total of 837 patients in our department had received pneumonectomy, including 74 patients who received pleuropneumonectomy. Among the 74 patients underwent pleuropneumonectomy, there were 66 patients with lung cancer, five patients with mesothelioma and two patients with malignant thymoma and one patient with tuberculous empyema. The 66 patients with lung cancer and underwent pleuropneumonectomy were included in our research, including 38 males and 28 females, with the mean age of 54 years (ranging from 35 to 68 years). All the patients had received certain conservative treatments, such as chemotherapy, radiotherapy, thoracentesis, thoracic instilling chemotherapy or chest drainage. However, malignant pleural fluids in most patients were poorly controlled. Most of the patients were examined by computed tomographic (CT) scan, technetium bone scan, cardiac ultrasound, bronchoscopy and pulmonary function tests prior to operation. Patients with primary carcinoma and merely local metastasis in homolateral thorax were subject to the operation. Patients with reduced pulmonary function received a quantitative pulmonary perfusion scan.
Before being admitted or transferred to our department, seven patients had received thoracic instillation chemotherapy, local radiotherapy or systematic chemotherapy. However, the pleural fluid was poorly controlled. After being admitted to our department, most of the 66 patients were treated by thoracocentisis to relieve symptoms, such as serious dyspnea, chest discomfort and recurrent cough. All patients were asked to cease smoking for at least 3 weeks and take medicines to improve lung function. The patients systemically administered antibiotics 3 days prior to operation. Patients with lung infections were treated with sensitive antibiotics for a longer time in order to eliminate or control pulmonary infection.
Patients received posterolateral thoracotomy under regular anesthesia. The pneumonectomy was performed for a start to facilitate the whole partial pleural decortication and ensure the thorough pleural decortication. When the pulmonary vessels were hard to handle, the pericardium was opened to conduct further procedure. Pleural decortication was initiated from the thoracic incision. The decortication of diaphragmatic and pericardial pleuras was more difficult compared with the procedure of the pleura in other regions. Occasionally, partial diaphragm or pericardium had to be resected in order to eliminate the metastatis lesion. After diaphragmatic resection, dacron patches was used to repair the missed diaphragm. Electrosurgical unit was adopted to cauterize the undecorticated metastasis. Lymph nodes including R2 nodes should be removed completely. After pleurapneumonectomy, anti-neoplasm medicines were used to rinse the semithorax so as to prevent implantation of residual tumor cells.
Post-operative care and follow-up
After the operation, the patients were extubated in the recovery room and transferred to the intensive care unit. Meanwhile, patient-controlled analgesia was adopted. In general, the chest tube was removed within 48-72 h. Subsequently, the patients were followed-up at month 1, 3, 6, 9 and yearly thereafter. Chest CT scanning was performed annually during follow-up. A total of 61 patients were successfully followed-up and the remaining three patients were lost. Patients were staged based on histological examination of the resected specimen and classified according to the latest TNM/International Union Against Cancer (UICC) criteria.
Patients' data is listed in [Table 1] and [Table 2]. Mean survival times were compared by t-test. Survival rates were calculated by the Kaplan-Meier method and the log-rank test was used to compare survival rates. Other comparisons were made by using χ2 -test or Fisher's exact test. A P < 0.05 was regarded as statistically significant.
| > Results|| |
All the 66 patients were successfully pleuropneumonectomized, including 38 patients in early years (1978-1993) and 28 patients in recent years (1994-2011). Patients' major data are described in 1. In early years, two patients died after the operation. One adenocarcinoma (AC) patient develops chylothoraxin on day 10 and the other bronchoaveola carcinoma (BAC) patient suffered mental disorder on day 22. No death was present in recent years after the operation. Surgery-related complications that were present in this patient population were heart arrhythmia, respiratory insufficiency and bacterial infection in residual lung, chylothoraxin and mental disorder [Table 1].
A total of 64 patients were successfully followed-up, three patients in early years were lost in 1 year after being discharged from the hospital. The diagnosis of the three lost patients was AC, BAC and squamous carcinoma (SC) respectively. Among the remaining 61 follow-ups, local recurrence was found in seven cases (4 in early years, 3 in recent years) and distant metastasis in 48 cases (29 in early years, 19 in recent years). A total of 54 patients died of tumors and the other seven patients were still alive. The actuarial 1, 2 and 3-year survival rates of the 36 patients in early years are 72.7%, 27.2% and 6.1%, respectively. The 1, 2 and 3-year survival rates of 28 patients in recent years are 85.7%, 46.4% and 21.4%, respectively [Figure 1]. According to the log-rank analysis, survival rates in recent years are higher than those in early years (P = 0.025). The mean survival time of patients in recent stage is 23.4 ± 11.3 months, longer than the survival of 17.2 ± 9.7 months in patients of early years (P = 0.022). The median survival of the patients in early years and in recent years was 15 months and 18 months respectively.
|Figure 1: Kaplan-Meier survival plots for the 64 lung cancer patients in group comparison. The outcome of the patients in early years (n = 38) was significantly worse than that of the patients in recent years (n = 26)|
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Gender-based data were listed in [Table 2]. In the male group, there are 6 with SC, 22 with AC, 9 with BAC and 3 with adenosquamous carcinoma (ASC), compare to 0, 18, 7 and 1 in the female group, respectively. Comparison of survival rates is showed in [Figure 2]. Statistical significance was detected (P = 0.041). The mean survival time in the female group was 23.3 ± 11.6 months and was significant longer than that in the male group (17.8 ± 9.9 months, P = 0.045). The median survival of the female patients was 21 months, compared with 16 months of 38 male patients.
|Figure 2: Kaplan-Meier survival plots for the 64 lung cancer patients in gender comparison. The outcome of the males (n = 38) was significantly worse than that of the females (n = 26)|
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In pathology, AC was present in 39 patients including 21 males and 18 females. The 1, 2 and 3-year survival rates of patients with AC are 82.0%, 43.6% and 12.8%, respectively. The 39 patients with adenocarcinoma were divided into early years or recent years. The survival rates in 1, 2 and 3 years of the 20 patients rested in early years were 75%, 30% and 5% respectively. In contrast, the 1, 2 and 3-year survival rates in the 19 patients in recent years were 84.2%, 57.9% and 21.4% respectively. In [Figure 3], the log-rank analysis of the 39 patients with adenocarcinoma indicates that the survival rate is significantly higher in recent years than those in early years (P = 0.024). When patients with AC were analyzed on a gender basis, significance was found in the survival rates between the females and the males (P = 0.033) [Figure 4]. The number of patients with SC, ASC or BAC is small and listed in [Table 2] without calculation.
|Figure 3: Kaplan-Meier survival plots for the 39 adeno carcinomas in group comparison. The outcome of the patients in early years (n = 20) was significantly worse than the patients in recent years (n = 19)|
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|Figure 4: Kaplan-Meier survival plots for the 39 adeno carcinomas (ACs) in gender comparison. The survival of the males (n = 20) was significantly worse than the females (n = 19) in ACs|
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| > Discussion|| |
International Association for the Study of Lung Cancer has published the latest version of TNM staging of lung cancer in 2009.  The non-small cell lung cancer (NSCLC) with disseminated nodules in ipsilateral lobes besides the lobe where the primary tumor is located is attributed to T 4 , while malignant pleural fluid is classified as M 1a . As pleuropneumonectomy is frequently associated by a relative higher rate of complications and mortality, it is generally regarded as a palliative surgery for malignant pleural effusion and diffuse pleural metastasis. Furthermore, the extended radical resection would be a heavy strike to the patient. Thus the feasibility and essentiality for pleuropneumonectomy is still controversial. ,, However, the median survival of such patients is usually less than 6 months.  Different treatments would result in different median survivals. Local therapies including thoracentesis, chest drainage and thoracic instilling medical therapy, are frequently used in the treatment of patients with malignant pleural fluid. , Pleura resection or regional pulmonary resection is regarded as a suitable surgery for patients with malignant pleural fluid to palliate patients' symptoms. Although the pleuropneumonectomy is usually thought as a surgical contraindication , of its application in patients with lung cancer and malignant pleural fluid are still in debates.
Reshad et al.  reported a satisfactory treatment for malignant pleural effusion by using thoracentesis or chest drainage, plus thoracic instilling chemotherapy. The outcome of this conservative therapy showed a median survival of 11.3 months in primary pulmonary carcinomas.
Shimizu et al. compared pleuropneumonectomy and limited surgery for lung cancer with pleural dissemination and concluded that the 1-year survival rate of patients underwent pleuropneumonectomy was only 20% and nine cases of these patients died within 18 months post-operation. In contrast, the 1, 3 and 5-year survival rates for local resection plus parietal pleurectomy were 85.1%, 35.5% and 35.5%, respectively. In general, in Shimizu's report, most patients in the pleuropneumonectomy group had larger tumors and more nodal metastases, while most patients in the limited surgery group had smaller tumors and less nodal metastases. Hiyoshi, et al.  evaluated surgery for primary lung cancer with dissemination or malignant effusion of the pleura and concluded that the mean survival time and 2-year survival rate of 19 cases with lobectomy, five cases with pneumonectomy including pleuropneumonectomy and 15 cases with no surgical procedure were 2.77 ± 0.60 years, 53.4%, 1.51 ± 0.50 years, 26.7% and 0.99 ± 0.15 years, 6.7%. Hiyoshi stated that lobectomy with lymph node dissection for R2 over may be a beneficial treatment of lung cancer with dissemination or malignant effusion of pleura. Nagai's report on eight patients with lung cancer and malignant pleural effusion showed a poor prognosis, with six patients died within 1 year after the operation.  In the view of this author,  adjutant chemotherapy was not effective to improve the survival rates of patients.
However, there are also optimistic reports. Watanabe's et al. reported  that 15 patients were treated with pulmonary resection, pleural decortication and intrathoracic infusion of chemotherapy or sclerotherapy, none of them survived after 3 years' follow-up. Another report revealed a mean survival of 8 months in six patients underwent pleuropneumonectomy. Reyes et al. reported a study enrolled 20 patients with NSCLC and malignant pleural effusion, 10 of them received systemic chemotherapy and showed a median survival of 12 months (the longest survivor was 21 months). In the four patients underwent resection, one died of operation and three survived in a follow-up of 23, 23 and 59 months respectively (post-operative chemotherapy). Reyes et al. believed that pleuropneumonectomy was useful to improve long-term survival in combination with chemotherapy in patients with malignant pleural effusion. Koike et al. reported that three patients out of eight with carcinomatous pleuritis were treated with pleuropneumonectomy followed by chemotherapy survived for more than 4 years after surgery. Furthermore, one patient survived for 5 years. Yokoi and Miyazawa  reported a 5-year survivor with lung adenocarcinoma accompanied by carcinomatous pleuritis who underwent pleuropneumonectomy followed by systemic chemotherapy. Dobashi et al. also indicated that pleuropneumonectomy contributed to a long-term survival for primary lung cancer patients with pleural dissemination. These authors believed pleuropneumonectomy was a benefit to the disease. In our data, the mean survival and the median survival of the 64 patients was 20.0 ± 10.9 months and 17 months respectively. The mean survival and the median survival of 36 patients in early years is 17.2 ± 9.7 months and 15 months, in contrast to 23.4 ± 11.3 months and 18 months of 28 patients in recent years. Our results is consistent with the findings of these authors despite of a somewhat lower survival rate than they reported.
In our department, pleuropneumonectomy has been adopted as a conventional therapy for more than 32 years. Certainly, local treatment can control the majority of malignant pleura fluids.  However, primary tumors always reduce patients' survival and life quality. Malignant tumors could secrete immunosuppressive factors such as interleukin (IL)-4, IL-10, and transforming growth factor beta, ,, etc., In our opinion, pleuropneumonectomy could remove obvious tumors and metastasis, alleviate tumor load and recover the patients' immune functions benefit to further combined therapies. In early years, patients with uncontrolled malignant pleura fluid were selected for the operation. As a palliative treatment of severe disease, the prognosis of the patients in early years was poor. In recent years, we realized that pleuropneumonectomy should be used as a radical and active treatment for patients with primary pulmonary carcinoma and pleura metastasis. Prompt pleuropneumonectomy would benefit to the survival and life quality of patients with such disease. However, following strict standard for patient enrollment should be adopted: (a) The primary pulmonary carcinoma, the metastatic lesions in pulmonary lobes and the pleura metastasis or malignant pleural effusion should confined in the homolateral semithorax; (b) There should be no distant metastasis detected by pre-operative examinations; (c) The functions of heart, liver and kidney are satisfactory for the radical procedure; (d) The heterolateral lung should be in good condition; (e) The patient's age is less than 70 years old.
Currently, combined therapy is thought to be effective for NSCLC.  Neoadjuvant chemotherapy plus surgery is a hot spot in research on NSCLC, but it is also controversial. ,, In recent three decades, a variety of chemotherapeutic drugs had been used in the treatment of advanced-stage NSCLC, including cisplatin (DDP), carboplatin (Carbo), ifosfamide (IFO), cyclophosphamide (Cytoxan), adriamycin (ADM), vinblastinum (VDS), mitomycin (MMC), etoposide (VP-16), and teniposide (Vm26). All these medicines have a poor therapeutic effect and the single-used effective rate was lesser than 15%. In 1990s, paclitaxel (Taxol), Taxotere, gemcitabine (GEM) and irinotecan (CPT-11) were introduced, with their single-used effective rate of more than 20%. The combined chemotherapy composed of new invented medicines and DDP or Carbo achieved satisfactory results compared with old medicines. In 1980s, patients with lung cancer used to be treated by the following regimen: CAP (Cytoxan + ADM + DDP), EP (VP-16 + DDP), CIE (Carbo + IFO + VP-16) and CE (Carbo + VP-16), et al. From 1990s, NP (vinorelbine + DDP), CT (Taxol + Carbo), TP (Texotere + DDP), and GP (GEM + DDP) were adopted in our hospital. The applications of latest medicines and more available plans in the treatment of patients with lung tumors that are less chemotherapeutically sensitive may contribute to the rise in long-term survival rates.
Adjunctive therapy consists of chemotherapy, radiotherapy, immunotherapy, traditional Chinese medicine and targeted medical therapy. Yasumoto et al. first applied interleukin-2 by instilling into the thorax to activate lymphokine-activated killer (LAK) cells, thus to reduce malignant pleural fluid.  In our hospital, from 1990, IL-2 and LAK cells were frequently used for lung cancer, especially for those with malignant pleural fluid. The combination of IL-2 and DDP was a conventional treatment for patients with lung cancer after operation.
Targeted therapy, e.g., gifitinib, erlotinib, trastuzumab, bevacizumab and Endostar et al., has become available since 2000 in the treatment of patients with lung cancer especially for those with pulmonary adenocarcinoma. In our cohort, two female patients with AC who were operated on in 2007 had received gifitinib therapy since 2008. Another female with ASC was operated in 2007, and accepted Endostar and natural killer cells therapies in 2008. All the three females were staged as T 4 N 2 M 1a and accepted 4-6 cycles of chemotherapy after operation, and survived. Gefitinib, approved by American food and drug administration in May 2003, has effect on some patients who failed in chemotherapy. Researches indicated that Asian females with adenocarcinoma are more sensitive to gefitinib than Caucasian females do.  In comparison of NP on NSCLC, NP plus Endostar can improve the therapeutic effective rate about 18% and prolong the mid tumor progress time about 2.7 months. 
Patients in our cohort were divided into two groups based on the post-operative palliative treatments. Compared with the patients in early years, several factors may result in a higher long-term survival rate of the patients in recent years: First, the patients in recent years have a significantly younger mean age than the patients in early years (P = 0.006); second, more effective medicines and more options of therapeutic plans may result in a better survival rate of the patients in recent years.
Gender significantly affects survival rate (P = 0.041). The mean survival time in female group was 23.3 ± 11.6 months, longer than that in the male group (17.8 ± 9.9 months) (P = 0.045). The median survival of 26 female patients was 21 months, in contrast to 16 months of 38 male patients. The following several factors may contribute to the results: firstly, the majority of the females are non-smokers, while most of the males are heavy smokers; secondly, the number of chemotherapeutic cycles adopted by the females were more than that did by the males; finally, six of the females were wealthy and able to afford better therapeutic plans, thus contributed to the long survival time of the females.
| > Conclusion|| |
Pleuropneumonectomy is still controversial in the treatment of advanced-stage lung cancer. In our experience, pleuropneumonectomy is considered as a good choice to treat advanced-stage lung cancer associated with uncontrolled malignant pleural fluid by conservative therapies. Meanwhile, strict standard for patient selection, comprehensive resection of obvious tumors and metastasis, and enhancing post-operative combined therapy are critical and benefit to patients' long term survival. Post-operative mortality and complications could be minimized by careful selection of patients, scrupulous operative procedure and adopting strict administration of patients' physical conditions in the pre-operative period.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]