This phase II trial was designed to evaluate efficacy and safety of a highly intensified therapy in locally advanced squamous cell carcinoma of the oro-, hypopharynx and larynx. In this prospective, mono-centric, open-label, non-randomized phase II trial the single treatment arm consisted of a combined induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil, followed by bioradiation with the monoclonal antibody cetuximab, carbon ion boost (24Gy(RBE) in 8 fractions) and IMRT (50 Gy in 25 fractions). The trial was closed early due to slow accrual. Eight patients (median age 52.5 years) were enrolled into the trial. The median follow-up was 13 months and the 12-months locoregional tumor control, progression-free survival and overall survival rates were 100.0% each. Complete remission was achieved in 7 patients. The most commonly late radiation adverse event was xerostomia (85.7% at 12 months). Five serious adverse events with recovery were documented in 4 patients: mucositis grade 3 (n = 2), decreased lymphocyte count grade 4, febrile neutropenia grade 4 and hypersensitivity grade 3 to cetuximab (n = 1 each). Most symptom scales had their worst value at the last treatment day and recovered until the 4th follow-up visit. The study treatment was tolerable and promising. Reduced quality of life recovered for most aspects until the last follow-up visit.
Annals of oncology : official journal of the European Society for Medical Oncology •
To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.
Matuschek C, Bölke E, Belka C, Ganswindt U, Henke M, et al.
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] •
Close resection margins < 5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article. Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1-36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m(2), days 1-5 and days 29-33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m(2), days 1-5 + days 29-33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m(2) followed by weekly doses of 250 mg/m(2). Maintenance cetuximab began after radiochemotherapy at 500 mg/m(2) every 2 weeks for 6 months. Of the 55 patients (46 male, 9 female, mean age 55.6, range 29-70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14 % of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22 % of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80 % were still on cetuximab at 3 months and 63 % at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48 % of patients. Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3-5 months is moderate.
Vandekerckhove F, Schenkman S, Pontes de Carvalho L, Tomlinson S, Kiso M, et al.
Glycobiology •
Trypanosoma cruzi trypomastigotes acquire sialic acid (SA) from host glycoconjugates by means of a plasma membrane-associated trans-sialidase (TS). Here we study the substrate specificity of TS, which differs from all known sialyltransferases in that it does not require cytidine monophosphate (CMP)-SA as donor. The T. cruzi TS reversibly transfers SA to saccharides with terminal beta-Gal (but not alpha-Gal) residues. Donors are saccharides with SA linked to terminal beta-Gal residues by (alpha 2-3), but not (alpha 2-6) bonds. The type of beta-linkage of the terminal Gal residue is of minor importance (beta 1-4 and beta 1-6 are slightly better than beta 1-3), whereas chain length and the structure of additional vicinal sugar residues are not relevant. SA on the surface of living trypomastigotes of T. cruzi is transferred back and forth between the parasite surface and acceptor molecules with terminal beta-Gal, either in solution or on the surface of neighbouring mammalian cells. Addition of fucose residue on or close to the terminal galactose impairs TS activity. As a consequence, the enzyme acts poorly on the E-selectin ligand sialyl-Lewisx and its precursor Lewisx, and in vitro adhesion of TS-treated neutrophils to L-cells expressing L-selectin is not affected. Modifications in the structure of the (alpha 2-3)-linked N-acetyl-neuraminic acid (Neu5Ac) (deoxy or methoxy) of the donor molecules do not impair transfer if the changes are at C9, whereas changes at C4, C7 and C8 impair the ability to donate the modified SA.(ABSTRACT TRUNCATED AT 250 WORDS)
