Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism.

OBJECTIVE: To study the impact of the 79A>C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Patients (n = 20) received gemcitabine 1,125 mg/m(2) as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0-6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A>C genotype was determined with PCR and DNA sequencing. RESULTS: Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A>C polymorphism was 0.40. Diplotypes were distributed as A/A n = 8, A/C n = 8 ,and C/C n = 4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life. CONCLUSION: The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.

Gemcitabine and epirubicin plasma concentration-related excretion in saliva in patients with non-small cell lung cancer.

AIM: The excretion in saliva of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as well as epirubicin (Epi) and its metabolite epirubicinol (Epi-ol) was studied in patients with non-small cell lung cancer, treated with gemcitabine plus epirubicin. METHODS: Patients (n = 12) were treated with gemcitabine 1125 mg/m, followed by Epi 100 mg/m. Blood, saliva, and oral mucosa cells were collected during 22 hours for analysis of gemcitabine, Epi, and their metabolites. Gemcitabine, dFdU, Epi, and Epi-ol were quantified by high-performance liquid chromatography. RESULTS: Gemcitabine was cleared rapidly from plasma and undetectable after 3 hours in all patients. Gemcitabine was detectable in saliva during only the first hour after infusion. The Cmax in saliva was 0.66 +/- 0.61 mg/L, and the saliva to plasma ratio (S/P ratio) was 0.038 +/- 0.037. The Cmax of dFdU was reached 1.5-2 hours after gemcitabine infusion and was 1.03 +/- 0.63 mg/L. The dFdU S/P ratios gradually increased from 0.021 +/- 0.013 at t = 1 hour to 0.050 +/- 0.027 at t = 6 hours after infusion. Epi displayed a triexponential plasma concentration-time profile. The Epi and Epi-ol concentrations in saliva at t = 6 hours after administration were 55 +/- 27 and 9 +/- 9 microg/L, respectively, and decreased to 28 +/- 14 and 7 +/- 4 microg/L, respectively, at t = 22 hours. The corresponding S/P ratios were 1.28 +/- 0.73 and 0.36 +/- 0.31 at t = 6 hours and 1.72 +/- 1.00 and 0.62 +/- 0.34 at t = 22 hours, respectively. The amount of Epi in mucosal cells ranged from 135-598 ng per 10 cells at t = 3 hours and decreased to 33-196 ng per 10 cells at t = 22 hours. CONCLUSION: Gemcitabine and Epi, as well as their main metabolites dFdU and Epi-ol, are excreted in detectable amounts in saliva, although their absolute concentrations remain relatively low.

Clinical assessment of patients with advanced non-small-cell lung cancer eligible for second-line chemotherapy: a prognostic score from individual data of nine randomised trials.

PURPOSE: Knowledge of prognostic factors for advanced non-small-cell lung cancer (NSCLC) patients eligible for second-line treatment is scarce. The aim of this study was to assess the prognostic role of a number of routinely collected clinical variables and to provide a summary index to discriminate patients according to probability of survival. METHODS: Individual data from nine randomised trials of second-line treatment in advanced NSCLC were analysed. Primary end-point was overall survival (OS). Cox model, stratified by trial, was used for multivariate analyses, and a prognostic index was provided and validated according to an internal/external procedure. RESULTS: Out of 1239 patients, 1197 patients (97%) had complete information. Median OS was 7.4months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males), performance status (PS), tumour histology (worse in squamous and other histology versus adenocarcinoma), stage (worse in IV versus IIIB), type of previous treatment (worse for patients pretreated with platinum) and response to first-line (worse for patients not obtaining objective response). Prognostic score values range from 0 to 14. When three categories were derived, median overall survival values were equal to 11.6, 7.5 and 3.0months for best (<5), intermediate (5-9) and worst (>9) categories, respectively. CONCLUSION: Prognosis of patients eligible for second-line treatment of advanced NSCLC is significantly conditioned by gender, PS, histology, stage, previous use of platinum and response to first-line. A prognostic score was derived that discriminates well subjects with a relatively more favourable prognosis and those with very short life expectancy.

Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer.

PURPOSE: Doublet chemotherapy is more effective than single-agent as first-line treatment of advanced non-small-cell lung cancer (NSCLC). As second-line treatment, several randomized trials have been performed comparing single-agent with doublet chemotherapy, but each trial had an insufficient power to detect potentially relevant differences in survival. METHODS: We performed meta-analysis of individual patient data from randomized trials, both published and unpublished, comparing single-agent with doublet chemotherapy as second-line treatment of advanced NSCLC. Primary end point was overall survival (OS). All statistical analyses were stratified by trial. RESULTS: Eight eligible trials were identified. Data of two trials were not available, and data of six trials (847 patients) were collected. Median age was 61 years. Performance status was 0 or 1 in 90%; 80% of patients had received previous platin-based chemotherapy. OS was not significantly different between arms (P = .32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% CI, 0.79 to 1.08). Response rate was 15.1% with doublet and 7.3% with single-agent (P = .0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for single agent (P = .0009; HR, 0.79; 95% CI, 0.68 to 0.91). There was no significant heterogeneity among trials for the three efficacy outcomes. Patients treated with doublet chemotherapy had significantly more grade 3 to 4 hematologic (41% v 25%; P < .0001) and grade 3 to 4 nonhematologic toxicity (28% v 22%; P = .034). CONCLUSION: Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent.

Cardiotoxicity in advanced non-small cell lung cancer patients treated with platinum and non-platinum based combinations as first-line treatment.

BACKGROUND: One of the major dose-limiting toxicities of anthracyclines is cardiotoxicity due to irreversible cardiomyopathy. Whether cisplatin-based treatment induces caridiotoxicity in the short term, especially in non-small cell lung cancer (NSCLC) patients with cardiovascular comorbidity, has not been studied previously. The aim of this study was to evaluate cardiotoxicity in advanced NSCLC patients receiving cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) as first-line treatment. PATIENTS AND METHODS: Patients were randomised to receive gemcitabine 1125 mg/m2 (days 1 and 8) plus either cisplatin 80 mg/m2 (day 2) or epirubicin 100 mg/m2 (day 1) every 3 weeks for a maximum of 5 cycles. Patients had to have a left ventricular ejection fraction (LVEF) > 45%, measured by multiple gated acquisition (MUGA) scan. A second MUGA scan was performed 12 weeks after the end of treatment. RESULTS: Sixty-nine patients were included. The mean total dose of cisplatin was 349 mg/m2 and of epirubicin 452 mg/m2. The mean difference in decline in LVEF from baseline was 2% in the CG arm versus 6% in the EG arm (p=0.016). Clinically evident cardiac failure was not observed during 12 months follow-up. No correlation was found with total drug doses administered. In patients with a history of cardiac disease a trend towards a higher decrease in LVEF was observed. CONCLUSION: Although in the EG arm the LVEF significantly declined and in the CG arm a trend for LVEF to decline was observed, the risk of cardiac failure is limited in advanced NSCLC patients.

Phase II study of docetaxel and carboplatin as second-line treatment in NSCLC.

Aim of this study was to evaluate activity and toxicity of docetaxel and carboplatin as second-line treatment in advanced non-small-cell lung cancer (NSCLC) patients who failed or relapsed after previous chemotherapy. Patients had to have unresectable stage IIIb or IV NSCLC, previous chemotherapy, a performance status < or = 2, a normal bone marrow reserve, and an adequate renal and liver function. Treatment consisted of docetaxel 75 mg/m2 and carboplatin AUC 6 mg/ml min administered every 3 weeks for a maximum of 5 cycles. Fifty-seven patients with a median age of 57 years were included. Prior treatment consisted of gemcitabine alone (n = 2) or gemcitabine in combination with cisplatin (n = 26) or epirubicin (n = 29). Median number of cycles for carboplatin and docetaxel was 4. Granulocytopenia and thrombocytopenia common toxicity criteria (CTC) grades 3 and 4 occurred in 79 and 30% of patients, respectively. Febrile neutropenia occurred in eight patients (14%), of whom two patients died. Fatigue grades 2 and 3 occurred in 42% of patients. Other non-haematological toxicity was mild. Tumour response rate was 37%, irrespective of the previous regimen. Median survival was 31 weeks, 1-year survival was 32%. In conclusion, the combination of docetaxel and carboplatin is active as second-line treatment in platinum and non-platinum pre-treated patients.

Selective targeting of homologous DNA recombination repair by gemcitabine.

PURPOSE: Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a potent radiosensitizer. The mechanism of dFdC-mediated radiosensitization is yet poorly understood. We recently excluded inhibition of DNA double-strand break (DSB) repair by nonhomologous end-joining (NHEJ) as a means of radiosensitization. In the current study, we addressed the possibility that dFdC might affect homologous recombination (HR)-mediated DSB repair or base excision repair (BER). METHODS AND MATERIALS: DFdC-mediated radiosensitization in cell lines deficient in BER and in HR was compared with that in their BER-proficient and HR-proficient parental counterparts. Sensitization to mitomycin C (MMC) was also investigated in cell lines deficient and proficient in HR. Additionally, the effect of dFdC on Rad51 foci formation after irradiation was studied. RESULTS: DFdC did induce radiosensitization in BER-deficient cells; however, the respective mutant cells deficient in HR did not show dFdC-mediated radiosensitization. In HR-proficient, but not in HR-deficient, cells dFdC also induced substantial enhancement of the cytotoxic effect of MMC. Finally, we found that dFdC interferes with Rad51 foci formation after irradiation. CONCLUSION: DFdC causes radiosensitization by specific interference with HR.

Determination of epirubicin and its metabolite epirubicinol in saliva and plasma by HPLC.

We present a high-performance liquid chromatography (HPLC) method suitable for the analysis of epirubicin and its metabolite epirubicinol in saliva and plasma. Preparation of saliva and plasma samples was performed by extraction of analytes with a chloroform:2-propanol mixture (6:1, vol/vol) and evaporation of the organic phase to dryness under vacuum at a temperature of approximately 45 degrees C. The chromatographic analysis was carried out by reversed-phase isocratic elution of the anthracyclines with a Chromsep stainless steel HPLC column (150 x 4.6 mm I.D.) filled with Nucleosil 100 S C(18) material, particle size 5 micro m. The detection was accomplished by spectrofluorimetry at excitation and emission wavelengths of 474 and 551 nm, respectively. The anthracyclines eluted within 10 min of injection, and the method appeared to be specific. The method is linear over a concentration range of 5 to 1000 micro g/L for epirubicin and 2 to 400 micro g/L for epirubicinol (r > 0.99) in both saliva and plasma. The recoveries from saliva and plasma of epirubicin, epirubicinol, and the internal standard doxorubicin were 88.9 and 69.0%, 87.6 and 77.3%, and 80 and 67.9%, respectively. The lower limit of quantification was 5 micro g/L for epirubicin and 2 micro g/L for epirubicinol. The method proved to be precise and accurate, as the within-day and between-day coefficients of variation were less than 10%. Overall results indicate that our method is suitable for the bioanalysis of epirubicin and epirubicinol in saliva as well as plasma.