Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial.

BACKGROUND: Most patients (pts) with metastatic non-small cell lung cancer (NSCLC) receive either single agents or chemotherapy doublets. Recent studies have demonstrated that triple-agent therapies may improve the response rate, but are associated with significant toxicity, and frequently do not prolong survival. A sequential triple-agent schedule may combine acceptable tolerability and good efficacy. We therefore conducted a multicentre, prospectively randomized study that evaluates a sequential three-drug schedule and a platinum-free doublet regimen. PATIENTS AND METHODS: The pts with union international contre le cancer (UICC) stage IV NSCLC were randomized to one of two schedules: in arm Doc-Gem, they received gemcitabine (900 mg/m(2), 30 min infusion) on days 1 and 8, and docetaxel (75 mg/m(2), 1 h infusion) on day 1, repeated every 3 weeks up to six cycles. In arm Cis-Gem-->Doc, gemcitabine (900 mg/m(2), days 1 and 8) and cisplatin (70 mg/m(2), 1 h infusion, day 1) were given for three cycles, followed by three cycles of docetaxel (100 mg/m(2), day 1, repeated every 3 weeks). RESULTS: One hundred and thirteen pts were randomized to arms Doc-Gem (55 pts) and Cis-Gem-->Doc (58 pts). With Doc-Gem, 20.4% of pts responded to the treatment whereas 31.0% responded in arm Cis-Gem-->Doc (overall response, intent-to-treat, difference not significant). The median time to progression was 3.6 months in arm Doc-Gem [95% confidence interval (CI) 1.4, 5.9] and 5.2 months in arm Cis-Gem-->Doc (95% CI 3.1, 7.3). The median survival was 8.7 months with treatment Doc-Gem (95% CI 5.7, 11.6) and 9.4 months with treatment Cis-Gem-->Doc (95% CI 7.8, 11.0). The 1-year survival rates were 34 and 35%, respectively. Mild to moderate leukopenia was frequently seen with both schedules. Other common adverse events (AE) were nausea/vomiting, thrombocytopenia, anaemia, diarrhoea, and infections. No significant differences in AEs were observed between the schedules except for nausea/vomiting, which occurred more frequently with Cis-Gem-->Doc. CONCLUSION: The sequential therapy comprising cisplatin, gemcitabine, and docetaxel demonstrated promising tumour control whereas the platinum-free combination (docetaxel/gemcitabine) was very well tolerated. However, the schedules resulted in comparable survival to recent large trials in pts with advanced NSCLC. The present results do not justify further phase III investigation.

[Brain metastases of lung cancer]. / Hirnmetastasen beim Lungenkarzinom.

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Invasive staging of non-small cell lung cancer--a prospective study.

OBJECTIVES: Clinical prognosis and treatment schedules of non-small cell lung cancer (NSCLC) are dependent on tumor stage. This explains the importance of an exact pretreatment staging of the primary tumor and lymph nodes especially in locally advanced NSCLC, to differentiate between resectable and non-resectable disease. To assess the lymph node status of the upper mediastinum, the diagnostic value of mediastinoscopy is accepted to be superior to radiological methods. In contrast, thoracoscopy is not yet established as a standard staging tool. PATIENTS AND METHODS: Seventy-three consecutive patients with CT-based suspicion of advanced NSCLC have been investigated as part of a phase II study on neoadjuvant treatment of NSCLC. All patients underwent mediastinoscopy and mediastinal lymph node sampling. In the case of a negative result we performed additional thoracoscopy. RESULTS: In 52.1% (n = 38) of the patients the invasive diagnostic methods led to results that were effectively different from those of the radiological findings. In 11 patients (15.1%) CT-assessed lymph node metastases could invasively not be confirmed, whereas nine patients (12.3%) had positive mediastinal lymph nodes but no corresponding CT signs (diameter <1 cm). The results were achieved by mediastinoscopy in 15 (20.5%) and by thoracoscopy in five (6.8.%) patients. A radiologically unexpected T4 stage has been found in four (5.5%) and a M1 stage in four (5.5%) patients by thoracoscopy. On the contrary, in seven patients a suspected infiltration of mediastinum or parietal pleura could be thoracoscopically excluded. Four patients have been in an unexpected high stage of tumor progression at the moment of diagnostic procedures and therefore have been included in palliative therapy schedules. Ten patients have been 'overstaged' by radiological methods and benefited from a primarily curative resection after invasive staging. CONCLUSIONS: Of the 73 prospectively studied patients with locally advanced NSCLC, 12 (16.4%) have been staged too low and 13 (17.8%) too high. If exclusively staged by radiological methods, about 34% of lung cancers have been classified incorrectly. Therefore, these tools are not a sufficient basis for diagnosis of stage III NSCLC disease. Mediastinoscopy with consecutive thoracoscopy is an essential part of the therapeutic planning in locally advanced NSCLC, and results are significantly superior to clinical staging.

Detection of amplifiable messenger RNA in the serum of patients with lung cancer.

Recently, in addition to the detection of circulating tumor cells in peripheral blood of patients with solid tumors, the presence of free circulating nucleic acids in the plasma and serum has also been described. We have focused on the possibility of isolating and amplifying intact extracellular, tumor-related mRNA from the plasma/serum of patients with lung cancer. For this purpose, we established several RT-PCR-based amplification systems for the detection of a panel of five different genes. The expression of these genes was either shown to be restricted to lung tissue or associated with malignancy. We examined two small groups of 18 patients with lung cancer before and during chemotherapy, respectively. The message for beta-actin (control for integrity of the RNA) was detected in all of the analyzed sera from the control group and patients with lung cancer. Analysis of CK-19 expression was positive in the majority of tumor patients, but positive results were also shown in all of the control sera. The expression of MAGE-2 and TTF-1 genes was not observed in any of the patients in either the lymphocyte preparations or serum samples. Expression of the PGP 9.5 gene was observed in the cells of all 18 patients, but mRNA in the serum was only detectable in one case. The hnRNP-B1 mRNA was detectable in 14/18 sera, and Her2/neu-specific mRNA could be amplified from the serum of 7/18 patients. Combining the last two markers, we were able to detect all patients with a malignant lung tumor.

[Hybrid 3-D rendering of the thorax and surface-based virtual bronchoscopy in surgical and interventional therapy control]. / Hybride 3D-Visualisierung des Thorax und oberflächenbasierte virtuelle Bronchoskopie in der operativen und interventionellen Therapiekontrolle.

PURPOSE: The aim of this study was to demonstrate the possibilities of a hybrid rendering method, the combination of a color-coded surface and volume rendering method, with the feasibility of performing surface-based virtual endoscopy with different representation models in the operative and interventional therapy control of the chest. MATERIAL AND METHOD: In 6 consecutive patients with partial lung resection (n = 2) and lung transplantation (n = 4) a thin-section spiral computed tomography of the chest was performed. The tracheobronchial system and the introduced metallic stents were visualized using a color-coded surface rendering method. The remaining thoracic structures were visualized using a volume rendering method. For virtual bronchoscopy, the tracheobronchial system was visualized using a triangle surface model, a shaded-surface model and a transparent shaded-surface model. RESULTS: The hybrid 3D visualization uses the advantages of both the color-coded surface and volume rendering methods and facilitates a clear representation of the tracheobronchial system and the complex topographical relationship of morphological and pathological changes without loss of diagnostic information. Performing virtual bronchoscopy with the transparent shaded-surface model facilitates a reasonable to optimal, simultaneous visualization and assessment of the surface structure of the tracheobronchial system and the surrounding mediastinal structures and lesions. CONCLUSIONS: Hybrid rendering relieve the morphological assessment of anatomical and pathological changes without the need for time-consuming detailed analysis and presentation of source images. Performing virtual bronchoscopy with a transparent shaded-surface model offers a promising alternative to flexible fiberoptic bronchoscopy.

Neuropathy under chemotherapy.

Neuropathy is a dose-limiting side effect for a number of effective chemotherapeutic agents. A better understanding of effective mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy. The assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital, for a determination of the maximum allowable dose. The introduction of chemotherapy in the 50s and 60s of the twentieth century has resulted in the development of curative therapeutic interventions for patients with several types of solid tumours and hemopoietic neoplasms. The important obstacles encountered in the use of chemotherapy have been the toxicity to the normal tissue. During the past 8 years there has come about a new level of understanding of the mechanisms through which chemotherapeutic agents work. This has opened the door to new paradigms of treatment in which molecular, genetic, and biologic therapy can be used together to increase the sensitivity of abnormal cells to treatment, and to protect the normal tissues of the body from therapy-induced side effects. The implementation of new strategies could change the way therapy is delivered over the next few years and improve the outcome especially in patients with neoplasms that are currently resistant to conventional dose therapy.

Further evidence for oxidant-induced vascular endothelial growth factor up-regulation in the bronchoalveolar lavage fluid of lung cancer patients undergoing radio-chemotherapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent inducer of physiological and neoplastic blood vessel growth. Moreover, in vitro studies have demonstrated that VEGF can be up-regulated by conditions associated with the generation of free radicals and reactive oxygen species. In a previous study we reported on strongly increased VEGF concentrations in the bronchoalveolar lavage fluid (BALF) of patients with lung cancer under therapy. In this study we aimed to reveal whether this increase was due to the therapy-associated intrapulmonary oxidative burden. PATIENTS AND METHODS: A total of 103 BALF samples from 94 patients with lung cancer (82 patients with non-small-cell lung cancer, 12 patients with small-cell lung cancer) were studied at different times before, during or after cancer treatment. VEGF levels in the lavage fluid and ratios of oxidised methionine in proteins of epithelial lining fluid (ELF) were determined. RESULTS: As reported previously, strongly increased VEGF levels in the ELF were observed in patients undergoing chemotherapy when radiotherapy had been administered before. Increased levels of oxidised methionine indicated that these patients suffered from severe pulmonary oxidative stress that was significantly less in patients undergoing only chemotherapy. Similarly, VEGF concentrations in the ELF were significantly elevated in cancer patients at the time of diagnosis, but the oxidised methionine levels did not reveal significant oxidant/antioxidant imbalances in these patients. CONCLUSION: Systemic chemotherapy is associated with oxidative stress in vivo, which is more pronounced if patients are additionally treated with radiation. VEGF levels in the ELF are increased by this condition as well as by the activity of the tumour itself.

Pulmonary glutathione levels in acute episodes of Farmer's lung.

Acute episodes of farmer's lung (FL) are associated with activation and migration of neutrophils into the lungs, causing oxidative stress. We conducted a study to evaluate the effect of episodes of FL on antioxidant defense of the lung by glutathione (GSH). A total of 15 patients with symptomatic FL (one female and 14 males, age 42 +/- 1 yr [mean +/- SEM]) underwent a standardized hay exposure test for 1 h and were then monitored through lung function measurements for 6 h, after which bronchoalveolar lavage (BAL) was performed. As a control, 10 asymptomatic farmers (AF) (two males and eight females, age 43 +/- 1 yr) underwent the same diagnostic procedures. At 3 to 6 h after antigen exposure, the lung function of FL patients was significantly impaired (VC: -31 +/- 4%; single-breath diffusing capacity of carbon monoxide [DL(CO)]: -17 +/- 3%; and Pa(O(2)): -14 +/- 2%, all versus baseline, whereas in AF, only minor changes occurred VC: -4 +/- 5%; DL(CO): -9 +/- 3%, and Pa(O(2)): -5 +/- 2%, all versus baseline). The number of neutrophils in bronchoalveolar lavage fluid was increased in FL patients as compared with AF (29 +/- 7 x 10(4)/ml versus 10 +/- 7 x 10(4)/ml, p < 0.05). The concentrations of total and reduced glutathione (GSH(T) and GSH, respectively) in epithelial lining fluid were decreased in FL patients and increased in AF (GSH(T): 292.5 +/- 27.5 microM versus 1, 185.0 +/- 189.9 microM, respectively, p < 0.001; GSH: 256.8 +/- 22.1 microM versus 1,054.5 +/- 172.9 microM, respectively, p < 0.001). These findings suggest that the individual ability to upregulate GSH in the alveolar space in response to an inflammatory stimulus may have implications for the development of symptomatic FL. We conclude that intrapulmonary GSH levels are distinctly different in patients with FL and AF, and that the regulation of GSH may play an important role in the pathogenesis of FL.

Detection of microsatellite alterations in the DNA isolated from tumor cells and from plasma DNA of patients with lung cancer.

In this paper, we show that the same panel of three microsatellite markers is useful for the detection of alterations in the DNA of tumor cells and plasma from patients diagnosed with SCLC and NSCLC. In 31% of the SCLC patients, we detected a microsatellite alteration(s) or LOH in at least one locus. In the group of patients diagnosed with NSCLC, a microsatellite alteration or LOH was detected in at least one locus in 33% of the patients. In all but 2 patients, the identical alteration observed in the DNA from tumor cells was also detected in the DNA isolated from blood plasma. This work confirms the results described by other groups and it extends the diagnostic possibilities of finding tumor cell-specific DNA alterations also in the DNA freely circulating in plasma and serum of patients with cancer.

Increased expression of the tetraspanins CD53 and CD63 on apoptotic human neutrophils.

The recently discovered tetraspanin superfamily comprises a group of cell-surface proteins that are suggested to be involved in cell activation and signal transduction as well as in cell adhesion, motility, and metastasis. In this study, we have assessed the expression of two tetraspanins, CD53 and CD63, and two principal leukocyte adhesion molecules, CD11b and CD62L, on human apoptotic neutrophils. After aging of human neutrophils for 20 and 40 h in vitro, apoptosis was analyzed by light microscopy and flow cytometry. The binding of monoclonal antibodies directed against CD11b, CD62L, CD53, and CD63 on apoptotic and nonapoptotic cells was determined by dual-color flow cytometry. Aging of neutrophils in vitro resulted in a significant (P < 0.05) down-regulation of expression of the selectin CD62L, and a significantly increased expression of the two tetraspanins CD53 and CD63. The selective analysis of apoptotic versus nonapoptotic cells proved that both the increased expression of the tetraspanins and the loss of CD62L were restricted to the apoptotic subpopulation. An identical pattern of surface molecule expression was detected at 12 h after induction of apoptosis by an agonistic anti-Fas IgM monoclonal antibody. Further studies are required to clarify whether tetraspanins participate in the recognition of apoptotic circulating or extravasated neutrophils by macrophages.

An evaluation of the tumour markers, carcinoembryonic antigen (CEA), cytokeratin marker (CYFRA 21-1) and neuron-specific enolase (NSE) in the differentiation of malignant from benign solitary pulmonary lesions.

PURPOSE: The aim of this prospective study was to assess the diagnostic value of the tumour markers carcinoembryonic antigen (CEA), cytokeratin 19 fragment marker (CYFRA 21-1) and neuron-specific enolase (NSE) in the differentiation of malignant (MSPLs) from benign solitary pulmonary lesions (BSPLs). METHODS: Solitary pulmonary lesions (SPLs) were diagnosed using plain radiography and spiral computed tomography (SCT) and then completely removed by surgery in 104 consecutive patients (MSPLs; n = 81, BSPLs; n = 23). The serum concentrations of the tumour markers were determined 1-3 days prior to surgery by ELISA for CEA and CYFRA 21-1 and by IRMA for NSE using commercially available assay kits. The cut-off values were set at 3 ng/ml (for non-smokers) and 5 ng/ml (for smokers) for CEA, at 3.3 ng/ml for CYFRA 21-1 and at 12.5 ng/ml for NSE. RESULTS: MSPLs were identified with a sensitivity between 13.6 and 45.7%, a specificity between 87.0 and 100% and an accuracy between 32.7 and 54.8%. Using the tumour markers alone, the highest sensitivity (27.2%) and accuracy (40.4%) was found with CEA, the highest specificity (100%) with CYFRA 21-1 and with NSE. Primary lung cancers (n = 39) were identified with a sensitivity between 17.9 and 61.5%, a specificity between 87.0 and 100% and an accuracy between 48.4 and 71.0%. Using the tumour markers alone, the highest sensitivity (35.9%) and accuracy (59.7%) was found with CYFRA 21-1, the highest specificity (100%) with CYFRA 21-1 and with NSE. The combination of all three tumour markers resulted in a greater sensitivity and greater diagnostic accuracy but a loss in specificity compared with CYFRA 21-1 and NSE. CONCLUSION: The use of the tumour markers alone or in combination showed a low sensitivity and low accuracy for the diagnostic differentiation of MSPLs from BSPLs and primary lung cancers from BSPLs. However, both CYFRA 21-1 and NSE exhibited a specificity of 100% and may be useful complements to standard clinical imaging methods.

Eosinophilia during fludarabine treatment of chronic lymphocytic leukemia.

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9x10(9)/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized.

Increased levels of vascular endothelial growth factor in bronchoalveolar lavage of patients with bronchial carcinoma effect of tumour activity and oxidative stress due to radio-chemotherapy?

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a crucial role in physiological and neoplastic angiogenesis. Moreover, VEGF has been found to be upregulated by conditions associated with the generation of free radicals and reactive oxygen intermediates. In patients with cancer, studies to evaluate VEGF as a measure of tumour activity were carried out. We tested the hypothesis that VEGF is additionally affected by oxidative stress due to anticancer therapy. Moreover, the suitability of epidermal growth factor (EGF) to estimate tumour activity was studied. PATIENTS AND METHODS: 60 patients with non-small cell lung cancer (NSCLC) covering different therapy progress and modalities underwent bronchoalveolar lavage. VEGF-, EGF-, albumin- and total protein-concentrations in bronchoalveolar lavage fluid (BALF) and VEGF-levels in blood plasma were studied. RESULTS: BALF VEGF-levels were increased in patients with advanced NSCLC before and in anticancer therapy. In patients who had received radiotherapy to the lung prior to chemotherapy, VEGF concentrations were noticeably higher than under sole chemotherapy. Pulmonary endothelial hyperpermeability was found in patients with recently diagnosed tumours and patients undergoing anti-cancer therapy. Evaluation of EGF-levels in BALF revealed no significant influence of tumour activity or cancer therapy on this parameter. CONCLUSION: BALF-levels of VEGF are affected by tumour activity and oxidative stress due to anticancer therapy.

Molecular genetic characteristics of lung cancer--useful as real' tumor markers?

The increased knowledge about the molecular mechanisms leading to the development of a tumor has opened new horizons for basic and applied research. Lung cancer is among the tumor entities with the highest incidence and mortality rates. Recently new drugs and therapeutic options for patients with lung cancer were developed. These developments demand new and improved techniques for the sensitive and specific detection of lung tumor cells. Some of the molecular genetic features of lung tumor cells are summarized and the possibilities to use these characteristics as new tumor markers are discussed.

Tumour markers - new aspects of an old discussion?

The knowledge about the molecular genetic features of cancer has been vastly increased within the last few years. Tumor markers used so far for diagnosis, monitoring, and follow-up of cancer patients are tumor-associated rather than tumor-specific. Therefore, the development of more sensitive and specific tumor markers is urgently needed. In this review, the possibilities of using molecular genetic characteristics of cancer as specific and sensitive tumor markers are discussed.