Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014).

PURPOSE: To assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU). PATIENTS AND METHODS: Patients with measurable disease >4 cmN0 or N+ received RT (36Gy+2 week gap+23.4Gy) with either MMC/CDDP or MMC/5-FU (MMC 10mg/m(2) d1 of each sequence; 5-FU 200mg/m(2)/day c.i.v. daily; CDDP 25mg/m(2) weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, alpha=10%, beta=10%). RESULTS: The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment (p=0.005). CONCLUSIONS: Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.

Evaluation des Nationalen Krebsbekämpfungsprogrammes, Phase I, 1999. Studie 2: Inventar der vorhandenen Datenquellen und Indikatoren

[Table des matières] 1. Allgemeine Schlussforschungen und Empfehlungen. 2. Einleitung. 3. Methodik. 4. Ergebnisse. 4.1. Zentrale Datenquellen : Kontinuierliche und periodische Erhabungen, Mortalitätsstatistik, Spitalstatistik, Vereinigung Schweizerischer Krebsregister, Schweizerische Gesundheitsbefragung, Trendstudie zum Konsum von Alkohol, Tabak, Medikamenten und illegalen Drogen SFA, SChülerbefragung SFA, Warenkorb BFS, Schweizer Haushalt-Panel, Traditioneller Haushaltspanel IHA-GfM, Pharmaabsatzzahlen IHA-GfM, Sonnenexposition und Sonnenschutz, Indikatoren für den Tabakkonsum in der Schweiz, Statistische Erhebungen und Schätzungen über Landwirtschaft und Ernährung, Participants' Report SIAK, Trial guide SAKK, Guidelines, Berufskrankheiten SUVA, Krebstelefon SKL. 4.2. Weitere Datenquellen : Kontinuierliche und periodische Erhebungen, Statistik der verteilten Broschüren SKL, Jahresbericht von im Bereich Krebs tätigen Institutionen, Invalidenversicherung BSV, Andere Statistiken des BSV, Konkordat der Schweizerischen Krankenversicherer, Nestlé-Studie. 4.3. Zentrale Einzelerhebungen : Frauen und Krebs, Vorstudie für eine nationale Kampagne zur Früherfassung des kolorektalen Karzinoms, Ausmass und Intensität von Krebsschmerzen in der Schweiz. 4.4. Weitere Einzelerhebungen : IUMSP : die Gesundheit Jugendlicher in der Schweiz, Stillhäufigkeit und Stilldauer in der Schweiz 1994, Kohortenstudie Alkohol- und Drogenkonsum SFA. 4.5. Abgeschlossene Erhebungen : Krebsvorsorge, MONICA-Studie und Basler Ernährungsstudie. 5. Schlussfolgerungen und Empfehlungen : Zusammenfassende Schlussfolgerungen und Empfehlungen. 6. Anhang. 6.1. Zentrale Datenquellen im Uberblick : Globalkonzept, Brustkrebsprogramm, Lungenkrebsprogramm, Hautkrebsprogramm, Darmkrebsprogramm. 6.2. Zieltabelle : formulierte Ziele des nationalen Krebsbekämpfungsprogramms. 6.3. Abkürzungen.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Preoperative hyperfractionated accelerated radiotherapy (HART) and concomitant CPT-11 in locally advanced rectal carcinoma: a phase I study.

PURPOSE: Patients with locally advanced rectal carcinoma are at risk for both local recurrence and distant metastases. We demonstrated the efficacy of preoperative hyperfractionated accelerated radiotherapy (HART). In this Phase I trial, we aimed at introducing chemotherapy early in the treatment course with both intrinsic antitumor activity and a radiosensitizer effect. METHODS AND MATERIALS: Twenty-eight patients (19 males; median age 63, range 28-75) with advanced rectal carcinoma (cT3: 24; cT4: 4; cN+: 12; M1: 5) were enrolled, including 8 patients treated at the maximally tolerated dose. Escalating doses of CPT-11 (30-105 mg/m(2)/week) were given on Days 1, 8, and 15, and concomitant HART (41.6 Gy, 1.6 Gy bid x 13 days) started on Day 8. Surgery was to be performed within 1 week after the end of radiochemotherapy. RESULTS: Twenty-six patients completed all preoperative radiochemotherapy as scheduled; all patients underwent surgery. Dose-limiting toxicity was diarrhea Grade 3 occurring at dose level 6 (105 mg/m(2)). Hematotoxicity was mild, with only 1 patient experiencing Grade 3 neutropenia. Postoperative complications (30 days) occurred in 7 patients, with an anastomotic leak rate of 22%. CONCLUSIONS: The recommended Phase II dose of CPT-11 in this setting is 90 mg/m(2)/week. Further Phase II exploration at this dose is warranted.

High-throughput and sensitive quantitation of plasma catecholamines by ultraperformance liquid chromatography-tandem mass spectrometry using a solid phase microwell extraction plate.

Plasma catecholamines provide a reliable biomarker of sympathetic activity. The low circulating concentrations of catecholamines and analytical interferences require tedious sample preparation and long chromatographic runs to ensure their accurate quantification by HPLC with electrochemical detection. Published or commercially available methods relying on solid phase extraction technology lack sensitivity or require derivatization of catecholamine by hazardous reagents prior to tandem mass spectrometry (MS) analysis. Here, we manufactured a novel 96-well microplate device specifically designed to extract plasma catecholamines prior to their quantification by a new and highly sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Processing time, which included sample purification on activated aluminum oxide and elution, is less than 1 h per 96-well microplate. The UPLC-MS/MS analysis run time is 2.0 min per sample. This UPLC-MS/MS method does not require a derivatization step, reduces the turnaround time by 10-fold compared to conventional methods used for routine application, and allows catecholamine quantification in reduced plasma sample volumes (50-250 μL, e.g., from children and mice).