Chemo-radiotherapy integration in unresectable locally advanced non-small-cell lung cancer: a review.

Approximately one-third of all non-small-cell lung cancer (NSCLC) are locally-advanced at diagnosis, and 15-17% of these tumors are unresectable at presentation. Definitive chemo-radiotherapy (CRT) represents the standard therapeutic approach. However, the literature has shown that only 15% of patients are alive at 5 years and this percentage has remained unchanged despite various attempts of improvement. The recent introduction of immunotherapy has not only strongly changed the clinical scenario but has also drawn attention to a stage of disease apparently forgotten for decades. Stage III NSCLC can represent an interesting setting for the combined use of chemo-radiation and immunotherapy, due to the potential synergistic effect between radiation and immune checkpoint inhibitors. We reviewed the available literature in order to report the state of art of stage III NSCLC, by focusing on trials that evaluate different combinations of CRT and new drugs of PD-1/PD-L1 axis, and anti-CTLA-4. The future goal in the management of unresectable stage III NSCLC will be the optimal patients' selection combined with the use of individualized immuno/chemotherapies that could potentially improve clinical outcomes.

PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients.

BACKGROUND: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. METHODS: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. RESULTS: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01). CONCLUSIONS: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011.

OBJECTIVE: We used data from a national study of pregnant women with HIV to evaluate the prevalence of congenital abnormalities in newborns from women with HIV infection. DESIGN: Observational study. SETTING: University and hospital clinics. POPULATION: Pregnant women with HIV exposed to antiretroviral treatment at any time during pregnancy. METHODS: The total prevalence of birth defects was assessed on live births, stillbirths, and elective terminations for fetal anomaly. The associations between potentially predictive variables and the occurrence of birth defects were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs) for exposed versus unexposed cases, calculated in univariate and multivariate logistic regression analyses. MAIN OUTCOME MEASURES: Birth defects, defined according to the Antiretroviral Pregnancy Registry criteria. RESULTS: A total of 1257 pregnancies with exposure at any time to antiretroviral therapy were evaluated. Forty-two cases with major defects were observed. The total prevalence was 3.2% (95% CI 1.9-4.5) for exposure to any antiretroviral drug during the first trimester (23 cases with defects) and 3.4% (95% CI 1.9-4.9) for no antiretroviral exposure during the first trimester (19 cases). No associations were found between major birth defects and first-trimester exposure to any antiretroviral treatment (OR 0.94, 95% CI 0.51-1.75), main drug classes (nucleoside reverse transcriptase inhibitors, OR 0.95, 95% CI 0.51-1.76; non-nucleoside reverse transcriptase inhibitors, OR 1.20, 95% CI 0.56-2.55; protease inhibitors, OR 0.92, 95% CI 0.43-1.95), and individual drugs, including efavirenz (prevalence for efavirenz, 2.5%). CONCLUSIONS: This study adds further support to the assumption that first-trimester exposure to antiretroviral treatment does not increase the risk of congenital abnormalities.

First-line chemotherapy with planned sequential administration of cisplatin/gemcitabine followed by docetaxel in elderly 'unfrail' patients with advanced non-small-cell lung cancer: a multicenter phase II study.

PURPOSE: The role of cisplatin in the first-line treatment for elderly advanced non-small-cell lung cancer is not completely defined. We previously reported in this subset of patients an interesting efficacy and tolerability of a sequential schedule of gemcitabine followed by docetaxel. METHODS: Patients aged ≥70 years and with Eastern Cooperative Oncology Group performance status 0 or 1 received cisplatin 60 mg/m(2) on Day 1 and gemcitabine 1,000 mg/m(2) on Day 1 and 8 every 3 weeks for 3 courses followed by 3 courses of docetaxel 37.5 mg/m(2) on Day 1 and 8 every 3 weeks, provided there was no evidence of disease progression. Patients were excluded if considered 'frail' according to the Multidimensional Geriatric Assessment. The main objective of the study was the 4-month progression-free survival rate. Simon's two-stage minimax design was applied to calculate the sample size. RESULTS: After 30 patients were enroled into the study, the 4-month progression-free survival rate was 53.3 % and the study was closed at the first stage for futility; the overall response rate was 16.7 %; the median time to progression and median duration of survival were 5.1 and 8.6 months, respectively; the 1-year survival rate was 30 %. CONCLUSION: The incorporation of cisplatin in a sequential schedule of gemcitabine followed by docetaxel is feasible but did not yield a substantial advantage to deserve further investigations.

Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients.

BACKGROUND: The aim of this study was to evaluate whether cytidine deaminase (CDA) polymorphisms 79A>C and 435C>T and/or CDA enzymatic activity influenced clinical outcome in 126 advanced non-small-cell lung cancer patients treated with gemcitabine-platinum-regimens. PATIENTS AND METHODS: CDA polymorphisms and activity were analysed by PCR and high-performance liquid chromatography, respectively. Univariate and multivariate analyses compared biological/clinical parameters with response, clinical benefit, time to progression (TtP) and overall survival (OS) using Pearson's χ(2) test, log-rank test and Cox proportional hazards model. RESULTS: Patients with CDA A79A/A79C genotypes had significantly longer TtP (6.0 versus 3.0 months; P = 0.001) and OS (11.0 versus 5.0 months; P = 0.001) than patients with C79C genotype. Patients harbouring CDA C435C/C435T genotypes also had a longer OS (P = 0.025), but no correlations were observed with TtP. Conversely, patients with low-CDA activity had a significantly higher response rate (37.7% versus 13.8%; P = 0.006), clinical benefit (91.8% versus 51.7%; P < 0.001), as well as longer TtP (8.0 versus 3.0 months; P < 0.001) and OS (19.0 versus 6.0 months; P < 0.001). Furthermore, enzymatic activity emerged as an independent predictor for death/progression risk at multivariate analysis. CONCLUSIONS: CDA enzymatic activity appears to be the strongest candidate biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy and should be validated in a prospective study.

Consequences of targeted treatments for second-line therapy.

The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non-squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC.

Simple and selective method for the determination of various tyrosine kinase inhibitors used in the clinical setting by liquid chromatography tandem mass spectrometry.

A fast, sensitive, universal and accurate method for the determination of four different tyrosine kinase inhibitors from biological material was developed using LC-MS/MS techniques. Utilizing a simple protein precipitation with acetonitrile a 20 microl sample volume of biological matrixes can be extracted at 4 degrees C with minimal effort. After centrifugation the sample extract is introduced directly onto the LC-MS/MS system without further clean-up and assayed across a linear range of 1-4000 ng/ml. Chromatography was performed using a Dionex Ultimate 3000 with a Phenomenex prodigy ODS3 (2.0 mm x 100 mm, 3 microm) column and eluted at 200 microl/min with a tertiary mobile phase consisting of 20mM ammonium acetate:acetonitrile:methanol (2.5:6.7:8.3%). Injection volume varied from 0.1 microl to 1 microl depending on the concentration of the drug observed. Samples were observed to be stable for a maximum of 48 h after extraction when kept at 4 degrees C. Detection was performed using a turbo-spray ionization source and mass spectrometric positive multi-reaction-monitoring-mode (+MRM) for Gefitinib (447.1 m/z; 127.9 m/z), Erlotinib (393.9 m/z; 278.2 m/z), Sunitinib (399.1 m/z; 283.1 m/z) and Sorafenib (465.0 m/z; 251.9 m/z) at an ion voltage of +3500 V. The accuracy, precision and limit-of-quantification (LOQ) from cell culture medium were as follows: Gefitinib: 100.2+/-3.8%, 11.2 nM; Erlotinib: 101.6+/-3.7%, 12.7 nM; Sunitinib: 100.8+/-4.3%, 12.6 nM; Sorafenib: 93.9+/-3.0%, 10.8 nM, respectively. This was reproducible for plasma, whole blood, and serum. The method was observed to be linear between the LOQ and 4000 ng/ml for each analyte. Effectiveness of the method is illustrated with the analysis of samples from a cellular accumulation investigation and from determination of steady state concentrations in clinically treated patients.

Declining HCV seroprevalence in pregnant women with HIV.

We assessed recent trends in hepatitis C virus (HCV) prevalence in pregnant women with HIV using data from a large national study. Based on 1240 pregnancies, we observed a 3.4-fold decline in HCV seroprevalence in pregnant women with HIV between 2001 (29.3%) and 2008 (8.6%). This decline was the net result of two components: a progressively declining HCV seroprevalence in non-African women (from 35.7% in 2001 to 16.7% in 2008), sustained by a parallel reduction in history of injecting drug use (IDU) in this population, and a significantly growing presence (from 21.2% in 2001 to 48.6% in 2008) of women of African origin, at very low risk of being HCV-infected [average HCV prevalence 1%, adjusted odds ratio (aOR) for HCV 0.09, 95% CI 0.03-0.29]. Previous IDU was the stronger determinant of HCV co-infection in pregnant women with HIV (aOR 30.9, 95% CI 18.8-51.1). The observed trend is expected to translate into a reduced number of cases of vertical HCV transmission.

Vaginal and endocervical microorganisms in symptomatic and asymptomatic non-pregnant females: risk factors and rates of occurrence.

Physiological or non-physiological factors may affect the vaginal flora. The occurrence of genital microorganisms in non-pregnant females of all ages was studied, as were the risk factors associated with each microorganism. A retrospective analysis of vaginal and endocervical cultures and wet smears from 27,172 non-pregnant women, between 1996 to 2005, was performed taking into consideration clinical and socio-demographic characteristics. No microorganisms were observed in 55.7% of the individuals studied and 44.3% had positive cultures. There was no microbiological aetiology in 49% of women with genital symptoms. Poor hygiene, chemical irritants, sexual behaviour, vaginal blood, birth control type, and/or the lack of an oestrogen effect may have caused the symptoms. The highest occurrence of Gram-negative bacteria (p<0.01), mainly Escherichia coli, was observed in prepubescent girls. The highest occurrence of Candida species (p<0.01) was in women of childbearing age, and of Gram-positive bacteria (p<0.01) in menopausal women. Adolescents, particularly asymptomatic girls, carried more frequently Ureaplasma urealyticum and Chlamydia trachomatis (p<0.01). Hormonal contraception and consistent condom use was protective against bacterial vaginosis and U. urealyticum colonization. Users of intrauterine devices had an increased risk of bacterial vaginosis or of contracting U. urealyticum, Mycoplasma hominis and Candida species. Genital complaints were an independent indicator of Candida species, Gram-negative and Gram-positive bacteria, Trichomonas vaginalis and bacterial vaginosis.Chlamydia trachomatis infections were often asymptomatic. It is concluded that the hormonal milieu and non-physiological factors are major determinants of the vaginal flora. If diagnosis of genital infections is based on symptoms alone and not on culture results, it may be erroneous. Sexual abuse should be investigated when a child presents with a sexually transmitted disease.

Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples.

Cytidine deaminase (CDA) is the major enzyme of gemcitabine inactivation. The aim of this study was to determine whether the CDA Lys27Gln polymorphism influenced gemcitabine deamination in blood samples from 90 lung cancer patients. The polymorphism was studied with Taqman probes-based assay; CDA activity was evaluated by HPLC in cytoplasmic extracts from red blood cells. Mean enzymatic activity was significantly lower in patients carrying the CDA Lys27Lys than in patients with the Lys27Gln or Gln27Gln protein (P < 0.05). CDA genotyping may be useful in screening patients before gemcitabine treatment, in order to identify subjects with lower CDA activity and potentially better clinical outcomes after gemcitabine-based chemotherapy.

Hepatitis B or hepatitis C coinfection in HIV-infected pregnant women in Europe.

OBJECTIVES: The aim of the study was to investigate the prevalence of and risk factors for hepatitis C or B virus (HCV or HBV) coinfection among HIV-infected pregnant women, and to investigate their immunological and virological characteristics and antiretroviral therapy use. METHODS: Information on HBV surface antigen (HBsAg) positivity and HCV antibody (anti-HCV) was collected retrospectively from the antenatal records of HIV-infected women enrolled in the European Collaborative Study and linked to prospectively collected data. RESULTS: Of 1050 women, 4.9% [95% confidence interval (CI) 3.6-6.3] were HBsAg positive and 12.3% (95% CI 10.4-14.4) had anti-HCV antibody. Women with an injecting drug use(r) (IDU) history had the highest HCV-seropositivity prevalence (28%; 95% CI 22.8-35.7). Risk factors for HCV seropositivity included IDU history [adjusted odds ratio (AOR) 2.92; 95% CI 1.86-4.58], age (for > or =35 years vs. <25 years, AOR 3.45; 95% CI 1.66-7.20) and HBsAg carriage (AOR 5.80; 95% CI 2.78-12.1). HBsAg positivity was associated with African origin (AOR 2.74; 95% CI 1.20-6.26) and HCV seropositivity (AOR 6.44; 95% CI 3.08-13.5). Highly active antiretroviral therapy (HAART) use was less likely in HIV/HCV-seropositive than in HIV-monoinfected women (AOR 0.34; 95% CI 0.20-0.58). HCV seropositivity was associated with a higher adjusted HIV RNA level (+0.28 log(10) HIV-1 RNA copies/mL vs. HIV-monoinfected women; P=0.03). HIV/HCV-seropositive women were twice as likely to have detectable HIV in the third trimester/delivery as HIV-monoinfected women (AOR 1.95; P=0.049). CONCLUSIONS: Although HCV serostatus impacted on HAART use, the association between HCV seropositivity and uncontrolled HIV viraemia in late pregnancy was independent of HAART.

Baseline elevated leukocyte count in peripheral blood is associated with poor survival in patients with advanced non-small cell lung cancer: a prognostic model.

PURPOSE: We aimed to investigate the prognostic significance of several baseline variables in stage IIIB-IV non-small cell lung cancer to create a model based on independent prognostic factors. METHODS/RESULTS: A total of 320 patients were treated with last generation chemotherapy regimens. The majority of patients received treatment with cisplatin + gemcitabine or gemcitabine alone if older than 70 years or with an ECOG performance status (PS) = 2. Performance status of 2, squamous histology, number of metastatic sites >2, presence of bone, brain, liver and contralateral lung metastases and elevated leukocyte count in peripheral blood were all statistically significant prognostic factors in univariate analyses whereas the other tested variables (sex, stage, age, presence of adrenal gland and skin metastases) were not. Subsequently, a multivariate Cox's regression analysis identified PS 2 (P < 0.001, hazard ratio 2.57), elevated leukocyte count (P < 0.001, hazard ratio 1.79), squamous histology (P = 0.005, hazard ratio 1.45) and presence of brain metastases (P = 0.035, hazard ratio 1.5) as independent prognostic factors for poor survival. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the four independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 10.2 months (95% confidence interval (CI) 8.9-11.6), 5.1 months (95% CI 4.0-6.2) and 2.8 months (95% CI 0.5-5.2), respectively. The high-risk group encompassed PS 2 patients with two or three adjunctive unfavourable independent prognostic factors. CONCLUSIONS: Performance status, white blood cells count, histology and brain metastases resulted in our series prognostic factors of survival in NSCLC patients treated with chemotherapy at a multivariate analysis. Leukocyte count resulted the stronger factor after performance status. If prospectly validated, the proposed prognostic model could be useful to stratify performance status 2 patients in specific future trials.

First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study.

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB-IV NSCLC, age >or=70 and with a performance status 0-2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m(-2) on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m(-2) on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6-28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6-6.0 months) and median duration of survival was 8.0 months (95% CI 5.6-10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients.

Pregnancy outcomes and antiretroviral treatment in a national cohort of pregnant women with HIV: overall rates and differences according to nationality.

We used data from the main surveillance study of HIV and pregnancy in Italy to evaluate possible differences in pregnancy care and outcomes according to nationality. Among 960 women followed in 2001-06, 33.5% were of foreign nationality, mostly from African countries. Foreign women had lower rates of preconception counselling and planning of pregnancy. They had more frequently HIV diagnosed during pregnancy, with a later start of antiretroviral treatment and lower treatment rates at all trimesters but not when the entire pregnancy, including delivery, was considered. No differences were observed between the two groups in ultrasonography assessments, hospitalisations, AIDS events, intrauterine or neonatal deaths, and mode and complications of delivery. Foreign women had a slightly lower occurrence of preterm delivery and infants with low birthweight. The results indicate good standards of care and low rates of adverse outcomes in pregnant women with HIV in Italy, irrespective of nationality. Specific interventions, however, are needed to increase the rates of counselling and HIV testing before pregnancy in foreign women.

Lipid profile during pregnancy in HIV-infected women.

PURPOSE: We investigated the evolution of serum lipid levels in HIV-infected pregnant women and the potential effect of antiretroviral treatment during pregnancy using data from a national surveillance study. METHOD: Fasting lipid measurements collected during routine care in pregnancy were used, analyzing longitudinal changes and differences in lipid values at each trimester by protease inhibitors (PIs) and stavudine use. Multivariate analyses were used to control for simultaneous factors potentially leading to hyperlipidemia. Study population included 248 women. RESULTS: Lipid values increased progressively and significantly during pregnancy: mean increases between the first and third trimesters were 141.6 mg/dL for triglycerides (p < .001), 60.8 mg/dL for total cholesterol (p < .001), 13.7 mg/dL for HDL cholesterol (p < .001), and 17.8 mg/dL for LDL cholesterol (p = .001). At all trimesters, women on PIs had significantly higher triglyceride values compared to women not on PIs. The effect of PIs on cholesterol levels was less consistent. Stavudine showed a dyslipidemic effect at first trimester only. Multivariate analyses confirmed these observations and suggested a potential role of other cofactors in the development of hyperlipidemia during pregnancy. CONCLUSION: The changes observed point to the need to further explore the causes and the clinical correlates of hyperlipidemia during pregnancy in women with HIV.

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I-II study.

The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m-2 and paclitaxel (P) 175 mg m-2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m-2, P 175 mg m-2, etoposide (E) 100 mg m-2 intravenous (fixed dose) days 1-3 with courses repeated every 21 days. The prophylactic use of colony-stimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50-70), median Eastern Cooperative Oncology Group performance status 0 (0-2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1-6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% (95% confidence interval=60.4-96.6). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

Diagnosis of HIV infection in pregnancy: data from a national cohort of pregnant women with HIV in Italy.

We analysed the characteristics of the pregnancies with a previously undetected HIV infection in a national observational study of pregnant women with HIV in Italy. In a total of 443 pregnancies with available date of HIV diagnosis, 118 were characterized by a previously undetected HIV infection (26.6%, 95% CI 22.5-30.8). The following factors were independently associated with this occurrence in a multivariate analysis (adjusted odds ratios; 95% CIs): foreign nationality (5.1, 2.8-9.3); no pre-conception counselling (35.9, 4.8-266.1); first pregnancy (2.1, 1.2-4.0); asymptomatic status (6.8, 1.5-30.6). Women with previously undetected infection started antiretroviral treatment significantly later during pregnancy (P < 0.001). Missed diagnosis was responsible for one case of transmission. A high rate of previously undetected HIV infection was observed. This suggests a good HIV detection during pregnancy, but also the need to reinforce HIV testing strategies among women of childbearing age. We identified some determinants which may be considered for intervention measures.

Prolonged gemcitabine infusion in advanced non-small-cell lung cancer with stable disease after gemcitabine 30-min infusion.

BACKGROUND: Although 30-min gemcitabine infusion has become the standard administration, pre-clinical and clinical studies have suggested the possibility that an infusion rate of 10 mg/m(2) per minute may be more effective. The main objective of this study was to investigate whether the pursuance of gemcitabine, administered at a prolonged infusion rate, was able to convert stable disease to objective response after two or three cycle of standard administration. The secondary end-point was the evaluation of the new schedule toxicity. PATIENTS AND METHODS: Thirty-eight patients, with stage IIIA-B and IV NSCLC already treated by two or three cycles of 30-min gemcitabine infusion, alone or in combination with cisplatin, were enrolled: 26 patients (aged <70 years) were treated with cisplatin 80 mg/m(2) on day 1 plus gemcitabine 1200 mg/m(2) over 120 min on day 1 and 8 every three weeks and 12 patients (aged > or =70 years) were treated with gemcitabine alone 1200 mg/m(2) over 120 min on day 1 and 8 every three weeks, for two courses. Simon's two stage minimax design was applied to calculate the sample size. Assuming p(0) (low conversion rate) 5%, p(1) (target conversion rate of interest) 20%, alpha error 0.05, beta error 0.10 a total of 29 evaluable patients had to be accrued during stage 1. In case at least one objective response was observed, a further nine evaluable patients had to be enrolled into the study during stage 2. The regimen was considered promising if > or =4 objective responses out of 38 evaluable patients were observed. RESULTS: Thirty-eight patients were evaluable for response and in five patients (with stable disease after two courses of gemcitabine 30' infusion) a partial response was observed (conversion rate 13.1%, 95% confidence interval 4.4-28%). Toxicities were more frequently observed with cisplatin plus 120-min gemcitabine infusion: grade 3-4 neutropenia, thrombocytopenia and anaemia in 28, 22 and 16% of the courses, respectively. CONCLUSIONS: The prolongation of gemcitabine infusion time is able to convert stable disease to partial response in 13% of the cases. The haematological toxicity seems enhanced with cisplatin plus gemcitabine prolonged infusion.