No abstract

Cutaneous toxicities associated with EGFR inhibitors (EGFRIs) have a significant impact on patient treatment continuation, quality of life and healthcare resource utilization. This paper reviews the current prophylaxis and management of EGFRI-induced cutaneous toxicities in patients with colorectal cancer, and combines these findings with the authors' clinical expertise to define a novel algorithm for healthcare professionals managing patients receiving EGFRIs. This tool includes a grading system based on the location, severity and psychological impact, and provides a standard prescription pack, advice on prophylaxis/self-management of cutaneous symptoms for patients initiating EGFRIs, and essential guidance on subsequent review and treatment escalation. It aims to optimize treatment of metastatic colorectal cancer by minimizing cutaneous toxicities to maintain dose intensity and efficacy of EGFRI-based chemotherapy.

Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m À2 , although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.

Purpose: To study the safety, pharmacokinetics, and recommended dose of the combination of pertuzumab, a humanized monoclonal antibody HER2-dimerization inhibitor, and capecitabine in patients with advanced malignancies. Experimental Design: Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v. on day 1 plus capecitabine at doses of 825-1,000-1,250 mg/m 2 , twice daily orally on days 1 to 14 of each 21-day treatment cycle, in three sequential cohorts. The pharmacokinetics of capecitabine and pertuzumab were studied. Patients received a single dose of capecitabine in a pretreatment phase (day -7) followed by serum sampling for capecitabine and its metabolites. Results: Nineteen patients were accrued and 18 were assessable. The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed. The most frequent adverse event was asthenia, which was grade 3 in two patients. One asymptomatic pulmonary embolism occurred. No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported. There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab. The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine. Disease stabilization was observed in 11patients. Conclusions: Pertuzumab and capecitabine were well tolerated at all dose levels. Escalation beyond the highest dose level tested was not planned, as this included the recommended doses of monotherapy for both drugs. In conclusion, this combination is ready for phase II testing.

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m À2 ) in combination with 250 mg m À2 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m À2 . However, three out of five patients at the 100 mg m À2 irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m À2 . The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m À2 ) combined with a continuous infusion of 5-FU (250 mg m À2 ) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study. Colorectal cancer (CRC) is second in the league of cancer deaths in developed countries. Approximately 25% of patients have liver metastases at presentation and eventually 50% of newly diagnosed patients will succumb to metastatic disease. The liver is the most common site of disease spread, and approximately 60% of patients with liver metastases have no evidence of extrahepatic disease (Faivre et al, 1995). However, only 10 -20% of these patients are candidates for surgical resection (Adam, 2003), and although there are new treatment techniques evolving, such as radiofrequency ablation (Nordlinger and Rougier, 2002) and the regional delivery of chemotherapy by hepatic arterial infusion (Kemeny and Ron, 1999;Kemeny, 2000), systemic chemotherapy still plays the major role in the treatment of metastatic CRC.The fluoropyrimidine 5-fluorouracil (5-FU) has been the cornerstone of therapy for CRC for over 30 years and during this time has been the subject of extensive investigation with regard to the optimisation of its use. In combination with the biochemical modulator leucovorin (folinic acid (FA)), it remains the reference drug for the treatment of CRC in adjuvant, first-line and secondline settings, with response rates of 22 and 14% for continuous infusion a...