Phase II study of repeated intrapleural chemotherapy using implantable access system for management of malignant pleural effusion

STUDY OBJECTIVE: To examine the effectiveness of repeated intrapleural chemotherapy using an implantable access system (INFUSE-A-PORT; Horizon Medical Products; Manchester, GA) for the management of a malignant pleural effusion (MPE). METHODS: Twenty-two patients with histologically proven MPEs (11 men and 11 women; mean age, 63.8 years; age range, 51 to 81 years; performance status, less-than-or-equal 3) were enrolled in this study. There were 17 patients with MPEs resulting from primary lung cancer; of whom 7 had metastatic disease (stage IV), 3 had stage IIIB disease, and 7 had postoperative recurrences. Three patients had MPEs that were caused by mesothelioma, and two had MPEs caused by breast cancer. Intrapleural catheters were placed by a video-assisted thoracoscopic procedure. The intrapleural administration of 5-fluorouracil (5-FU; 250 mg per body) and cisplatin (10 mg per body) using the implantable access system was performed biweekly at the outpatient clinic. Drainage of the MPEs through the port was performed only when the patients had some manifestations that occurred due to increasing effusion. RESULTS: The mean total administered doses of 5-FU and cisplatin were 3,290 and 124 mg, respectively. The mean follow-up period was 431 days (range, 209 to 792 days). The median survival period was 403 days, and the longest survival period was 792 days. No treatment-related mortality, renal dysfunction, bone marrow suppression, or infection occurred. One patient experienced a hemothorax after eight instances of intrapleural administration. The port and the catheter were involved with the tumor in one patient. CONCLUSIONS: Repeated intrapleural chemotherapy using the implantable access system is useful and safe for patients with MPEs. In the future, prospective randomized studies will be necessary to compare the efficacy of therapy for MPE using the implantable access system with that of pleurodesis.     

Eosinophil colony stimulating activity induced by administration of interleukin-2 into the pleural cavity of patients with malignant pleurisy

Systemic administration of interleukin-2 (IL-2) in patients with malignant diseases induces peripheral eosinophilia. In the present study, to clarify the mechanisms of eosinophilia induced by IL-2, we examined the changes in the number of eosinophils and in eosinophil colony stimulating activity (Eo-CSA) in the pleural fluid of six patients with malignant pleurisy caused by lung cancer or malignant mesothelioma, during and after intrapleural administration of IL-2. Results showed that intrapleural administration of IL-2 induced marked eosinophilia in the pleural fluid and mild eosinophilia in the peripheral blood, and that during IL-2 administration, marked Eo-CSA appeared in the pleural fluid before increase in the number of eosinophils. The Eo-CSA seemed to be a polypeptide or protein because it was trypsin-sensitive and had a molecular weight of 40-60 kDa.     

Pleural mesothelioma.

The increasing incidence of malignant pleural mesothelioma (MPM), better knowledge of its pathogenesis with a strong implication of asbestos fibers, and some promising therapeutic results have led to a new interest in the management of patients with this disease. The diagnosis of MPM is easier because of new immunohistochemical markers that recognize the mesothelial cells with good specificity and sensitivity on pleural biopsy samples ideally obtained by thoracoscopy. Moreover, this endoscopic procedure allows the physician to make the diagnosis of MPM at an early stage, which is the key of the therapeutic management of this disease. If radiotherapy is necessary in preventing the malignant seeding after pleural procedures in patients, the lack of comparative studies did not show the superiority of a given treatment against another. A new international staging of the disease, however, allows physicians to discriminate several groups of patients for such comparative studies--in particular, for testing the efficacy of intrapleural therapy, e.g., cytokines--for early-stage MPM and multimodal management, i.e., extrapleural pneumonectomy, radiotherapy, and chemotherapy for more advanced diseases, has led to prolonged survival in carefully selected patients. To reach this target, all patients must be enrolled in protocols. The usual pessimism for the management of patients with malignant pleural mesothelioma is over.     

Tissue factor pathway inhibitor expression by human pleural mesothelial and mesothelioma cells.

The mesothelial lining of the pleura and malignant mesothelioma promote fibrin deposition in pleural injury or neoplasia via expression of tissue factor (TF). It was hypothesized that these cells might also regulate intrapleural coagulation by elaborating TF pathway inhibitor (TFPI). TFPI activity and antigen in pleural fluids were assayed from patients with congestive heart failure (CHF), pneumonia, empyema, metastatic pleural cancer and malignant mesothelioma. The authors also assessed expression of TF and TFPI messenger ribonucleic acid (mRNA) as well as TFPI activity and antigen by human pleural mesothelial cells, malignant mesothelioma cells (MS-1 cell line) and human lung fibroblasts. Immunohistochemical analyses of normal, fibrotic, and neoplastic pleura were performed to determine whether TFPI antigen was expressed in vivo. The study revealed that TFPI was present in transudates from patients with CHF and exudative pleural effusions from patients with pneumonia, empyema or pleural carcinoma. TFPI mRNA, activity and antigen were expressed by pleural mesothelial cells, MS-1 cells and lung fibroblasts. Cytokines and serum stimulated a significant early increase in TF mRNA levels with minimal enhancement of TFPI mRNA, activity and antigen levels. TFPI antigen was found in normal, fibrotic and neoplastic pleural tissues. The current observations indicate that tissue factor pathway inhibitor is locally expressed in pleural disease, but that it does not prevent the development of a prothrombotic environment favouring local fibrin deposition in pleural inflammation or cancer.     

Clinicopathological analysis of lung cancer resembling malignant pleural mesothelioma

OBJECTIVE: The aim of this study was to evaluate the clinicopathological features of lung cancer resembling malignant pleural mesothelioma. METHODOLOGY: The seven patients studied had tumours showing an extensive pleural growth pattern, and were chosen from 1516 lung cancer patients diagnosed at two affiliated hospitals over a 17-year period. RESULTS: Histologically, five of these lung cancers were adenocarcinomas, one was a small cell carcinoma, and one a large cell carcinoma. Tumour markers such as carcinoembryonic antigen (CEA) were elevated in six patients at admission. However, a clinical diagnosis was difficult and these cancers could only be distinguished from malignant pleural mesothelioma by thoracentesis in two cases, pleural biopsy in two, thoracotomy in two, and in case 7 at autopsy. Treatment consisted of chemotherapy or radiation therapy in four patients, but with little clinical effect. The mean survival time was 6.7 months, which is much less than for true malignant pleural mesothelioma. CONCLUSIONS: Lung cancer resembling malignant pleural mesothelioma is most frequently observed in patients with adenocarcinoma, which is suspected to occur peripherally. To distinguish pseudomesotheliomatous carcinoma from malignant pleural mesothelioma in patients with diffuse pleural thickening and effusion, requires adequate tissue sampling by thoracotomy or video-assisted thoracoscopic surgery and a panel of immunohistochemical stains.     

Mesothelioma and mesothelial hyperplasia

Twenty cases of pleural mesothelioma (2 localized and 18 diffuse malignant pleural mesothelioma), 6 cases of diffuse malignant peritoneal mesothelioma and 1 case of mesothelial hyperplasia were reported. The prominent clinical manifestations of malignant mesothelioma was serosal effusion. The exudate was bloody, mucinous and of high specific gravity. It contained numerous mesothelial cells. The diagnosis is difficult because mesothelial hyperplasia and other malignant tumors may mimic mesothelioma in some clinical aspects. Roentgenography, CT scan, cytology of serosal fluid and biopsy world help to establish the diagnosis of mesothelioma. Immunohistochemical features of 4 cases of mesothelioma is negative immunostaining for carcino embryonic antigen (CEA) and positive for keratin antigen. In one case ultrastructural examination showed characteristic features of epithelial mesothelioma cells. The average survival period in case of chemotherapy and/or surgical intervention in patients of this series was 31.3 months. Mesothelial hyperplasia has rather good prognosis; but the strategy of therapy may be conservative.     

Novel intrapleural therapies for malignant diseases

Pleural malignancies, either primary or metastatic, are common and problematic clinical issues in thoracic oncology and pulmonary medicine. Malignant pleural mesothelioma and metastatic pleural effusions often present late in the course of a disease and have a dramatic impact on the patient's quality of life and survival. Novel approaches to manage mesothelioma and malignant pleural effusions are desperately needed and the pleural space provides a unique platform as an easily accessible body cavity for developing and assessing these treatments and their responses. In this review, we discuss the unique intrapleural chemotherapeutic, immunotherapeutic and genetic treatments that have been investigated, as well as those under current clinical development. While responses have been demonstrated to variable degrees with all these approaches, an integrated multimodality approach incorporating these methods with other anti-neoplastic interventions ultimately will ensure the best responses and patient outcomes.     

A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report.

Malignant pleural mesothelioma is an aggressive tumour with poor prognosis and short duration of response probably due to the high chemo-refractoriness. Multimodality treatment based on preoperative chemotherapy, surgery and adjuvant radiotherapy seems to be a feasible and effective therapeutic option in selected patients.We report on a case of pathological complete response in a patient affected by malignant pleural mesothelioma who was treated with four cycles of preoperative chemotherapy based on carboplatin plus pemetrexed followed by parietal pleurectomy and lung decortication. Carboplatin plus pemetrexed was a well tolerated regimen without grade 3-4 haematological toxicity, and this confirm the feasibility of such a treatment as an alternative to the current golden standard based on cisplatin plus pemetrexed.Complete resection allows the pathologist to better describe biological markers of mesothelioma cells, in order to select patients with different treatment outcome and prognosis.     

Note on the complications of pleural needle biopsy: neoplastic seeding of the wall (apropos of 300 effusions and 440 puncture biopsies)]

Out of 440 pleural biopsies done with Abrams or Castelain needle, performed over 11 years in 300 pleural effusions, only 14 incidents of accidents occurred. There were 9 minor ones (intrapleural bleeding, subcutaneous emphysema, pneumoserosa by aspiration). Neoplastic graft along the biopsy tract was observed in 5 cases, of which 4 were primitive malignant mesotheliomas and one a primitive appearing neoplastic pleurisy. The risk of parietal neoplastic seeding runs high in malignant mesothelioma, considering that 11 such cases were included in this series of biopsied patients. This risk is not specific to plaural biopsy and can be encountered in simple thoracentesis. This complication therefore is not a contra-indication to needle biopsy as it is only observed in diseases beyond surgical redemption.     

A case of malignant mesothelioma showing rapid progression during one month]

A 57-year-old man with massive right pleural effusion was admitted to our hospital. Thoracoscopy revealed, fine granulations and small nodules scattered on the parietal pleura. Biopsy specimens suggested malignant mesothelioma. We performed thoracoscopy again one month later under general anesthesia to make a definitive diagnosis. At that time, the parietal pleura was covered with a large tumor and malignant mesothelioma was diagnosed by biopsy. We could find early pleural lesions of malignant mesothelioma in thoracoscopy. While we managed to make a definitive diagnosis, the tumor progressed rapidly during one month. If malignant pleural mesothelioma is suspected, it is necessary to make all efforts, including surgical biopsy, to diagnose during the early stage of disease.     

Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma

STUDY OBJECTIVES: No established curative treatment is available for pleural thymoma metastases and malignant pleural mesothelioma (MPM). Recently, peritoneal malignancies have been treated by cytoreductive surgery and intraoperative hyperthermic intracavitary perfusion chemotherapy (HIPEC). We investigated the feasibility and safety of this multimodality treatment in the thoracic cavity. DESIGN: Patients with pleural thymoma metastases or early-stage MPM were enrolled in a feasibility study. Morbidity, recurrence, and survival rates were recorded. SETTING: The Netherlands Cancer Institute. PATIENTS: Three patients with pleural thymoma metastases and 11 patients with pleural mesothelioma were treated. INTERVENTIONS: Cytoreductive surgery and intraoperative hyperthermic intrathoracic perfusion chemotherapy (HITHOC) with cisplatin and adriamycin were performed. The mesothelioma patients received adjuvant radiotherapy on the thoracotomy wound and drainage tracts. MEASUREMENTS AND RESULTS: Morbidity and mortality rates were 47% and 0%, respectively. Reoperation was necessary in four cases. Severe chemotherapy-related complications were not observed. A solitary mediastinal and a contralateral pleural thymoma recurrence were successfully treated by radiotherapy and a contralateral HITHOC procedure. All thymoma patients were alive and free of disease after a mean follow-up period of 18 months. After a mean follow-up period of 7.4 months, nine mesothelioma patients are alive. Two mesothelioma patients died of contralateral pleural and peritoneal recurrent disease, while one patient is alive with locoregional recurrence. CONCLUSIONS: Cytoreductive surgery and HITHOC with cisplatin and adriamycin is feasible in patients with pleural thymoma metastases and early-stage MPM, and is associated with acceptable morbidity rates. Early data on locoregional disease control are encouraging, and a phase II study will be conducted.     

Concentration of hyaluronic acid in pleural fluid as a diagnostic aid for malignant mesothelioma

Hyaluronic acid (HA) was determined with a radiometric assay in the serum and pleural fluid of 85 patients with pleural effusions, including 15 with malignant mesothelioma, 32 with other cancer, 31 with nonmalignant inflammatory diseases, and seven with congestive heart failure. With a cutoff level at 100 mg/L, the pleural fluid concentration of HA was raised in 73 percent of patients (11 of 15) with malignant mesothelioma and in 23 percent with nonmalignant inflammatory diseases, but in none with other cancer and in none with congestive heart failure. The median concentration of pleural fluid HA was significantly higher in patients with mesothelioma than in those with other cancer (p less than 0.005). Determination of carcinoembryonic antigen (CEA) in pleural fluid further helped to differentiate between mesothelioma and other types of cancer; concentrations of CEA above 10 micrograms/L were found in four of 15 (27 percent) patients with mesothelioma, but in 38 percent of the patients with other cancer. We concluded that in the differential diagnosis of pleural effusions associated with malignant tumors a high concentration of HA in pleural fluid combined with a low concentration of CEA suggests malignant mesothelioma as opposed to other types of cancer.     

A case of diffuse malignant mesothelioma of the pleura with bilateral chylothorax]

We describe a case of bilateral chylothorax with malignant pleural mesothelioma. A 41-year-old woman was admitted to our hospital because of dyspnea. She had no history of exposure to asbestos. A chest radiograph and chest computed tomogram (CT) on admission revealed massive bilateral pleural effusion and a large tumor with pleural thickening in the left lateral and anterior parts of the pleura and mediastinum. Biochemical tests of pleural fluid revealed chyle. Two years before, she had been diagnosed through histological and histochemical examinations as having diffuse malignant pleural mesothelioma of the epithelial type. Chest-tube drainage was performed, and pleurodesis was induced by the intrathoracic injection of OK-432 at 10 KE per dose. The chylothorax disappeared after pleurodesis. To date, reports of malignant mesothelioma with nontraumatic chylothorax have been rare.     

A trial of intrapleural adenoviral-mediated Interferon-α2b gene transfer for malignant pleural mesothelioma

New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).     

甘露聚糖肽与高聚生治疗恶性胸腔积液的疗效比较

目的研究甘露聚糖肽与高聚生治疗恶性胸腔积液的疗效。方法 50例恶性胸腔积液患者随机分为两组,分别向胸腔内注入甘露聚糖肽、高聚生治疗,观察两组毒副反应,评价比较二者的有效率。结果两组毒副反应轻微,主要为消化道反应;甘露聚糖肽组治疗有效率52%,高聚生组治疗有效率为80%,两组比较差异有统计学意义。结论胸腔内注入甘露聚糖肽与高聚金葡素对恶性胸腔积液的治疗安全、有效,高聚金葡素的疗效高于甘露聚糖肽。     

Streptokinase for malignant pleural effusions: a randomized controlled study

Effective palliative treatment in malignant pleural effusion can only be carried out when the lung is fully expanded after drainage of effusion. We investigated the efficacy of intrapleural fibrinolytics for lysing fibrin deposits and improving lung reexpansion in patients with malignant pleural effusion. We randomly allocated 47 patients with malignant pleural effusion into 2 groups: a fibrinolytic group of 24 were given 3 cycles of 250,000 U intrapleural streptokinase; the control group of 23 received pleural drainage only. Pleurodesis with 5 mg of talc slurry was performed in all patients who had lung reexpansion after drainage. Patient characteristics, pleural drainage, lung expansion assessed by chest radiography, and pleurodesis outcomes were compared between the 2 groups. Patient characteristics were similar in both groups. Lung reexpansion was adequate for performing talc pleurodesis in 96% of patients in the fibrinolytic group and 74% in the control group. In the fibrinolytic group, the mean volume of daily pleural drainage before streptokinase administration was 425 mL, and it increased significantly to 737 mL after streptokinase infusion. Intrapleural administration of streptokinase is advisable for patients with malignant pleural effusion.     

Therapeutic options in malignant pleural mesothelioma

Malignant pleural mesothelioma may be treated with surgery, radiotherapy and chemotherapy. In most patients, the treatment remains palliative with symptom relief and a moderate survival gain. Only a minority of patients with early stage mesothelioma may be cured by a multimodal approach including radical surgery, chemotherapy, and radiotherapy. We discuss the role of surgery with either radical extrapleural pleuropneumonectomy or less invasive palliative pleurectomy and decortication, and the role of radiotherapy, in which the main problem is how to deliver sufficient doses to the pleural surface, sparing radiosensitive structures such as the lung, heart, liver, and kidneys. Chemotherapeutic options are discussed with 'older' mono- and combination regimens and the new promising combination cisplatinum/pemetrexed, now the 'standard regimen' for malignant pleural mesothelioma. Experimental approaches such as hyperthermia, interferons or interleukins, and 'small molecules' or antibodies inhibiting the EGFR oder VEGF receptor are under clinical evaluation. For the majority of our patients we recommend talcum pleurodesis either by medical thoracoscopy or VATS, followed by chemotherapy with platinum/pemetrexed. Radiotherapy may be applied in case of local tumour growth. The individual therapeutic decision will depend on tumour stage, concomitant diseases, performance status, and on the patient's preference.     

Malignant pleural mesothelioma produces functional granulocyte-colony stimulating factor

We report a patient with diffuse malignant pleural mesothelioma showing marked elevation of neutrophils. The level of serum granulocyte-colony stimulating factor (G-CSF) was elevated (138 pg/mL; normal range, < 20 pg/mL). The patient died 6 weeks after disease progression had been noted, and immunohistochemistry using a specific monoclonal antibody against recombinant G-CSF at autopsy demonstrated that the malignant mesothelioma cells actually produced G-CSF. Only three cases of malignant pleural mesothelioma, including the current patient, have been reported to produce G-CSF. We demonstrated an elevated serum level of G-CSF and G-CSF-bearing tumor cells by immunochemistry.     

Two cases of malignant mesothelioma controlled by pleurectomy]

Open biopsy and pleurectomy were performed in 2 cases of asbestos exposure with bloody pleural effusion. Pathological examination revealed marked proliferation of fibrous tissue containing tumor cells. The tumor was diagnosed as malignant pleural mesothelioma on the basis of histochemical staining and transmission electron microscopy. Almost complete excision of tumor tissue was performed, and malignant mesothelioma had not relapsed 10 and 12 months after the operation. We recommend open biopsy and pleurectomy for cases of exposure with bloody and intractable pleural effusion.     

Malignant diffuse peritoneal mesothelioma: clinical and therapeutic aspects. Apropos of a case with gelatinous ascites

Peritoneal mesothelioma ranks second in frequency after pleural mesothelioma. A well-established clinical entity since 1960, mesothelioma is increasingly frequent due to improvements in diagnostic methods and to the fairly wide industrial use of asbestos, a well-known carcinogenic substance for mesothelial cells. The diagnosis of malignant peritoneal mesothelioma rests on a corpus of convergent data. Treatment consists of surgery combined with radiotherapy and chemotherapy. The mean survival from the time of diagnosis is 8-10 months.