The "liver-first approach" for patients with locally advanced rectal cancer and synchronous liver metastases.

PURPOSE: This study was designed to investigate the outcome of "the liver-first" approach in patients with locally advanced rectal cancer and synchronous liver metastases. METHODS: Patients with locally advanced rectal cancer and synchronous liver metastases were primarily treated for their liver metastases. If successful, patients underwent treatment for the rectal tumor. RESULTS: Twenty-three patients were included. One patient had liver resection without neoadjuvant chemotherapy followed by chemoradiotherapy. All remaining 22 patients underwent laparotomy after chemotherapy. Eighteen patients underwent partial liver resection and subsequent chemoradiotherapy for the rectal cancer. One patient underwent in one session a partial liver resection and a low anterior resection. Six patients were not treated according to protocol because of extensive disease. Sixteen patients (73 percent) completed the full treatment protocol and all are alive after a median period of 19 (range, 7-56) months. CONCLUSIONS: This is the first sizable report on the "liver-first approach" demonstrating that it may be considered the preferred treatment schedule for patients with locally advanced rectal cancer and synchronous liver metastases. It allows most patients to undergo curative resections of both metastatic and primary disease and can avoid useless rectal surgery in patients with incurable metastatic disease

A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours

textabstractBackground: BN80915 (diflomotecan) is an E-ring modified camptothecin analogue, which possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors. This phase I study was carried out using a daily times five administration schedule (d×5) repeated three weekly. The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for phase II studies. Secondary objectives were to determine the safety and pharmacokinetic (PK) profile, and to make a preliminary assessment of antitumour activity. Patients and methods: Diflomotecan was administered intravenously on days 1-5 every 3 weeks. Patients were treated in cohorts of three to six per dose level and the dose of diflomotecan was escalated according to modified Fibonacci schedule. Plasma concentrations of diflomotecan and its metabolite BN80942 were quantified. Results: Thirty patients were assessable for toxicity. Dose levels explored were 0.05, 0.1, 0.125 and 0.15 mg/m2/day. The 0.15-mg/m2dose level was determined to be the MTD. Toxicity was acceptable at the 0.125-mg/m2/day dose level. PK analysis showed the principal parameters were neither time nor dose dependent. There was a wide interpatient variability in PK at all dose levels. One patient with colorectal cancer, previously treated with irinotecan, had a partial response. A further eight patients had disease stabilisation. Conclusions: The MTD and RD of diflomotecan administered according to a d×5 repeated three weekly are 0.15 and 0.125 mg/m2/ day, respectively. In general, treatment was well tolerated; the principal toxicity was reversible myelosuppression. An objective response was seen in a patient previously treated with irinotecan

Conjunctive Therapy of Cisplatin With the OCT2 Inhibitor Cimetidine: Influence on Antitumor Efficacy and Systemic Clearance

The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors such as cimetidine can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m(2)) in a randomized crossover fashion with or without cimetidine (800 mg×2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs 4.38 μg×h/mL; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity