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We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m(-2), day 1; folinic acid, 200 mg m(-2); and 5-fluorouracil: as a 400 mg m(-2) bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m(-2), from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times. [ABSTRACT FROM AUTHOR]

Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150-300 mg/m(2)) and two of continuous infusion of FU (800-1000 mg/m(2)) in a 3-weekly schedule. The most severe grade III-IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (+/-20, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (+/-16, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity. [ABSTRACT FROM AUTHOR]

Objective: The prognosis in T3–T4 or N+ gastric cancer is dismal, and the role of adjuvant therapy remains uncertain. Neoadjuvant chemotherapy could improve both resectability and survival. Here, we report the results of the long-term follow-up of a pilot study aimed at evaluating a neoadjuvant treatment in a group of patients carefully staged by computed tomography (CT), endoscopic ultrasound and laparoscopy. Methods: Twenty-five stage II–III patients with histologically proven gastric adenocarcinoma were enrolled in the study. All patients gave informed consent and were thoroughly staged. Patients were treated with epidoxorubicin (40 mg/m2 i.v.) on days 1 and 4, etoposide (VP-16; 100 mg/m2) on days 1, 3 and 4 and cisplatinum (80 mg/m2) on day 2, every 21–28 days for 3 pre-operative cycles before CT clinical restaging followed by laparotomy and D2 gastrectomy. Three further cycles of chemotherapy were planned after radical surgery. Results: Twenty-four patients received the planned pre-operative chemotherapy and underwent surgical resection; total (13 patients) or subtotal (7 patients) R0 D2 gastrectomy was possible in 20 patients. One patient died as a result of gastric bleeding. Perioperative complications occurred in 5 patients (failure of anastomosis in 1 patient and wound infection in the other 4). The pathologic response rate included 7 partial responses (29.1%) and 10 patients with stable disease (41.7%). The main toxicity was grade 3/4 neutropenia (68%), which occurred more frequently during the postoperative chemotherapy, and fatigue (68%). Fever or infection, however, were never observed. The median disease-free survival was 37 months, and median survival has not been reached after 40 months of median follow-up. One-, 2- and 3-year survival rates were 80, 64 and 60%, respectively. Conclusion: The notable long-term survival in the present study suggests a comparison between the neoadjuvant approach, including new drug combinations, and adjuvant chemo- or chemoradio-therapy in locally advanced gastric cancer. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sixteen healthy volunteers received dothiepin 25 mg, 50 mg, 75 mg and placebo in a double-blind crossover study. Each subject received the four treatments once, with a 6-day washout period between test days. On each occasion psychomotor performance and cognitive function were measured 30 min before dosing and 1, 2, 4, 6 and 8 h after drug administration. The test battery comprised: Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking and Short Term Memory. Subjective ratings of sedation were measured using Line Analogue Rating Scales. Dothiepin at the subtherapeutic dose of 75 mg was shown to produce statistically significant impairment (p <0·05) on several of the variables investigated. These included CFF at the 2- and 4-h test points, TRT at the 2-h test point and LARS at the 2- and 4-h test points. Lower doses also produced impairment of cognitive function and psychomotor performance as measured by the present test battery. © 1997 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Three doses of citalopram (10, 20 and 40 mg), and placebo were administered to healthy volunteers for periods of 8 days each. Dothiepin 75 mg was given as an acute dose on days 1 and 8 only, with placebo dothiepin on days 2–7. Subjects were tested on days 1 and 8 of the dosing periods on a battery of psychometric tests. The results showed that citalopram at all doses had no detrimental effects on psychomotor performance. The effect of citalopram on critical flicker fusion (CFF) was to raise thresholds. This indicates an improvement in CNS function, i.e. an elevation of cognitive processing ability, with no evidence of an arousing or alerting effect. The effects were apparent after both acute and sub-chronic dosing. These data are in contrast to those collected for dothiepin, which showed significant impairment of cognitive and psychomotor function on most of the measures employed. The most frequent adverse events reported for citalopram were drowsiness, nausea and headache, with the nausea appearing to be dose dependent. The main adverse events reported for dothiepin were drowsiness, sleepiness and dizziness. The rates of adverse events for all active treatments were not statistically significantly different to placebo. It is concluded that citalopram is relatively free from behavioural toxicity and so represents a significant improvement over the older antidepressant agents such as dothiepin. © 1997 by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Modulation of 5-fluorouracil (5-FU) is currently being investigated in advanced colorectal cancer. In an attempt to improve the results obtainable for the association of 5-FU and leucovorin, we decided to add cisplatin to 5-FU and (6 S)-leucovorin (S-LV) after disease progression. The hypothesis was that a pharmacological enhancement of the efficacy of 5-FU would result in responses in 5-FU-unresponsive patients or in a second response in previously responding patients. A group of 28 5-FU+S-LV-pretreated patients, with advanced measurable colorectal cancer, were treated with 80 mg/m cisplatin on day 1, 80 mg/m S-LV every 4 weeks. We obtained 3 partial responses (response rate: 11±11%), while 11 patients had stable disease (39±18%). Among the 3 responders, 1 patient had earlier achieved a partial response, a second stable disease and 1 had disease progression after the previous 5-FU+S-LV treatment. The median survival time for all 28 patients was 11 months. Toxicity was minimal and consisted of mild and reversible gastrointestinal symptoms and myelosuppression. We believe that further studies must be carried out to establish the real impact of the synergism between cisplatin, 5-FU and S-LV in untreated patients. [ABSTRACT FROM AUTHOR]