Multicenter phase II study evaluating docetaxel and cisplatin as neoadjuvant induction regimen prior to surgery or radiochemotherapy with docetaxel, followed by adjuvant docetaxel therapy in chemonaive patients with NSCLC stage II, IIIA and IIIB (TAX-AT 1.203 Trial).

OBJECTIVES: Neoadjuvant therapy with a platinum based doublet is an option in NSCLC patients with upfront resectable disease. However, the role of neoadjuvant induction in stages IIIA and IIIB and in initially not resectable patients is unclear. PATIENTS AND METHODS: In this phase II trial, 78 patients with locally advanced NSCLC, of whom 56 were considered not resectable at initial diagnosis, were treated with three neoadjuvant cycles of docetaxel and cisplatin and subjected to radical surgery if resectable. Definitive radiochemotherapy (RCT) using weekly docetaxel was the prespecified alternative if patients were not resectable at restaging. The primary objective was response to neoadjuvant induction. RESULTS: After induction, 36 (46%) were radically operated and 24 (31%) were treated with RCT. Overall, 32 patients (41%) completed the entire study plan. Partial response to induction therapy was observed in 43 patients (55%); furthermore, 19 of 56 initially not resectable cases (34%) became resectable upon induction. Median progression-free (PFS) and overall survival (OS) were 8.5 and 16.4 months for the whole cohort. Encouragingly, conversion to resectability was predictive for favorable outcome. On the other hand, patients who were not resectable at restaging and received RCT were characterized by a rather unfavorable prognosis (5-year and 10-year OS, whole cohort: 20% and 12%; RCT: 8% and 0%; surgery: 37% and 24%, respectively). CONCLUSION: Neoadjuvant induction with the doublet docetaxel/cisplatin and subsequent radical resection resulted in favorable survival. Of note, conversion to resectability was mandatory for the chance of cure in patients considered initially not resectable.

Cervical ultrasound (US) and US-guided lymph node biopsy as a routine procedure for staging of lung cancer.

PURPOSE: To assess the value of routine ultrasound evaluation and US-guided fine-needle aspiration biopsy of supraclavicular lymph nodes for the diagnosis, staging and treatment of patients with lung cancer. MATERIALS AND METHODS: 300 consecutive patients with lung cancer were evaluated with high-resolution ultrasound for the presence of pathological lymph nodes (criteria: short-axis >or= 5 mm, rounded shape, missing echogenic hilum). Suspicious lymph nodes were biopsied under ultrasound guidance if the result could influence further patient management RESULTS: In 41 of 257 NSCLC patients (16 %) and 15 of 43 (35 %) SCLC patients, enlarged lymph nodes were detected, in particular in patients with a CT stage N2 or N3 (NSCLC) or extensive disease (SCLC). 16 lymph node biopsies were positive for malignancy, 4 biopsies were negative for malignancy or not diagnostic. US had a higher sensitivity for the detection of pathological lymph nodes than CT. CONCLUSION: Routine ultrasound evaluation of supraclavicular lymph nodes reveals suspicious lymph nodes in a high number of patients with lung cancer. High-resolution US is superior to CT in the detection of pathological lymph nodes. Ultrasound-guided biopsy proves malignancy and thereby a N3 or M1 stage. Thus, more invasive and expensive diagnostic procedures can be avoided.

Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk.

Microsomal epoxide hydrolase (mEH) plays a dual role in the detoxification and activation of tobacco procarcinogens. Two polymorphisms affecting enzyme activity have been described in the exons 3 and 4 of the mEH gene, which result in the substitution of amino acids histidine to tyrosine at residue 113, and arginine to histidine at residue 139, respectively. We performed a hospital-based case-control study consisting of 277 newly diagnosed lung cancer patients and 496 control subjects to investigate a possible association between these two polymorphisms and lung cancer risk. The polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism and TaqMan assay using DNA from peripheral white blood cells. Logistic regression was performed to calculate odds ratios (ORs), confidence limits (CL) and to control for possible confounders. The exon 3 polymorphism of the mEH gene was associated with a significantly decreased risk of lung cancer. The adjusted OR, calculated relative to subjects with the Tyr113/Tyr113 wild type, for the His113/His113 genotype was 0.38 (95% CL 0.20-0.75). An analysis according to histological subtypes revealed a statistically significant association for adenocarcinomas; the adjusted OR for the His113/His113 genotype was 0.40 (95% CL 0.17-0.94). In contrast, no relationship between the exon 4 polymorphism and lung cancer risk was found. The adjusted OR, calculated relative to the His139/His139 wild type, was for the Arg139/Arg139 genotype 1.83 (0.76-4.44). Our results support the hypothesis that genetically reduced mEH activity may be protective against lung cancer.

Genetic polymorphisms of CYP1A1 and GSTM1 and lung cancer risk.

Susceptibility to lung cancer may, in part, be determined by interindividual differences in the cytochrome P450-catalysed bioactivation and the glutathione S-transferase-catalysed detoxification of procarcinogens. Therefore a lung cancer case-control study was set up to investigate the association of three polymorphisms of the CYP1A1 gene (CYP1A1*2A, CYP1A1*2B, CYP1A1*4) and GSTM1*0 genotype with lung cancer risk in Austrian Caucasians. Genomic DNA was isolated from the peripheral blood lymphocytes of 134 male lung cancer patients and 134 age-matched controls with nonmalignant conditions and PCR-based analyses were performed. There was no significant difference in risk between cases and controls, either for the CYP1A1*2A (OR=1.09, 95%CI=0.46-2.58), CYP1A1*2B (OR=1.09, 95%CL=0.46-2.58) or for the CYP1A1*4 polymorphism (OR=0.49, 95%CL=0.20-1.16). The prevalence of the GSTM1*0 genotype in the lung cancer group (47.8%) was comparable to that found in the control group (49.3%) and also had no effect on lung cancer risk (OR=0.94, 95%CL=0.54-1.57). Further, in a subgroup of male ever-smokers (n=126), no significant influence on the relative risk was found for these polymorphisms. Our results suggest that these investigated polymorphisms can not be considered as genetic susceptibility markers for lung cancer within the Austrian Caucasian population.

Vinorelbine-gemcitabine in advanced non-small-cell lung cancer (NSCLC): an AASLC phase II trial. Austrian Association for the Study of Lung Cancer.

PURPOSE: The purpose of the present phase 11 trial was to determine the efficacy and toxicity of vinorelbine-gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From December 1997 to February 1999, 78 chemotherapy-naive patients (median age 60 years, Karnofsky performance status of 100, 90, 80 and 70 present in 5%, 41%, 36% and 18% of the patients, respectively) with stage IIIB (17%) or IV (83%) NSCLC (65% adenocarcinomas, 22% squamous-cell carcinomas, 10% large-cell carcinomas, 3% mixed-cell carcinomas) received 25 mg/m2 vinorelbine and 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a four-week cycle. RESULTS: In an intent-to-treat analysis, partial responses were seen in 19% of the patients. The median duration of response was 4.4 months. The median survival time was seven months and the one-year survival rate was 32%. Myelosuppression was the main side effect with WHO grade 3/4 neutropenia and thrombocytopenia in 35% and 11% of the patients, respectively. Other side effects were usually mild to moderate. CONCLUSIONS: Vinorelbine-gemcitabine is active, well tolerated and easy to administer on an outpatient basis in advanced NSCLC. Thus a randomized comparison of this combination with platinum-based protocols is warranted in patients with advanced NSCLC.

Advanced non-small-cell lung cancer: adjunctive interferon gamma in induction and maintenance therapy.

PURPOSE: To evaluate the feasibility of interferon gamma (IFNgamma) as an adjunct to chemotherapy in advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 32 patients were recruited and received 25 mg/m2 cisplatin and 100 mg/m2 etoposide on days 8, 10 and 12 every 3 weeks for a total of three cycles. A dose of 100 microg IFNgamma was given subcutaneously three times weekly from days 1 to 8 and between days 15 and 29. After induction, all patients except those with progressive disease were offered IFNgamma maintenance therapy: 100 microg three times weekly. RESULTS: The following responses were obtained: partial response, 5 (16%); minor response, 12 (37%); stable disease, 4 (13%); progressive disease, 11 (34%). The survival rates after 1 and 2 years were 47% and 25% respectively. Patients receiving maintenance IFNgamma had a 2-year survival rate of 58%. Toxic side-effects were rare and included grade III/IV fever (7%/1%) and grade III/IV leucopenia (4%/1%). CONCLUSIONS: In patients with advanced NSCLC, an adjunctive dose of 100 microg IFNgamma, given three times weekly in the induction and maintenance phase, is feasible. Survival data seem favourable so this regimen may warrant further investigation in a phase III study.

Vinorelbine/gemcitabine in advanced non-small cell lung cancer (NSCLC): a phase I trial.

Vinorelbine and gemcitabine are both active as single agents in advanced non-small cell lung cancer (NSCLC). Because of their different mechanisms of action, good tolerability and possible administration on an out-patient basis, vinorelbine/gemcitabine should be an interesting combination for palliative chemotherapy. Thus, we initiated a phase I dose-escalation trial in order to determine the maximum tolerated doses of vinorelbine/gemcitabine that can be administered without haematopoietic growth factors, the dose-limiting toxicities and the most frequent side-effects of this novel combination. 40 chemotherapy-naïve patients with advanced NSCLC were treated with different doses of vinorelbine/gemcitabine on days 1, 8 and 15, and this treatment cycle was repeated on day 29. Vinorelbine and gemcitabine were escalated from 10 to 30 mg/m2 and 600 to 1200 mg/m2, respectively. A total of 63 treatment cycles were administered and 27 patients received at least two treatment cycles. Dose-limiting toxicities were leucopenia plus thrombocytopenia (2 patients) and mucositis (1 patient). The maximum tolerated dose was established at 25 mg/m2 vinorelbine combined with 1200 mg/m2 gemcitabine. Frequent side-effects were leucopenia, anaemia, nausea/vomiting, flu-like symptoms, skin rashes and elevation of liver enzymes. The recommended phase II doses are 20-25 mg/m2 vinorelbine combined with 1000-1200 mg/m2 gemcitabine on days 1, 8 and 15, but myelosuppression will have to be carefully monitored.

Evaluation of Cyfra 21-1 as a marker for lung cancer.

The sensitivity and specificity of Cyfra 21-1 as marker for lung cancer was evaluated in comparison with carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). Patients with histologically verified lung cancer and different groups without lung cancer were investigated. Sensitivity of Cyfra 21-1 (cut-off level 2.9 micrograms/l) was 40% for non-small cell lung cancer (NSCLC), 60% for rare histological types and 21% for small cell lung cancer (SCLC). In NSCLC sensitivity of Cyfra 21-1 was 35% for squamous cell carcinoma and 41% for adenomous carcinoma. The highest sensitivity for CEA was 45% in NSCLC, with 57% in the subtype of adenomous cell carcinoma; for SCC 30% was achieved in squamous cell carcinoma and for NSE 66% sensitivity was reached in SCLC. In our patients Cyfra 21-1 and CEA appeared equally useful for evaluating patients with NSCLC.

Circulating antineuronal antibodies reach neurons in vivo: an autopsy study.

In serum and cerebrospinal fluid of 6 out of 15 patients with small cell lung cancer circulating antineuronal antibodies could be detected by indirect immunofluorescence. None of the patients showed signs of a neurological paraneoplastic syndrome, usually associated with the presence of these antibodies. On sections of frontal brain, cerebellum, dorsal root ganglia and peripheral nerve, obtained at autopsy, a direct immunofluorescence test was performed. Only in antibody-positive individuals were membrane-bound immunoglobulin deposits detected on neurons of dorsal root ganglia and Purkinje cells. The present study showed that circulating antineuronal antibodies reach the central and peripheral nervous system in vivo. These findings support the theory that these antibodies might be directly involved in the pathogenesis of neurological paraneoplastic syndromes.