A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma.

After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.

Exploratory thoracotomy and its influence on the survival of patients with lung cancer.

PURPOSE: To evaluate diagnostic procedures, reasons for exploratory thoracotomy (ET), causes of unresectability of lung cancer, possibility for reducing numbers of ETs, and the influence of ET on survival. PATIENTS AND METHODS: Between 1990 and 1999, 1808 patients with lung cancer were operated on. ET was performed in 165 (9.1%) of these cases. In total, 131 ET patients were evaluable for analysis. The clinical stages were: three patients in stage IA, 28 in IB, one in IIA, 35 in IIB, 50 in IIIA, 10 in IIIB (all due to invasion of the mediastinum), and four patients in IV (three with ipsilateral pulmonary and one with solitary suprarenal metastasis). The control group for calculating survival difference consisted of 130 consecutive non-operated patients with comparable characteristics (age, sex, clinical stage, performance status, histology and comorbidity) who were diagnosed during the period 1996-1998. RESULTS: The diagnostic procedure before ET comprised bronchoscopy in all patients, transthoracic needle biopsy in 13, cervical mediastinoscopy in nine, parasternal mediastinotomy in two and thoracoscopy in two, in all patients without proving unresectability. A CT scan was performed in 118 patients indicating resectability in 33%, doubtful resectability in 64% and unresectability in 3%. Clinical and surgical staging were equal in 3% of stage IIB patients, in 24% of stage IIIA, 100% of stage IIIB and 75% of patients in stage IV. The 30-day operative mortality was 4.6%. The reasons for ET were: diagnosis of preoperatively unverified tumor in one patient, necessity for pneumonectomy in the case of poor pulmonary function in 11 patients, and unresectability in 119 (due to invasion of the mediastinum in 98 patients, thoracic wall in three and vertebral body in one, and due to pleural metastases in 17 patients). ET could have been avoided in 15 (11%) patients. The median survival for both ET and control group patients was 11.1 months. The survival difference was not statistically significant (p = 0.420). CONCLUSION: ET could be partly avoided through a more accurate preoperative staging procedure. It does not appear possible to avoid ET in patients with limited pulmonary reserve precluding a resection larger than that predicted, nor to avoid ET as a consequence of intraoperative complications. Despite operative mortality, ET did not significantly influence the survival rate in the present study.

Multidrug resistance in small cell lung cancer: expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease.

The aim of this study was to investigate the expression of multidrug resistance-associated proteins in metastatic small cell lung cancer (SCLC) cells correlated to cisplatin/etoposide chemotherapy response and the level of those proteins in relapsed disease. Samples were obtained by transbronchial fine needle aspiration biopsy (TBNA) of enlarged mediastinal lymph nodes in 17 patients. After cytological confirmation of SCLC, cells were stained by a panel of mAbs against internal epitopes of P-gp (JSB-1), MRP1 (MRPr1), LRP (LRP-56) and cytokeratin (MNF116) and analyzed by flow cytometry. We observed a significant negative correlation for better response rate to chemotherapy with individual expression of P-gp (r=-0.93, P<0.0001; Pearson correlation) and MRP1 (r=-0.78, P=0.0002; Pearson correlation) in chemo-naive SCLC cells and a non-significant correlation for LRP expression. P-gp and MRP1 expression was markedly increased in metastatic cells in four out of five patients with relapsed disease (4-12 months after starting chemotherapy), in comparison to their chemo-naive values. In conclusion, the results suggest that P-gp and MRP1 might be associated with SCLC cell survival during metastasis and chemotherapy, and that overexpression of those transporters in relapsed disease could assist short-term chemotherapy efficiency.