Induction chemotherapy with the TIP regimen (paclitaxel/ifosfamide/cisplatin) in stage III non-small cell lung cancer.

Induction chemotherapy may improve clinical outcome of locally advanced non-small cell lung cancer (NSCLC). To further pursue this, the Austrian Association for the Study of Lung Cancer (AASLC) performed a multi-center phase II trial with TIP induction chemotherapy (Taxol 175 mg/m2 over 3h on day 1, ifosfamide 1000 mg/m2 daily on days 1-3, cisplatin 60 mg/m2 on day 1, and prophylactic filgrastim 5 microg/kg daily on days 4-13). Treatment cycles were repeated every 3 weeks for 3 cycles. Then patients were re-staged and selected for local treatment. Forty-seven patients (33 male, 14 female; median age 58 years, range 36-78; 22 cIIIA, 25 cIIIB; 26 adenocarcinomas, 14 squamous cell carcinomas, 4 large cell carcinomas, 3 undifferentiated carcinomas) were included in this trial. Forty-five patients were evaluable for response and toxicity. An overall response rate of 43% (complete remission 4.5% and partial remission 38%) was achieved. Stable disease and progressive disease were seen in 38 and 15% of the patients, respectively. Down-staging occurred in 36% of the patients. The toxicities of the chemotherapy were mild and, in particular, no severe hematotoxicity was observed. Surgery was performed in 24 (51%) patients and resulted in complete tumor resection in 19 patients. Twenty-four patients received thoracic radiotherapy, 10 patients after surgery. Median survival was 10.3 months for the total population, 13.5 months for patients with cIIIA and 10 months for patients with clinical cIIIB. Survival was longer for patients with down-staging as compared to those without (median not reached versus 10 months, p=0.005) and for patients with complete tumor resection as compared to the remaining patients (27 months versus 10 months, p=0.05). In conclusion, the TIP regimen shows activity and good tolerance as induction chemotherapy in patients with locally advanced NSCLC.

Non-small cell lung cancer: evaluation of pleural abnormalities on CT scans with 18F FDG PET.

PURPOSE: To evaluate the accuracy of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in differentiation of pleural malignancy and cancer-unrelated pleural disease in patients with non-small cell lung cancer (NSCLC) and pleural abnormalities at computed tomography (CT). MATERIALS AND METHODS: In 92 patients, pleural abnormalities were detected at contrast material-enhanced thoracic CT, which was performed for newly diagnosed NSCLC (n = 41) or restaging (n = 51). CT findings were negative for pleural malignancy when pleural effusion with attenuation of 10 HU or less and/or rib fractures with no evidence of pathologic fracture were present; findings were indeterminate when pleural effusion with attenuation greater than 10 HU and/or solid pleural abnormalities without osseous destruction of the chest wall were present; and findings were positive if any osseous destruction of the chest wall adjacent to a pleural mass was present. All patients underwent FDG PET. Findings were negative for pleural malignancy if pleural activity was absent, equal to, or less than mediastinal background activity; findings were positive if pleural activity was higher than mediastinal background activity. Reading of CT and FDG PET scans was first performed separately and then was combined. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPP), and accuracy were calculated for CT and FDG PET separately and for CT and FDG PET combined, with cytologic and/or histologic analysis as standard of reference. RESULTS: In detection of pleural malignancies, CT findings were indeterminate in 65 (71%) patients and true-negative in 27 (29%). Respective sensitivity, specificity, PPV, NPV, and accuracy of FDG PET in detection of pleural malignancies were 100%, 71%, 63%, 100%, and 80%; and those of CT and FDG PET combined, 100%, 76%, 67%, 100%, and 84%. CONCLUSION: Findings suggest that a negative FDG PET scan for indeterminate pleural abnormalities at CT indicates a benign character, while positive findings on an FDG PET scan are sensitive for malignancy.

Photodynamic therapy enhanced by hyperbaric oxygenation in palliation of malignant pleural mesothelioma: clinical experience.

INTRODUCTION: Surgical debulking followed by radiotherapy/chemotherapy are the standards in the palliative treatment schedule of malignant pleural mesothelioma. The aim of this study was to evaluate the additional effect of intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) if compared to decortication alone. PATIENTS AND METHODS: From January 1993 to August 2003, decortication was done in 34 patients (28 males, 6 females; mean age: 65 years) suffering from advanced malignant pleural mesothelioma. Twenty-two patients received additional intraoperative PDT under HBO. The surgery and PDT/HBO was done 48h after photosensitization with a polyhematoporphyrin, 2mg/kg BW using a diode laser delivering red light at 630nm through a microlens. The light dose was calculated for 300J at a distance of 1cm from the tumour surface. RESULTS: At 6-month follow-up the Karnofsky performance status showed no significant difference (P≥0.05) between both groups. CT scans documented focal regrowth of the tumour after 6 months in 10/12 cases of the non-PDT group. However, in the PDT group tumour regrowth was detected in only 9/22 cases at 6-month follow-up. Survival analysis showed a significant advantage for the group with PDT (log-rank test: P=0.0179). CONCLUSION: Although the study includes only a small number of patients, it indicates that additional PDT/HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura.

Polyhematoporphyrin-mediated photodynamic therapy and decortication in palliation of malignant pleural mesothelioma: a clinical pilot study.

The aim of this study was to evaluate the additional effect of intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) when compared with decortication alone. From 1/1993 to 8/2002, palliation with decortication was done in 25 patients suffering from advanced malignant pleural mesothelioma. Fourteen patients received additional intraoperative PDT under HBO. The surgery and PDT/HBO was done 48 h after photosensitization with a polyhematoporphyrin, 2 mg/kg/BW using a diode laser delivering red light at 630 nm through a microlens. The light dose was calculated for 300 J with a distance of 1 cm from the tumor surface. At 6-month follow up local tumor control and survival showed a significant difference in both groups. Although the study only includes a small number of patients not allowing definite conclusions, it indicates that the additional PDT/HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura.

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis.

OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.