Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

Intra-arterial chemiotherapy for invasive bladder cancer.

Standard treatment for transitional cell carcinoma confined to the bladder is radical cystectomy that allow to obtain an overall 5-year disease-free survival rate only of 50-70%. It has been demonstrated that intra-arterial chemotherapy produces the same survival outcomes as radical cystectomy. This study aimed to evaluate the activity and toxicity of a bladder-sparing loco-regional treatment. Five patients with transitional cell carcinoma of the bladder (4 locally advanced and 1 pelvic relapse) were treated with doxorubycin 25 mg/m2, cisplatin 40 mg/m2 and methotrexate 50 mg/m2, all infused bolus via internal iliac arteries on day 1, every three weeks. We obtained 3 complete responses, 1 stable disease and 1 progression of disease. The treatment was well tolerated with a minimal hematological toxicity and no others major toxicity. Median disease free survival was 8 months (1-17), median overall survival was 22 months (2-55). This loco-regional regimen of chemotherapy is active and safe in locally advanced bladder cancer patients and permits a prolonged good quality of life regarding the maintenance of the physiological functions of the lower urinary tract.

Combination chemotherapy and interferon alpha 2b in the treatment of advanced non-small-cell lung cancer. The Italian Lung Cancer Task Force (FONICAP).

Thirty-four patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of polychemotherapy and recombinant interferon. Chemotherapy consisted of cyclophosphamide, 400 mg/m2, epidoxorubicin, 50 mg/m2, and cisplatin, 40 mg/m2 (CAP) i.v. on day 4; recombinant alpha 2b interferon (r alpha 2b IFN) was given i.m. daily at the dose of 3-5 MU from days 1 to 7. The treatment was repeated every 4 weeks. In the 32 eligible patients the overall response rate was 19.3% (95% C.L. 7.4-37.4%). Non-hematologic toxicity consisted formerly in flulike symptoms and fatigue complained of by 37.5% and 31.2% of patients, respectively, and vomiting reported in 68.7% of patients; grade III-IV myelotoxicity was observed in 12.5% of cases. In no case was the toxicity life threatening. The median overall actuarial survival and progression-free survival were 37 and 20 weeks, respectively. This study indicates that the combination of CAP chemotherapy and r alpha IFN is feasible and active in the treatment of advanced non-small-cell lung cancer.

Alternating chemotherapy with cyclophosphamide, doxorubicin, vincristine and cisplatin, etoposide followed by prophylactic cranial and thoracic irradiation for small cell lung cancer (SCLC): long-term results.

Both CAV (Cyclophosphamide, Doxorubicin, Vincristine) and PE (Cisplatin, Etoposide) are effective and non cross-resistant regimens in the treatment of SCLC. We designed a chemotherapeutic scheme including CAV and PE given in an alternating fashion with the following schedule: Cyclophosphamide 1000 mg/sm, Doxorubicin 50 mg/sm, Vincristine 2 mg/sm I.V. on day 1, alternated every 21 days with Cisplatin 20 mg/sm and Etoposide 80 mg/sm I.V. days 1-5 for 6 cycles. Following chemotherapy (CT) chest radiotherapy in patients (pts) with limited disease (LD) in complete response (CR) or partial response (PR) and prophylactic cranial irradiation (PCI) in CRs were given, 32 pts entered the study and 27 were evaluable: 9/27 (33.3%) had CR (8/15 with LD had CR) and 15/27 (55.5%) PR. The overall median survival was 53.71 weeks: 79.85 weeks for LD pts and 32.86 for ED.4 pts with LD were alive after 2 years and 2 of them are still alive without disease at 44 and 46 months. Toxicity was acceptable in all patients. Alternating chemotherapy with CAV and PE followed by chest and brain RT in responding LD pts is an effective induction treatment for SCLC although long-term survival still remains disappointing.

Oral chemotherapy with idarubicin plus cyclophosphamide in advanced breast cancer.

An oral chemotherapy schedule based on idarubicin and cyclophosphamide was evaluated in 31 advanced breast cancer patients. Out of 27 patients evaluable for response, 1 (3.7%) achieved a complete response and 5 (18.5%) a partial response, with an objective response rate of 22.2% (95% confidence limits 8.6-42.3%). The median time to progression was 7 months (range 3-12). Fourteen patients (51.9%) showed a disease stabilization, and 7 progressed (25.9%). Toxicity was mild. Considering the low response rate, but also the advantages of oral chemotherapy and the mild toxicity observed, oral idarubicin plus cyclophosphamide can be considered as a second-choice regimen in advanced breast cancer.

Oral chemotherapy for poor risk small-cell lung cancer patients with combined idarubicin and etoposide.

Sixteen patients with previously untreated small-cell lung cancer, unsuitable for standard aggressive intravenous chemotherapy due to advanced age or poor performance status or very advanced disease including brain metastases or either extensive liver or marrow involvement with impaired organ function, were treated with combined oral chemotherapy including 4-demethoxydaunorubicin (IMI30, idarubicin) 30 mg/sm on day 1 and etoposide (VP16) 150 mg/sm on days 2,3,4 every 4 weeks. Out of 13 evaluable patients 1 had a complete response and 2 had a partial response with an overall objective response rate of 23% (95% confidence-limits 5-53.8%). Toxicity was generally very mild. Although the compliance of this regimen is excellent, its antitumor activity seems unsatisfactory even in this category of poor-risk small-cell lung cancer patients.

Correlation of beta-lactamase stability and antibacterial activity of beta-lactams in beta-lactamase-producing bacteria and respective transconjugants.

A total of 343 Gram-negative bacteria were isolated and identified from urine specimens of patients with urinary tract infections. All the bacteria were investigated for their production of beta-lactamases by the nitrocefin test. beta-lactamase-producing strains were tested by the Datta method to detect any transfer of beta-lactamase production to a receiving E. coli K12 RN-strain. MICs of six beta-lactamase-stable compounds (ceftazidime, ceftriaxone, cefamandole, cefoxitin, cefotaxime, cefuroxime) were determined against all the beta-lactamase transferring bacteria and their respective transconjugants by a miniaturized dilution broth method. beta-lactamases produced by donors and transconjugants were purified and identified by determination of the isoelectric point by focusing; their hydrolytic activity was assessed by a spectrophotometric method using cytochrome c reduction. A total of 129 bacteria out of 343 produced beta-lactamases and 27 of these transferred the beta-lactamase production by conjugation. The beta-lactamases isolated from donors and transconjugants had the same pl and the same substrate profile. Ceftazidime was more stable to all the beta-lactamases isolated and more active against all the bacteria examined than the other compounds.

Occurrence of gram negative bacteria in midstream bladder urine and their sensitivity to quinoline derivatives.

326 gram negative bacteria have been isolated and quantitative bacteria counts performed from midstream urine of as many patients affected with symptomatic and non symptomatic urinary tract infections. Susceptibility of bacteria to four quinoline derivatives (Norfloxacin, Oxolinic acid, Pipemidic acid and Nalidixic acid) was studied determining the minimal inhibitory concentrations (MICs) of each drug by a miniaturized dilution broth method. The frequency of bacterial species isolated, the frequency of symptoms and the frequency of bacterial counts were studied to establish a possible relationship between these data. It has been observed that patients affected with pyuria without any other subjective symptoms demonstrate a colony count ranging between less than 10(4) and greater than 10(5) bacterial/ml of urine and these bacteriuria were determined by several different bacterial species. E. coli was much more frequently responsible for low or high count bacterial infections of the urinary tract than other species. In fact E. coli was detected in 64.4% of patients, P. mirabilis in 15.9%, E. agglomerans in 5.2%, P. aeruginosa in 4.9. Other species were detected in much lower percentages. Norfloxacin proved to be the most effective drug in vitro, out of those under examination. Its MIC50 never exceeded 8 mcg/ml even against Pseudomonas and Serratia strains, which were resistant to all the other antimicrobial agents.

Cross resistance of quinolone derivatives in gram-negative bacteria.

A total of 127 Gram-negative bacteria resistant to nalidixic acid were isolated from as many patients affected by urinary tract infections and hospitalized in the first Clinic of Infectious Diseases, University of Naples. Enterobacteria were identified by Enterotube system (Roche) and API 20 system (Ayerst). Non-fermentative bacteria were identified by OXI/FERM system (Roche). The following bacteria were collected: Escherichia coli 50, Proteus spp. 35, Enterobacter agglomerans 12, Serratia sp. 5, Pseudomonas aeruginosa 25. The in vitro antibacterial activity of nalidixic acid and three other quinoline derivatives (pipemidic acid, oxolinic acid and ciprofloxacin) were studied by determining the MICs by a miniaturized dilution broth method. The MICs were compared to evaluate the eventual cross resistance to the drugs under examination within each bacterial species. The results showed that 23% of bacteria were resistant to nalidixic acid, pipemidic acid and oxolinic acid; 49.6% to nalidixic and pipemidic acid and 0.7% to nalidixic acid and oxolinic acid. On the other hand none of the bacteria were resistant to ciprofloxacin. The last showed very low MICs against all the bacteria under examination, including Pseudomonas and Serratia. The high antibacterial activity of ciprofloxacin even against bacteria highly resistant to the other quinolines could be due to a greater affinity of the target sites or to the better permeability of resistant strains to the newer drug or because it is unaffected until now by mutations of genes responsible for cross resistance.

Comparative activity of ceftizoxime and four other cephalosporins against gram negative bacteria and their sensitivity to beta-lactamases.

The in vitro activity of ceftizoxime compared with other beta-lactamase stable compounds was assessed against recent urinary gram negative isolates. 343 bacterial strains were isolated from patients affected by UTI, identified by standard bacteriological methods and investigated for their production of beta-lactamases by Nitrocefin test. MICs and MBCs of ceftizoxime, ceftriaxone, cefamandole, cefoxitin and cefotaxime were determined by a miniaturized dilution broth method against all beta-lactamase producing bacteria (129 out of 343). Sensitivity of antibiotics to beta-lactamases isolated and semi-purified by ultrasonic disruption and high speed centrifugation was assessed by a spectrophotometric method. In vitro antibacterial activity of each antibiotics was correlated to their sensitivity to isolated beta-lactamases. Ceftizoxime showed lower MIC and MBC values and lower MBC/MIC ratio than the other compounds against all the bacteria including Pseudomonas. Ceftizoxime was not hydrolized by any isolated beta-lactamase.

Comparative in vitro activity of ciprofloxacin and five other quinoline derivatives against gram-negative isolates.

A total of 375 Gram-negative bacterial strains were isolated from midstream urine specimens of the same number of patients affected by urinary tract infections. All bacteria were identified by standard bacteriological methods and their susceptibility to six quinoline derivatives (ciprofloxacin, cinoxacin, norfloxacin, oxolinic acid, pipemidic acid, nalidixic acid) was studied by determining the MICs and MBCs for each compound using a miniaturized dilution broth method in microtitre plates and twofold dilutions of each drug from 256 to 0.12 mcg/ml. Ciprofloxacin, a new quinoline carboxylic acid compound structurally related to nalidixic acid, showed a much higher antibacterial activity against all bacterial strains under examination, including Pseudomonas, than the other compounds, except for norfloxacin. The MIC90 and MBC90 of ciprofloxacin never exceeded 1 mcg/ml with any of the bacterial species; and MBC/MIC ratios were very low, which represents an important clinical advantage. Only norfloxacin showed comparable effectiveness. No bacterial strain showed resistance to the drug and the MIC90 and MBC90 never exceeded 8 mcg/ml.

Comparative activity of ceftazidime and four other cephalosporins against gram-negative bacteria and their sensitivity to beta-lactamases.

The in vitro activity of ceftazidime compared with other beta-lactamase stable compounds was assessed against recent Gram-negative isolates. Three hundred forty-three bacterial strains were isolated from patients affected with UTI, identified by standard bacteriological methods and investigated for their production of beta-lactamases by the Nitrocefin test. MICs and MBCs (minimum inhibitory concentrations and minimum bactericidal concentration) of ceftazidime, cefamandole, cefoxitin, cefotaxime and cefuroxime were determined by a miniaturized dilution broth method against all beta-lactamase producing bacteria (129 out of 343). Sensitivity of the antibiotics to beta-lactamases isolated and semipurified by ultrasonic disruption and high-speed centrifugation was assessed by a spectrophotometric method. The in vitro antibacterial activity of each antibiotic was correlated to its sensitivity to isolated beta-lactamases. Ceftazidime showed lower MIC and MBC values and lower MBC/MIC ratios than the other compounds against all the bacteria including Pseudomonas spp. In addition, ceftazidime was not hydrolyzed significantly by any isolated beta-lactamases.

Comparative in vitro activity of norfloxacin and four other chemotherapeutics against urinary gram-negative isolates.

Three hundred seventy-five Gram-negative bacterial strains were isolated from urine specimens of as many patients affected by symptomatic or asymptomatic urinary tract infections. Susceptibility of bacteria to five chemotherapeutics (norfloxacin, oxolinic acid, pipemidic acid, nalidixic acid and nitrofurantoin) was studied determining minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of each compound by a miniaturized dilution broth method. Norfloxacin, a quinoline carboxylic acid compound structurally related to nalidixic acid, showed a much higher antibacterial activity against all bacterial strains under examination including Pseudomonas sp. The best activity of norfloxacin was expressed either by lower MICs and lower MBCs with respect to those of the other compounds, or by a low MBC/MIC ratio, which represents an important advantage in clinical practice.

[In vitro activity of beta-lactam antibiotics and their sensitivity to beta-lactamase]. / Attivita' in vitro di antibiotici beta-lattamici e loro sensibilita' alle beta-lattamasi.

beta-lactamase production was evaluated by chromogenic cephalosporin 87/312 in 116 E. coli isolated from clinical sources. Such test revealed beta-lactamase production in 54 strains out of 116 (46%): MICs of eight beta-lactam antibiotics (Ampicillin, Piperacillin, Cefazoline, Cephaloridine, Cephalexine, Cefuroxime, Cefotaxime, Cefotaxime) were determined using a miniaturized dilution broth method. Cefotaxime and Ceftriaxome and Ceftriaxone showed the highest antibacterial activity. All beta-lactamases produced by E. coli strains under examination were isolated and purified by ultrasonic disruption and high speed centrifugation. Sensitivity of the eight antibiotics to purified beta-lactamases was assessed by a spectrophotometric method that utilizes the velocity of cytochrome c reduction. The sensitivity to beta-lactamases was reflected in the in vitro activity of the antibiotics as assessed by the determination of the MICs.

Transferable drug resistance in Escherichia coli isolated from antibiotic-fed chickens.

The isolation and transferable drug resistance of Escherichia coli from the feces of chickens after oral administration of tetracylcine, chloramphenicol, rifampicin, and amoxicillin were studied. Each antibiotic was administered at two different dosages to four groups of 12 chickens. Treatment was carried out for 3 weeks. Feces were taken weekly and bacteriological examinations performed. E. coli biotypes were identified by fermentation and enzymatic reaction patterns. Antibiotic sensitivity tests were performed on all E. coli isolates. Rapid appearance of E. coli biotypes showing drug-resistance to each antibiotic was observed as soon as 1 week after treatment. Resistance was not detectable a few days after interruption of antibiotic administration. All E. coli strains showing drug resistance to the antibiotic under examination were studied to observe their capacity to transfer antibiotic resistance to E. coli K 12 E 711 F-strain. A high percentage of resistant E. coli strains transferred their antibiotic resistance to E. coli K 12. Transferable drug resistance was demonstrated mainly in tetracycline resistant E. coli.

[Antibiotic resistance and transfer in Enterobacteriaceae of avian origin]. / Antibiotico-resistenza e trasferimenti nelle enterobacteriaceae di provenienza avicola.

Thirty-six specimens of feces were taken from as many chicken farms, from which 118 different strains of Enterobacteriaceae were isolated. The resistances of the single isolated bacteria were studied, performing plate sensitivity tests by the Kirby-Bauer method. The capacity of the bacteria under examination to transfer their antibiotic resistances in vitro to a sensitive E. coli strain (E. coli K 12 E 711 F--) was observed. A very high percentage of strains has shown resistance to one or more antibiotics (91%). However a much lesser number of strains were capable of transferring their antibiotic resistances (12.9%). It is suggestive, then, that the animals under examination do not represent an important source of antibiotic resistance diffusion to man.