Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a highly specific monoclonal antibody directed against the vascular endothelial growth factor (VEGF), erlotinib, an EGFR tyrosine kinase inhibitor, and irradiation given alone and in combination. Investigations were performed using a VEGF-secreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, bevacizumab (5 mg kg À1 , 5 days a week, i.p.), erlotinib (100 mg kg À1 , 5 days a week, orally) and irradiation (6 Gy, 3 days a week) were administered alone and in combination for 10 days. As compared with the control, concomitant administration of drugs produced a marked and significant supra-additive decrease in tumour mass; the addition of irradiation almost completely abolished tumour growth. The drug association markedly reduced the number of metastatic nodes and the triple combination significantly reduced the total number of pathologically positive lymph nodes as compared with controls. The RT-induced proliferation, reflected by Ki67 labelling, was reduced to control level with the triple combination. Radiotherapy induced a strong and very significant increase in tumour angiogenesis, which was no longer observed when combined with erlotinib and bevacizumab. The efficacy of the combination of bevacizumab þ erlotinib and RT may be of clinical importance in the management of head and neck cancer patients.

Background:To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.Methods:This prospective multicentric study involved 251 stage I–III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12–13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4–9), CpG island methylation phenotype status, ploidy, S-phase, LOH.Results:The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR.Conclusions:Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.

Background: The aim of this phase I trial was to define the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of erlotinib combined with capecitabine and gemcitabine in the treatment of advanced pancreatic cancer (APC). Methods: Gemcitabine was administered intravenously at 1,000 mg/m²/week (days 1, 8 and 15) and oral capecitabine from day 1 to day 21 at 1,660 mg/m²/day. Oral erlotinib was administered daily continuously at escalating doses (28-day cycle). Dose levels (DLs) 1, 2, 3 and 4 were 50, 75, 100 and 125 mg/day, respectively. Pharmacokinetic analysis of the three drugs was performed in the first cycle. Results: Nineteen patients were enrolled. At the MTD (DL4; 125 mg/day erlotinib), 100% of patients developed DLT consisting of grade 4 febrile neutropenia and nonhematological grade 3 events (vomiting, diarrhea, stomatitis, rash). The most common toxicities, regardless of grade, were neutropenia, anemia, rash and diarrhea. Erlotinib systemic exposure was significantly related to the administered dose. Of note, toxicity was significantly associated with elevated systemic exposure of capecitabine anabolites. Conclusion: When combined concurrently with 1,000 mg/m²/week gemcitabine and 1,660 mg/m²/day capecitabine, erlotinib can be administered safely at a daily dose of 100 mg in APC patients.