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Background: Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours., Methods: We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421., Findings: By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients., Interpretation: These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer., Funding: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC)., Materials and Methods: Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR)., Results: 155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation., Conclusion: Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease., Methods: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more., Results: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%., Conclusions: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.

Purpose: This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination., Methods: Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods., Results: Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents., Conclusions: Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

Purpose: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents., Methods: Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene)., Results: Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions., Conclusions: A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

Background: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS)., Results: A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm)., Conclusions: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Purpose: To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1) or with dulanermin 8 mg/kg for 5 days (arm 2). Patients with nonsquamous NSCLC received PCB alone (arm 3) or with dulanermin 8 mg/kg for 5 days (arm 4) or 20 mg/kg for 2 days (arm 5). The primary end point was the objective response rate (ORR)., Results: Overall, 213 patients were randomly assigned (arm 1, n = 41; arm 2, n = 39; arm 3, n = 42; arm 4, n = 40; arm 5, n = 41). The ORR in arms 1 to 5 was 39% (95% CI, 24% to 56%), 38% (95% CI, 24% to 54%), 50% (95% CI, 35% to 65%), 40% (95% CI, 25% to 56%), and 40% (95% CI, 25% to 56%), respectively. The odds ratio for ORR was 1.04 (P = 1.000) for arm 1 versus arm 2, 1.53 (P = .391) for arm 3 and versus arm 4, and 1.53 (P = .391) for arm 3 versus arm 5. The most common grade ≥ 3 adverse events were neutropenia, asthenia, anemia, thrombocytopenia, and hemoptysis. Of 161 available serum samples, a trend toward increased caspase-cleaved cytokeratin-18 was observed after dulanermin treatment in cycles 1 and 2. Among 84 patients evaluated for GalNT14 expression, there was a trend toward favorable progression-free survival and overall survival with dulanermin treatment in those with high GalNT14 expression., Conclusion: The addition of dulanermin to PC and PCB did not improve outcomes in unselected patients with previously untreated advanced or recurrent NSCLC.

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit., Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798., Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1-20·6] vs 9·3 months [7·7-13·2]; HR 0·614 [0·453-0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6-16·0] vs 8·1 months [6·7-12·6]; HR 0·659 [0·472-0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2-16·4] vs 6·9 months [5·2-11·0]; HR 0·616 [0·392-0·966]; p=0·033)., Interpretation: First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: The placebo-controlled, phase III AVAiL trial evaluated bevacizumab plus cisplatin and gemcitabine as first-line therapy in patients with advanced, nonsquamous non-small cell lung cancer. A retrospective subgroup analysis was performed to assess the efficacy and safety of bevacizumab-based therapy in elderly patients aged 65 years or older in AVAiL., Methods: Patients received cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles plus 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, or placebo every 3 weeks until disease progression. The primary end point was progression-free survival. Secondary endpoints included objective response rate, overall survival, and safety., Results: Data were evaluated for 304 patients aged 65 years or older (median age 68 years). Most of the patients were Caucasian (87%) and the majority had adenocarcinoma (83%). In the combined bevacizumab arms, 143 patients (79%) completed ≥4 cycles of chemotherapy. Patients who received bevacizumab derived an improvement in progression-free survival compared with placebo (7.5 mg/kg bevacizumab: hazard ratio [HR] = 0.71, p = 0.023; 15 mg/kg bevacizumab: HR = 0.84, p = 0.25). Objective response rates were 40, 29, and 30% in the 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, and placebo arms, respectively. Overall survival was similar for each bevacizumab arm versus placebo (7.5 mg/kg bevacizumab: HR = 0.84, p = 0.31; 15 mg/kg bevacizumab: HR = 0.88, p = 0.44). There were no particular safety signals of concern in elderly patients., Conclusions: This analysis of the randomized, phase III AVAiL trial shows that bevacizumab-based therapy improves outcomes for elderly patients with non-small cell lung cancer. Furthermore, bevacizumab-based therapy is well tolerated in elderly patients.

Background: This study compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in small-cell lung cancer patients with extensive disease., Patients and Methods: Patients were randomly assigned to receive cisplatin 80 mg/m(2) and either irinotecan 65 mg/m(2), days 1 and 8 or etoposide 100 mg/m(2), days 1-3, every 3 weeks., Results: Baseline characteristics were balanced between patients receiving IP (N = 202) or EP (N = 203). Median overall survival was nonsignificantly superior for patients receiving IP versus EP, 10.2 versus 9.7 months [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.65-1.01, P = 0.06] and 1- and 2-year survival rates were 41.9% versus 38.9% and 16.3% versus 8.2%, respectively. Noninferiority of IP versus EP was established, upper bound of the 95% CI of HR 1.01 (prespecified margin IP/EP <1.25). Overall response (39.1% versus 46.6%) and time to tumor progression (5.4 versus 6.2 months) were not superior for IP. Grade 3/4 vomiting (10.9% versus 4.4%) and diarrhea (15.4% versus 0.5%) were more common in the IP versus EP arm; grade 3/4 neutropenia was more frequent in the EP (59.6%) versus IP arm (38.1%)., Conclusions: Our data demonstrate the noninferiority of IP versus EP for survival in primarily Western patients with SCLC-ED. A meta-analysis is required to finally assess the role of irinotecan in this setting.

Background: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial., Patients and Methods: Patients (n = 1043) received cisplatin 80 mg/m(2) and gemcitabine 1250 mg/m(2) for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point., Results: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64-0.87), P = 0.0003 and 0.85 (0.73-1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78-1.11), P = 0.420 and 1.03 (0.86-1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients ( approximately 62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported., Conclusions: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin-gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.

Purpose: To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy., Patients and Methods: Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m(2) or docetaxel 75 mg/m(2) every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety., Results: Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed., Conclusion: This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.

Background: Nitrite and nitrate are exhaled in droplets of an aerosol during breathing and can be assayed in the exhaled breath condensate (EBC) as markers of nitrossative stress in the airways of patients with asthma, COPD, and idiopathic pulmonary fibrosis (IPF)., Subjects and Methods: Using HPLC with fluorescence detection, nitrite and nitrate were assayed in EBC of 14 atopic patients with mild-to-moderate stable asthma, 18 atopic asthmatics with exacerbation, 14 COPD patients without exacerbation, 18 patients with exacerbated COPD, 13 patients with active IPF, and in 29 healthy subjects., Results: The geometric mean [exp(mean±SD)] EBC concentrations of nitrite (micromol/l) in patients with asthma [5.1(2.1-12.3)], exacerbation of asthma [5.1(2.8-9.6)], exacerbation of COPD [5.3(3.2-8.7)], and with IPF [5.5(2.9-10.2)] were higher (P<0.05) compared with those of healthy subjects [2.9(1.6-5.3)] and patients with stable COPD [3.0(1.3-6.7)]. Nitrite concentration increased with decreased lung function of patients with asthma (r(s)=-0.31, P<0.02). Presumably owing to the contamination of the EBC sample with nitrate during collection, nitrate levels were highly variable among healthy subjects and higher compared with all groups of patients., Conclusion: EBC nitrite is a suitable marker of nitrossative stress in adult patients with lung diseases but cannot differentiate controlled and exacerbated asthma. Further improvements to the methods of EBC collection and sample handling are warranted., (J. Clin. Lab. Anal. 24:317-322, 2010. © 2010 Wiley-Liss, Inc.)

Members of the inhibitor of apoptosis protein (IAP) family, survivin and X-chromosome-linked IAP (XIAP), contribute to apoptosis resistance of cancer cells, and an increase in their expression may elevate the apoptotic threshold of malignant tumours during their growth and progression. In the present study, we investigated the expression status of survivin and its interactants hepatitis B X-interacting protein (HBXIP) and XIAP in non-small cell lung carcinoma (NSCLC) cell lines and NSCLC tumours and matched lungs from surgically treated patients in relation to their clinicopathological data. The expression of survivin, HBXIP and XIAP mRNAs was quantitated by real-time RT-PCR. The expression of survivin and XIAP proteins was analysed by Western blotting and ELISA. Survivin mRNA and protein levels were highly upregulated in NSCLC cells and tissues as compared to the lungs. In fact, the levels of survivin mRNA and protein in the tumours were more than 10-fold higher in 96 (64%) and 72 (82%) of the 150 and 88 examined NSCLC patients, respectively. The expression of survivin mRNA was higher in squamous cell lung carcinomas than in lung adenocarcinomas (LACs; P=0.003) and in less-differentiated tumours than in well-differentiated ones (P=0.007). The level of survivin protein was higher in stage IB and stage II+III tumours (P=0.049 and P=0.044), than in stage IA tumours. The BIRC5 promoter polymorphism at nucleotide -31 did not influence the expression of survivin mRNA and protein in NSCLC cells and tumours. HBXIP mRNA was abundantly expressed in NSCLC cell lines and NSCLC tumours and lungs, while its level was comparable in the tumours and lungs. The expression of XIAP mRNA in NSCLC cell lines and NSCLC tumours and lungs was not significantly different. However, the expression of XIAP protein was higher in NSCLC tumours, particularly in LACs, as compared to the lungs (P=0.017 and P=0.004). In conclusion, the overexpression of survivin in the majority of NSCLCs together with the abundant or upregulated expression of HBXIP and XIAP suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions.

Purpose: To evaluate the antitumor activity and safety of YM155, a novel, small-molecule suppressor of survivin, as single-agent therapy in patients with previously treated, advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage IIIb/IV NSCLC who had experienced treatment failure during one or two prior chemotherapy regimens (at least one of which was platinum based) received YM155 as a continuous intravenous infusion (4.8 mg/m(2)/d) over 168 hours followed by observation for 14 days in 21-day treatment cycles. The primary end point was objective tumor response rate (ORR). Secondary end points included duration of stable disease (SD), progression-free survival (PFS), overall survival (OS), safety and pharmacokinetic profiles, and pharmacodynamic evaluations., Results: Thirty-seven patients received YM155. Two patients achieved a confirmed partial response, with an ORR of 5.4% (95% CI, 0.7% to 18.2%). An additional 14 patients (37.8%) achieved SD resulting in a disease control rate of 43.2% (95% CI, 27.1% to 60.5%). Median duration of PFS was 1.7 months (95% CI, 1.3 to 2.8 months). Median duration of OS was 6.6 months (95% CI, 4 to 12.2 months), with a 1-year survival rate of 35.1%. Treatment with YM155 was well tolerated with the majority of treatment discontinuations not treatment related., Conclusion: YM155 exhibited modest single-agent activity in patients with refractory, advanced NSCLC. A favorable safety/tolerability profile was reported. Further evaluation of YM155 in combination with chemotherapy and other targeted agents may be warranted.

Background: The study compared the efficacy of a first-line treatment with day 1 i.v. vinorelbine (NVBiv) and day 8 oral vinorelbine (NVBo) versus docetaxel (DCT) in a cisplatin-based combination in advanced non-small-cell lung cancer, in terms of time to treatment failure (TTF), overall response, progression-free survival (PFS), overall survival (OS), tolerance and quality of life (QoL)., Methods: Patients were randomly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 (arm A) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks (arm B), for a maximum of six cycles in both arms., Results: From 2 February 2004 to 1 January 2006, 390 patients were entered in a randomised study and 381 were treated. The patient characteristics are as follows (arms A/B): metastatic (%) 80.5/84.8; patients with three or more organs involved (%) 45.3/40.8; median age 59.4/62.1 years; male 139/146; squamous (%) 34.2/33.5; adenocarcinoma (%) 41.6/39.3; median TTF (arms A/B in months) [95% confidence interval (CI)]: 3.2 (3.0-4.2), 4.1 (3.4-4.5) (P = 0.19); overall response (arms A/B) (95% CI): 27.4% (21.2% to 34.2%), 27.2% (21.0% to 34.2%); median PFS (arms A/B in months) (95% CI): 4.9 (4.4-5.9), 5.1 (4.3-6.1) (P = 0.99) and median OS (arms A/B in months) (95% CI): 9.9 (8.4-11.6), 9.8 (8.8-11.5) (P = 0.58). The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B, respectively. Main haematological toxicity was grade 3-4 neutropenia: 24.4% (arm A) and 28.8% (arm B). QoL as measured by the Lung Cancer Symptom Scale was similar in both arms., Conclusions: Both arms provided similar efficacy in terms of response, time-related parameters and QoL, with an acceptable tolerance profile. In the current Global Lung Oncology Branch trial 3, NVBo was shown to be effective as a substitute for the i.v. formulation. This can relieve the burden of the i.v. injection on day 8 and can optimise the hospital's resources and improve patient convenience.

Purpose: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting., Patients and Methods: Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351)., Results: PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation., Conclusion: Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.

Aims: This study reports the symptom and HRQOL results in which standard treatment was compared to standard therapy plus Bec2, an anti-idiotypic antibody that mimics GD3, a ganglioside antigen., Methods: Five hundred and fifteen LD SCLC patients were randomised to receive five vaccinations of Bec2 (2.5mg)/BCG vaccine arm (VA) or an observational arm (OA) administered over a 10-week period. Survival was the primary end-point; HRQOL was a secondary end-point, assessed using the EORTC QLQ-C30/LC 13., Results: There was no improvement in survival or progression-free survival in the vaccination arm. At baseline patients in both arms demonstrated significantly impaired scores on the global QOL scale, when compared to a normative population. However, HRQOL and symptom scores between the two treatment arms were not statistically different at any time point., Conclusion: We found no benefits to patient HRQOL by additional vaccination with Bec2/BCG to LD SCLC for patients who have been undergoing standard therapy.

Purpose: This phase II, open-label, parallel-group study compared gefitinib with vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Chemotherapy-naïve patients (age >or= 70 years) were randomly assigned to gefitinib (250 mg/d orally) or vinorelbine (30 mg/m(2) infusion on days 1 and 8 of a 21-day cycle). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Exploratory end points included epidermal growth factor receptor (EGFR) gene copy number by fluorescent in situ hybridization (FISH)., Results: Patients were randomly assigned to gefitinib (n = 97) or to vinorelbine (n = 99). Hazard ratios (HR; gefitinib v vinorelbine) were 1.19 (95% CI, 0.85 to 1.65) for PFS and 0.98 (95% CI, 0.66 to 1.47) for OS. ORR and disease control rates were 3.1% (95% CI, 0.6 to 8.8) and 43.3% (for gefitinib) and 5.1% (95% CI, 1.7 to 11.4) and 53.5% (for vinorelbine), respectively. Overall QOL improvement and PSI rates were 24.3% and 36.6% (for gefitinib) and 10.9% and 31.0% (for vinorelbine), respectively. In the 54 patients who were EGFR FISH-positive, HRs were 3.13 (95% CI, 1.45 to 6.76) for PFS and 2.88 (95% CI, 1.21 to 6.83) for OS. There were fewer treatment-related grade 3 to 5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%)., Conclusion: There was no statistical difference between gefitinib and vinorelbine in efficacy in chemotherapy-naïve, unselected elderly patients with advanced NSCLC, but there was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib; this unexpected finding requires further study.

Introduction: This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity., Methods: Patients received either larotaxel (50 mg/m) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m), every 3 weeks (arm A), or gemcitabine (800 mg/m) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m) as a 1-hour infusion, on day 8 (following gemcitabine), every 3 weeks (arm B). The primary end point was the objective response rate (per-protocol population)., Results: Thirty-two patients were randomized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per-protocol (26.7% versus 18.2%) and intention-to-treat (28.1% versus 13.3%) populations. In the intention-to-treat population, median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months, respectively. Fifty percent of patients in arm A and 66.7% in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9% and 41.4% of patients, respectively., Conclusions: Both larotaxel combinations were effective and manageable, however all measured efficacy parameters (response rate, progression free survival, and survival) seemed to favor the combination with cisplatin.

Purpose: A placebo-controlled, double-blind, randomized, phase III study was conducted in patients with extensive-stage small-cell lung cancer receiving first-line platinum-containing chemotherapy to determine if increasing or maintaining hemoglobin concentration with darbepoetin alpha could increase patient survival., Patients and Methods: Darbepoetin alpha (300 microg) or placebo was administered once per week for 4 weeks then every 3 weeks for up to six cycles of chemotherapy (carboplatin plus etoposide or cisplatin plus etoposide) plus 3 weeks after the last dose of chemotherapy. Patients with disease progression were observed until death or until all patients completed their end-of-study visit and 496 deaths had occurred. The two coprimary end points were change in hemoglobin concentration from baseline to the end of the chemotherapy period and overall survival; statistical testing of survival was done if change in hemoglobin was significant at P < .05., Results: The study enrolled 600 patients. Patients' hemoglobin levels dropped due to the myelosuppressive chemotherapy; however, treatment with darbepoetin alpha maintained hemoglobin levels significantly higher than placebo (P < .001). There was no statistically significant difference in overall survival between the treatment groups (hazard ratio [HR], 0.93; 95% CI, 0.78 to 1.11; P = .431). As expected, darbepoetin alpha was associated with a higher incidence of thromboembolic events (darbepoetin alpha, 9%; placebo, 5%). The transfusion risk was lower in the darbepoetin versus placebo group (HR, 0.40; 95% CI, 0.29 to 0.55)., Conclusion: The results of this study did not demonstrate improved survival after treatment with darbepoetin alpha; however, they reinforce the benefit of erythropoiesis-stimulating agents in reducing transfusions and their neutral impact on survival in patients with chemotherapy-induced anemia.

Background: This phase III randomized trial compared pemetrexed 500 mg/m(2) (P500) with pemetrexed 900 mg/m(2) (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy., Patients and Methods: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week., Results: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories., Conclusions: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

Purpose: This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted., Results: A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm)., Conclusion: The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.

The objective of the study was to investigate the contribution of dietary factors and physical exercise to the variation in the risk of lung cancer and its major histological types among men and women in the Czech Republic, and reveal interactions between smoking and diet/physical exercise, if any. In a hospital based case-control study, data collected by in-person interviews from 1096 microscopically confirmed lung cancer cases (587 women, 509 men) and 2966 controls were analyzed using unconditional logistic regression stratified by appropriate factors. Among all nonsmoking women protective effects were observed for black tea (OR=0.69), among all smoking women for wine (OR=0.71), physical exercise (OR=0.64) and vitamin supplements (OR=0.71). Among all men, inverse associations were found in smokers between lung cancer risk and frequent intake of fruits (OR=0.69) or moderate intake of spirits (OR=0.64), and a direct association for fat foods (OR=1.68). Comparing the effects of diet/physical activity on lung cancer risk among nonsmokers versus smokers, interactions with smoking appeared for the intake of black tea and milk/dairy products among women, and for moderate intake of spirits in men. When the effects of diet/physical exercise on risk were analyzed by major cell types in women, the intake of wine and physical exercise were inversely associated with the risk of both adenocarcinoma and small cell cancer, the intakes of fruits and vitamin supplements were inversely associated with the risk of squamous cell cancer. In men, the intake of fat foods was directly associated with the risk of squamous cell cancer, while the frequent intake of apples was inversely associated with the risk of both squamous- and small cell cancers. In men an inverse association with the risk of squamous cell cancer was found for the intake of other fruits. These data suggest that diet/physical exercise may affect the risk of lung cancer and major cell types, and that interactions between some dietary items and smoking may occur. Lung cancer is a multifactorial disease, since smoking, its main determinant, and other environmental and lifestyle factors interact with one another and with genetic factors to cause the disease.

Background: Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed., Methods: Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided., Results: Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy., Conclusions: Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.

Background: Absorption rates of the phosphate-buffered insulin analogs aspart, lispro, and glulisine prevail over that of regular human insulin. The aim of this prospective observational open-label controlled study was to compare the effects of aspart and human regular insulin resulting from their sequential long-lasting routine administration in small preprandial boluses to individuals with type 2 diabetes according to identical algorithms., Methods: Fifty-seven individuals with type 2 diabetes 64.0 +/- 1.29 (mean +/- SE) years old with diabetes' duration of 12.4 +/- 1.06 years, treated with human regular insulin for 5.2 +/- 0.44 years, and a serum C-peptide level of 1.1 +/- 0.10 nmol/L were enrolled into the study. Following two checkups performed in the course of the 364 +/- 17.9-day baseline period, human regular insulin was replaced with aspart in equivalent boluses, and two checkups in the course of 330 +/- 11.1-day sequential period were performed. The control group consisted of 17 individuals with type 2 diabetes 68.4 +/- 2.36 years old with diabetes' duration of 9.9 +/- 1.57 years, treated with insulin for 4.2 +/- 0.57 years, and a C-peptide level of 1.1 +/- 0.11 nmol/L. Data were analyzed using the statistical program SPSS version 10.1. (SPSS, Inc., Chicago, IL)., Results: Following the switch from human regular insulin to aspart, hemoglobin A1c (HbA1c) decreased from 8.4 +/- 0.23% at baseline to 7.9 +/- 0.17% (P = 0.031), and thereafter to 7.5 +/- 0.20% (P < 0.001), while plasma glucose concentrations in 10-point profiles, daily insulin dose (37.1 +/- 1.39 IU/day), body mass index (BMI) (30.5 +/- 0.82 kg/m(2)), and frequency of hypo- and hyperglycemic episodes did not change (P > 0.05). Patients quote satisfaction was good. No adverse events were recorded. In the control group, no significant change of baseline HbA1c (8.4 +/- 0.54%), insulin dose (33.1 +/- 3.17 IU/day), and BMI (32.1 +/- 1.12 kg/m(2)) was found., Conclusion: Aspart appears to be more effective than human regular insulin for complementary insulin treatment in individuals with type 2 diabetes.

Unlabelled: The objective of the study is to estimate the differences in the impact of diet and physical exercise on lung cancer risk in female nonsmokers vs. smokers, and reveal interactions, if any. In a hospital based case-control study, data collected by in-person interviews from 569 female lung cancer cases and 2120 controls were analyzed using unconditional logistic regression stratifying by appropriate factors. Protective effects were observed for intake of milk/dairy products (OR=0.57, 95%CI 0.35-0.94), vegetables (OR=0.60, 95%CI 0.40-0.91), apples (OR=0.69), wine (OR=0.77), and physical exercise (OR=0.59, 95%CI 0.42-0.83) among smokers only, while no similar effects were found among nonsmokers. In contrast, the intake of black tea was associated with a protective effect (OR=0.66, 95%CI 0.47-0.94) among nonsmokers only. Comparing the effects of dietary items and physical activity on lung cancer risk among nonsmokers versus smokers, statistically significant effect modifications were found for black tea (P 0.005), and milk/dairy products (P 0.047). Borderline effect modifications emerged for physical exercise (P 0.077)., Conclusions: These results indicate protective effects of some components of healthful diet and physical exercise among smokers, and of the intake of black tea among nonsmokers. The observed interactions of the impact of black tea, milk/dairy products and physical activity upon lung cancer risk in women at different levels of the smoking habit deserve further studies.

Purpose: Tumour cells killing by cytotoxic therapies largely depends on triggering the intrinsic apoptosome-mediated caspase activation pathway but it had never been evaluated whether the expression of transcripts encoding the core components of apoptosome pathway is altered in non-small cell lung carcinoma (NSCLC)., Methods: We investigated the expression status of several apoptosome pathway-related transcripts including Apaf-1, procaspase-9, -3, -6, -7 and Smac in tumour and lung tissue samples from 65 surgically treated NSCLC patients and in 10 NSCLC cell lines with using real time RT-PCR., Results: NSCLC tissues and cell lines showed significantly increased expression of procaspase-9, -3, -6 and Smac mRNAs as compared to the lungs and expression of these transcripts was simultaneously upregulated in a subset of NSCLCs belonging to different histopathological type, grade and stage categories. The expression of procaspase-7 mRNA in NSCLC tissues and cell lines and lungs was not significantly different. By contrast, the expression of Apaf-1 mRNA was frequently downregulated in the tumours as compared to matched lungs. Nevertheless, the examined NSCLC cell lines showed significantly higher expression of Apaf-1 mRNA than the lungs. The expression of Apaf-1, procaspase-9 and -6 mRNAs was higher in lung adenocarcinomas as compared to squamous cell lung carcinomas but the expression levels of the studied apoptosome pathway-related transcripts in the tumours were independent of tumour's grade and stage., Conclusions: The results of the present study suggest that there is a subgroup of NSCLCs, which may be intrinsically primed for apoptosis through upregulated expression of transcripts encoding the apoptosome pathway components.

Purpose: Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation., Patients and Methods: Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination., Results: A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets., Conclusion: Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.

Purpose: The incidence of bronchioloalveolar carcinoma (BAC) has risen steadily over the last decades along with the increasing frequency of adenocarcinomas. BAC is relatively resistant to commonly used chemotherapy regimens. A phase II study with single agent paclitaxel in patients with stages IIIB, IV or recurrent BAC was performed., Experimental Design: Patients with BAC with at least one target bidimensionally measurable lesion staged as unresectable stages IIIB, IV or recurrent disease, not previously irradiated; ECOG performance status 0-2; life expectancy greater than 3 months; age range between 18 and 75, received paclitaxel at a dose of 200 mg/m2 i.v. as 3h continuous infusion on day 1 every 21 days. Treatment was continued until progression or up to a maximum of six cycles., Results: Nineteen patients were eligible. Median number of cycles was 3 (range 0-6); 35% of patients received the planned six cycles of chemotherapy. One patient died of unrelated cause before the start of treatment. Both hematological and non-hematological toxicities were generally mild. Only one partial response (PR) was observed among the 18 eligible patients who started protocol treatment, with a response rate of 5.6% (95% CI: 0.1-27.3%). After an independent review, two PR were confirmed, for a response rate of 11.1% (95% CI: 1.4-34.7%); nine patients had stable disease (50.0%), three patients had progressive disease (11.1%) and four patients were not assessable (22.2%). Median survival was 8.6 months (95% CI: 5.8-14.5) and 1-year survival was 35.0% (95% CI: 14.1-55.8). Median progression free survival for all patients was 2.2 months (95% CI: 1.5-6.0). The study was terminated due to the low response rate., Conclusions: Paclitaxel as single agent in stages IIIB-IV BAC was well tolerated and manageable but of limited efficacy. BAC should not be excluded from trials of new forms of chemotherapy.

The objectives of the project were the following: (1) to establish a group of patients with a confirmed diagnosis of systemic sclerosis (Ssc), (2) to perform a detailed entrance examination of each patient, (3) to determine concentrations of potential activity markers, and (4) to make a comprehensive examination of each patient 1 year after inclusion into the study. A total of 49 patients were examined, 36 with a limited form of SSc, 9 with diffuse SSc, and 4 with other forms of SSc. We determined plasma or serum levels of the N-terminal propeptide of procollagen type III (NPIIIP), interleukin-6 (IL-6), soluble receptor for interleukin-2 (sIL-2r), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), von Willebrand factor antigen (vWFAg), and big endothelin-1 (BET-1) using commercial kits, and urinary excretion of pyridinoline (PYR) and deoxypyridinoline (D-PYR) using high-performance liquid chromatography. Correlations of these markers with selected clinical data were calculated. The mean levels of all potential activity markers were increased compared with normal values, but differences were not significant. The levels of NPIIIP, D-PYR, and IL-6 were normal. The measured values after 1 year did not differ from the entry values. At entry, NPIIIP concentrations correlated with the finger-to-palm distance, and D-PYR corresponded with findings on a simplified health assessment questionnaire (FQ). IL-6 levels correlated with the leukocyte count, sIL-2r with the FQ, and ET-1 with the diffuse lung capacity for carbon monoxide. In general, we found only a few clinical correlates of potential activity markers. Our data confirmed the correlations of collagen metabolism markers with skin involvement and FQ, as was reported previously. Larger studies in this field are needed.

Lung cancer is one of the most important avoidable causes of death around the world, it is the most widespread carcinoma with a very poor prognosis, and is the leading cause of cancer death in both developed and developing countries. At present more men than women die each year from lung cancer, but in recent years a rapid increase in lung cancer mortality has been observed among women in developed countries, contrasting with a levelling off or decrease among men. The rising trend in female lung cancer mortality has been observed to parallel with the past and current prevalence of cigarette smoking among women in the United States and elsewhere. An important role of other factors acting either as independent risk factors or interacting with the effect of smoking has been suggested by some studies among women, among them genetic, biologic and hormonal factors, and probably some factors related to the environment and lifestyle. There is a controversy concerning the claim that women have a different susceptibility to tobacco carcinogens, which might or might not be greater than men do. Since tobacco is far and away the strongest epidemiological risk factor for the development of lung cancer, comprehensive smoking control efforts are the priority in the prevention of lung cancer among women.

Mutations of the K-ras gene are found in a subset of non-small- cell lung carcinomas (NSCLC). The aim of our study was to determine the K-ras codon 12 mutation in the first, singular bronchoscopy specimen in parallel with the cytological examination for the diagnosis of lung cancer. Samples were obtained by diagnostic bronchoscopy in 140 patients with suspected lung tumors. The analysis of K-ras mutations was carried out by a sensitive two-step mutation- enriched polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. This method has been confirmed earlier to be positive for mutated tumor cells and negative for normal lung parenchyma and bronchus. Of the 140 patients with suspected cancer, 93 were diagnosed as NSCLC by cytology or histology in either the same specimen used for the detection of K-ras mutation or in later biopsies. However, only four K-ras codon 12 mutations were detected in the first bronchoscopic material: one in adenocarcinoma, two in squamous cell tumors, and one mutation was found in a patient with dysplasia which was diagnosed later as a squamous cell carcinoma. Our findings indicate that although the K-ras (codon 12) mutation is a gene lesion infrequently detectable in a singular specimen taken at the first bronchoscopy examination in cases of clinically suspected lung cancer, the detection of this mutation can help to confirm the cytological diagnosis of NSCLC or may be even diagnostic in cytologically negative cases.

A case-control study was conducted to investigate the relationship between diet and the risk of lung cancer among women non-smokers and to compare with women smokers in the same population. Data collected by personal interviews from 435 microscopically confirmed cases and 1710 controls were analysed using unconditional logistic regression. In addition to results for all study subjects, associations between diet and lung cancer risk were compared between two highly contrasting groups: smokers (odds ratio (OR) 7.03) and non-smokers (OR 1.00). A protective effect of frequent (daily or several times per week) black tea drinking appeared among non-smoking women (OR 0.65, 95% confidence interval (CI) 0.43-0.99). Among smoking women, protective effects were observed for frequent intake of milk/dairy products (OR 0.56, 95% CI 0.32-0.96), coffee (OR 0.47, 95% CI 0.25-0.88), and wine consumption (daily or weekly OR 0.60, 95% CI 0.37-0.98; monthly OR 0.60, 95% CI 0.39-0.94). Inverse associations with the risk appeared for physical exercise for smokers only, and for the body mass index both among non-smoking and smoking women. Some items of diet may contribute to variation in risk among women in the Czech Republic; their importance seems to vary in relation to their status in smoking, the dominant factor in the aetiology of lung cancer.

Purpose: The superiority of chemoradiotherapy (CRT) over radiation alone in locally advanced non-small cell lung cancer (NSCLC) has been proven, but the relative merits of a concurrent schedule versus their sequential administration are less clear. This study compared the safety and efficacy of concurrent and sequential CRT, with chemotherapy (CT) consisting of a cisplatin and vinorelbine regimen, in patients with locally advanced NSCLC., Patients and Methods: One hundred and two previously untreated patients (aged 42-75 years) with locally advanced, stage IIIA (n = 15) or stage IIIB (n = 87) NSCLC were entered into the study. The CT schedule consisted of up to four cycles of cisplatin 80 mg/m(2) on day 1, and vinorelbine 25 mg/m(2) at the first and fourth cycles (12.5 mg/m(2) during the 2nd/3rd cycles) on days 1, 8, 15 of a 28-day cycle. Radiotherapy (RT) was prescribed at a dose of 60 Gy/30 fractions, given as five fractions per week for 6 weeks. In the concurrent arm (arm A), RT was started on day 4 of cycle 2; whilst in the sequential arm (arm B), RT started within 2 weeks after completion of CT. Fifty-two patients were randomized to concurrent treatment and 50 to the sequential schedule., Results: Overall survival was significantly longer in arm A (median survival 16.6 months) versus arm B (median survival 12.9 months) (P = 0.023 by means of log-rank test; hazard ratio HR = 0.61, 95% CI of HR (0.39-0.93)), and time to progression (TTP) was also significantly longer in arm A (median time to progression 11.9 months) versus arm B (median time to progression 8.5 months) (P = 0.024 by means of log-rank test; HR = 0.62, 95% CI of HR (0.38-0.93)). Ninety-eight patients were evaluable for response and 101 for toxicity. The overall response rate was significantly higher in arm A, 80% (with 21% complete response (CR)) compared with 47% (with 17% CR) in arm B (P = 0.001 by means of chi(2)-test). WHO grade 3 or 4 toxicity was more frequent in arm A than in arm B, with a significantly greater incidence of leucopenia (53% versus 19%, P = 0.009 by means of chi(2) test) and nausea/vomiting (39% versus 15%, P = 0.044 by means of chi(2) test). There were no treatment related deaths., Conclusion: In this study population, concurrent CRT demonstrated significant benefit in terms of response rate, overall survival and time to progression over sequential CRT. The concurrent CRT schedule was associated with higher toxicity; however, the adverse event profile was acceptable in both arms.

Background: Vinorelbine and carboplatin are both active agents in the treatment of non-small-cell lung cancer (NSCLC). Vinorelbine has recently been developed in an oral formulation, which is as active as the intravenous (i.v.) form., Patients and Methods: Fifty-two chemonaive patients with unresectable localised or metastatic NSCLC received i.v. vinorelbine 25 mg/m(2) plus carboplatin (AUC 5) on day 1 and oral vinorelbine 60 mg/m(2) on day 8 (or day 15 if neutrophils <1500/mm(3)) every 3 weeks in an open-label, multicentre phase II study., Results: A total of 224 cycles were given, with the median number per patient of four (range one to eight). Eight responses out of 52 enrolled patients were documented and validated by an independent panel review, yielding a response rate of 18.2% [95% confidence interval (CI) 6.8-29.6%] in the evaluable population. This response rate was balanced by a high rate of disease control (78.9% in the intention-to treat population and 90.9% in the evaluable population). The median progression-free and median survival were 5.1 months (95% CI 4.3-8.1) and 9.3 months (95% CI 6.8-11.4), respectively. Overall, the safety profile of the combination regimen alternating i.v. and oral vinorelbine appeared similar to that expected for each individual agent. Some lung cancer-specific items (pain, dyspnoea) improved or were stabilised by assessment using the EORTC QLQ-C30 and QLQ-LC13 questionnaires., Conclusions: The combination of carboplatin with an alternating regimen of i.v./oral vinorelbine is a well tolerated regimen with a low level of toxicity and a low rate of serious adverse events. A high rate of disease control (partial response + no change) was achieved. Progression-free survival and overall survival fell within the expected range. This regimen is convenient and safe for the treatment of patients with locally advanced or metastatic NSCLC patients.

To investigate the relationship between diet, physical activity, and the risk of lung cancer among female nonsmokers, and to compare it with female smokers in the same population, we conducted a case-control study. Data collected by personal interviews from 419 cases and 1593 controls were analyzed using unconditional logistic regression. As expected, among 130 nonsmoking cases, adenocarcinoma was the predominant cell type (49.2%), followed by squamous cell (20.2%) and small cell cancers (10.5%). The corresponding figures for 289 smoking cases were 29.3%, 27.5%, and 28.2%, respectively. Excess lung cancer risk was associated with consumption of red meat among nonsmokers (OR=2.20, 95%CI 1.07--4.51). Protective effects were observed for vegetables (OR=0.61, 95%CI 0.39--0.96), apples (OR=0.67, 95%CI 0.48--0.95), milk/dairy products (OR=0.54, 95%CI 0.32--0.93), coffee (OR=0.56, 95%CI 0.34--0.91), and wine (OR=0.69, 95%CI 0.49--0.98) among smokers only, and for black tea (OR=0.67, 95%CI 0.46--0.99) among nonsmokers only. An inverse association with risk emerged for physical exercise (or sport, walking), among smokers only. Some items of diet and physical activity appear to be important factors contributing to variation in lung cancer risk among women in the Czech Republic, however, their effects in nonsmokers may differ from those in smokers.

To investigate the role of tobacco and some other known or suspected factors responsible for the risk of developing adenocarcinoma of the lung, and to compare with other cell types (squamous-, small- and large-cell cancers) in Czech women, we conducted a case-control study. Data collected by personal interviews from 145 cases of adenocarcinoma of the lung, 221 lung cancer cases of other cell types, and 1624 controls were analyzed using unconditional logistic regression. Cigarette smoking was the main determinant of all major cell types of lung cancer among Czech women, its effect was weaker on adenocarcinoma than on squamous-, small- and large-cell cancers. Among never smokers, passive smoking in childhood (before age 16) did not significantly increase the risk of adenocarcinoma (OR=1.35, 95%CI 0.75-2.45), contrasting with an elevation in the risk of squamous-, small- and large-cell cancers combined (OR=2.10, 95%CI 1.02-4.33). Excess risk associated with consumption of red meat daily or several times per week (OR=1.81, 95%CI 1.04-3.18) was restricted to squamous-, small- and large-cell cancers combined. Wine drinking, at higher frequency than once per month, was inversely associated with the risk of adenocarcinoma (OR=0.46, 95%CI 0.23-0.92), however, not with squamous-, small- and large-cell cancers combined (OR=0.77, 95%CI 0.47-1.28). Inverse associations with the risk of squamous-, small- and large-cell cancers combined emerged for the quantity of menstrual flow (OR=0.63, 95%CI 0.40-0.99), and pains or mental tension related to menses (OR=0.61, 95%CI 0.42-0.89).

Purpose: This randomized, multicenter, phase III trial was conducted to compare the tolerability of gemcitabine plus cisplatin (GP) vs. gemcitabine plus carboplatin (GC) in chemonaive patients with stage IIIb and IV non-small cell lung carcinoma (NSCLC). Secondary objectives were to evaluate response, duration of response, time to progressive disease (TTPD), and survival., Patients and Methods: Eligible patients were required to have stage IIIb or IV NSCLC, no previous chemotherapy, Karnofsky performance status of at least 70, bidimensionally measurable disease, and age 18-75 years. Randomized patients in both arms were given gemcitabine 1200 mg/m(2) on days 1 and 8, followed on day 1 by cisplatin 80 mg/m(2) (GP) or carboplatin AUC=5 (GC). Treatment cycles were repeated every 21 days for a maximum of six cycles, or until disease progression or unacceptable toxicity occurred., Results: Enrolled patients in both arms, 87 in GP and 89 in GC, were well balanced for demographics and disease characteristics. Dose intensity was 93.8 and 92.7% for gemcitabine in GP/GC arms, respectively; 97.7% for cisplatin and 99.9% for carboplatin. Patients with at least one grade 3/4 toxicity excluding nausea, vomiting or alopecia, were 44% in GP arm and 54% in GC arm. The only significantly different toxicities were, nausea and vomiting in GP and thrombocytopenia in GC group. The overall response rates, median TTPD, response duration and survival were, 41/29%, 5.87/4.75 months, 7.48/5.15 months, and 8.75/7.97 months for GP and GC arms, respectively., Conclusion: GP and GC are effective and feasible regimens for advanced NSCLC, and are comparable in efficacy and toxicity. GC may offer acceptable option to patients with advanced NSCLC, especially those who are unable to receive cisplatin.

A case of disseminated infection with Nocardia asteroides in a 55-year-old immunocompetent woman after mild trauma to the arm is reported. Secondary dissemination was identified in the skin, right kidney, liver, peritoneal cavity, lungs and thigh. The patient was successfully treated with surgical drainage and a 9-week course of antibiotics including cefotaxime, amikacin, chloramphenicol, trimethoprim/sulfamethoxazole (TMP/SMX) and doxycycline. The administration of TMP/SMX in combination with doxycycline was clinically beneficial despite in vitro resistance.

The objective of the present study was to evaluate clinical condition and results of surgical treatment of patients with typical and atypical bronchial carcinoids. The study was based on retrospective analysis of a total of 96 patients (mean age 47.3 year, age range 21-76, 44 men and women 52), who were surgically treated for bronchial carcinoid between 1985-2001. We assessed symptomatology of the disease, type of surgical intervention, tumor histology and staging, and postoperative 5-year and 10 year survival rates. The main sign of disease was respiratory inflammation. The carcinoid syndrome was not found in any patient. Most patients (n=68) were operated for central form of the tumor. The micromorphological tumor diagnosis was established prior to surgery in 76.5% patients with the central form of carcinoid. Surgical treatment included lobectomy (n=49), bronchoplastic procedure (n=14), sleeve lobectomy (n=9), atypical resection and segmentectomy (n=11), pneumonectomy (n=7) and tumor enucleation (n=5). Histological analysis revealed typical carcinoid in 77 cases (80.2%) and atypical carcinoid in 19 (19.8%). Lymph nodes (N1 and/or N2) were examined by histology in 84 patients and lymph node metastases were found in 13 (19.4%) of 67 patients with typical carcinoid and in 5 cases (29.4%) of 17 with atypical carcinoid. In the postoperative period on patient died from embolism to the arteria pulmonalis. Postoperative complications (atelectasis, prolonged air leak, bronchopleural fistula) were observed in 11.4% of patients. Tumor relapse occurred only in two patients with typical carcinoid. Postoperative 5-year and 10-year rates amounted to 98.6% and 87.3%, respectively, in typical carcinoid 94.5% and 73.5% in atypical carcinoid. The survival rates of patients with typical and atypical bronchial carcinoids were not significantly different (p>0.05). The surgical management is the treatment of choice in bronchial carcinoids. Results of this study indicate that the 5-year survival in patients with either histological type of bronchial carcinoid is excellent and the prognosis of operated patients is very good even in the case of regional lymph nodes infiltration by the tumors.

Gemcitabine/cisplatin is among the most widely used regimens in Europe for first-line treatment of non-small cell lung cancer (NSCLC). Problems with cisplatin use in this setting include significant nonhematologic toxicity and difficulty of use in outpatients. Carboplatin constitutes a reasonable alternative to cisplatin in this combination, since it shows synergy with gemcitabine in vitro, is easier to use in ambulatory patients, and has a better nonhematologic toxicity profile. Studies of gemcitabine/cisplatin on a 28-day schedule (gemcitabine on days 1, 8, 15 and carboplatin on day 1) generally indicate excessive thrombocytopenia. Use of a 21-day schedule (e.g. gemcitabine on days 1 and 8, carboplatin on day 1) is associated with reduced toxicity and comparable efficacy. Results of one randomized phase II study suggest reduced toxicity and reduced objective response rate with gemcitabine/carboplatin versus gemcitabine/cisplatin. We are currently conducting a phase III comparison of gemcitabine 1200 mg/m(2) on days 1 and 8 plus carboplatin at an area under the curve of 5 mg/ml/min on day 1 versus gemcitabine at the same dose plus cisplatin 80 mg/m(2) on day 1 every 21 days in chemotherapy-nai;ve patients with stage IIIB/IV NSCLC; interim analysis indicates comparable response rates (47 and 48%). A better understanding of the relative toxicities of these regimens should be provided by the final results of this trial., (Copyright 2002 Elsevier Science Ireland Ltd.)

Unlabelled: Tracheal stenosis represents a serious complication of tracheostomy or of endotracheal intubation. The objective of this article was to evaluate the results of resective therapy of patients with tracheal stenosis., Methods: In 41 patients treated by tracheal resection for tracheal stenosis the diagnosis was established by bronchoscopy, tracheal tomography or CT. The following parameters were evaluated: the reasons for artificial pulmonary ventilation, basic parameters of stenosis (site of stenosis, length, diameter), the relationship between the duration of cannulation and asymptomatic interval, and postoperative complications., Results: The most frequent reason for cannulation was trauma (n = 23), most patients were cannulated for 4-5 weeks (n = 16), the symptoms of stenosis appeared mostly within 4-5 weeks (n = 11) after decannulation. The asymptomatic interval was longer in patients with longer periods of cannulation (p < 0.01) than in patients with a shorter cannulation period. The most frequent site of stenoses was the medium third of the trachea (n = 22). The longest resected section measured 60 mm. In 3 patients (7.3 %) a tracheoesophageal fistula was found together with the stenosis. In 3 patients (7.3 %) restenosis appeared. Tracheocutaneous fistula with osteomyelitis of the sternum developed in one patient. Granulation tissue on the anastomosis site (n = 4, 9.7 %) was treated by laser or disappeared spontaneously. None of the patients died within 30 days after operation., Conclusion: Resection is the optimum therapeutic method for tracheal stenosis with low postoperative mortality and a small number of postoperative complications. Successful tracheal resection is a definitive solution in comparison with stent placement.

Background: Few data are available to explain the ongoing increase in lung cancer mortality among Czech women. The study is aimed at examining the role of smoking and known or suspected cofactors., Methods: Data collected by in-person interviews from 269 female lung cancer cases and 1079 controls were analyzed using unconditional logistic regression and other methods., Results: Cigarette smoking was the most important factor associated with excess risk of lung cancer among women. Risk was increased both among current smokers (OR = 10.30), long-term ex-smokers (> or =10 years ago; OR = 3.79), and short-term ex-smokers (<10 years ago; OR = 14.63), all compared against never-smokers. In addition, significant associations with risk were found for chronic cough, chronic phlegm of less than 2-year duration, and shortness of breath. Inverse associations emerged for physical exercise and body mass index. Excess risk associated with consumption of red meat and poultry, and protective effects associated with intake of vegetables were restricted to squamous-, small-, and large-cell cancers combined, but were not apparent for adenocarcinoma., Conclusions: While smoking has been verified to be the main determinant of lung cancer risk among Czech women, cofactors such as diet, history of lung disease, and lifestyle factors may have a contributory role., ((C)2002 Elsevier Science (USA).)

Purpose: A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week., Results: One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate., Conclusion: The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.

Background: The aim of this study was to evaluate local control and its relation to survival in patients with locally advanced breast cancer treated with curative irradiation and systemic therapy., Patients and Methods: 240 patients with unresectable breast cancer were treated with curative radio- and chemo- or hormonotherapy from 1990-1995. The frequency of distant dissemination and the overall survival of patients with and without complete local control were compared., Results: Complete local control was achieved in 63% of patients. Complete local control correlated with decrease of distant metastases and increase of survival in comparison with patients without complete local control., Conclusion: Radiotherapy without surgery provides insufficient local control in patients with locally advanced breast cancer. Complete local control is an important factor for prevention of distant dissemination and for survival., (Copyright 2001 S. Karger GmbH, Freiburg)

Few data are available to explain the continuing increase in lung cancer mortality among Czech women. The study was designed to examine the role of active smoking and other known or suspected factors. Data collected by personal interviews during the 15 months of a hospital-based case control study are reported. A total of 140 microscopically confirmed cases and 280 frequency-matched controls were analysed using multiple logistic regression. Cigarette smoking was the most important factor associated with excess risk for lung cancer among women. Significantly increased risk was found both among current smokers (OR=11.20, 95% CI 5.9-21.2), and ex-smokers (OR=10.02, 95% CI 5.5-18.4). Positive dose-response gradients (P<0.001) were observed between lung cancer risk and the daily number of cigarettes, duration of smoking, number of pack-years, inhaling, and grade of nicotine dependence assessed by the Fagerström test (Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. Br J Addict 1991;86:1119-1470; Pomerleau OF. In: Bolliger CT, Fagerström KO, editors. The Tobacco Epidemic. Basle: Karger, 1997: 122-131). Exposure to environmental smoke was associated with elevated lung cancer risk (OR=3.58, for lifetime non-smokers exposed both in childhood and in adult age). Physical exercise and body mass index were inversely associated with lung cancer risk. For the category of physical exercise of more than 5 h per week, the odds ratio was 0.38, compared to subjects admitting no physical exercise. For body mass index, the odds ratio for the highest (compared to the lowest) quartile was 0.50. Chronic cough and phlegm (at least 3 months per year) were associated with excess risk (OR=6.07) only if their duration was less than 2 years before diagnosis of lung cancer, and, therefore, they were suspected of being more likely early symptoms of preclinical lung cancer rather than its cause. Our results support the statement that cigarette smoking is by far the most important cause of the on-going epidemic of lung cancer among Czech women, and are consistent with the concept of a balance between risk and protective factors whose eventual maintenance or alteration determine the development of disease (as suggested by Rylander R, Axelsson G, Andersson L, Liljequist T, Bergman B. Lung Cancer 1996;14(Suppl 1): S75-S83). Concerted control of smoking appears to be an urgent priority in lung cancer prevention among women, including specific approaches targeted on the female population.