Béatrice Gerard

Activity of a new antiemetic agent: alizapride. A randomized double-blind crossover controlled trial.

SummaryAlizapride is a methoxy-2-benzamide derivative three times more potent than its parent compound, metoclopramide, as an antagonist of apomorphine-induced emesis in dogs. The antiemetic activity of alizapride plus dexamethasone (DXM) was compared with that of placebo plus DXM in a randomized, double-blind, crossover study in cancer patients receiving cisplatin (DDP). Alizapride, given at the maximally tolerated dose of 4 mg/kg x 5, or placebo was given in a sequence determined by randomization during two successive, identical courses of antitumor chemotherapy. The antiemetic treatment was given 30 min before and 1.5, 3.5, 5.5, and 7.5 h after starting. DXM, in a dose of 12 mg, was given IV with the first administration of alizapride or placebo. A total of 39 patients completed the two courses of chemotherapy. The severity of gastrointestinal symptoms was influenced by previous treatment but not by the treatment sequence. Although our overall results suggest that alizapride does not add to the activity of DXM against DDP-induced amesis, a statistically significant difference favoring alizapride plus DXM was found among patients with the lowest gastrointestinal tolerance to DDP: women, patients under 50 years of age, and patients pretreated with chemotherapy including DDP and non-DDP agents. Side effects consisted of orthostatic hypotension, which was symptomatic in two patients, and a single occurrence of severe extrapyramidal syndrome. We conclude that alizapride is more active than placebo when combined with DXM for DDP-induced emesis in patients at high risk of severe nausea and vomiting. The severity of the side effects in this study indicates that a dose reduction of alizapride might be appropriate for further studies.

Long-term survival of patients downstaged by oxaliplatin and 5-fluorouracil combination followed by rescue surgery for unresectable colorectal liver metastases.

OBJECTIVES To evaluate long-term survival of patients resected for primarily unresectable colorectal liver metastases downstaged by systemic chemotherapy. METHODS Among a group of 82 patients with advanced colorectal cancer, 39 had unresectable liver metastases. After treatment with systemic 3-weekly 5FU/folinic acid/oxaliplatin chemotherapy, the outcome of 11 patients made resectable thanks to chemotherapy was compared to that of 28 patients who were not. Criteria for non-resectability consisted of diffuse bilobar invasion with inability to achieve complete resection, unilobar or bilobar invasion plus vascular extension (invasion of inferior vena cava or 2 supra-hepatic veins plus continuity with the 3rd) or involvment of hepatic pedicle. Before and after surgery, CT scan evaluation was performed every 2 months. Progression free survival was defined as the time between starting chemotherapy and recurrence of the disease. We used Kaplan-Meier survival curves and log-rank test for comparisons, P values were two-sided and considered significant if<0.05. RESULTS Progression free survival times were 14 and 6 months, median overall survival were 60 and 18.5 months, respectively, in favour of secondary resected subjects. CONCLUSION Considering the magnitude of the survival benefit, one may question the need and feasibility for trials to assess more formally the impact of surgery in that setting.

Adjuvant therapy in resectable gastric cancer.

Gastric cancer still represents one of the most challenging problems for oncologists. Despite diagnostic and technologic advances with improvement of perioperative care, gastric carcinoma remains the fifth leading cause of death due to cancer in Western countries. The age standardised incidence has shown a decrease, during the first and last quinquennium, from 17.42 to 15.30 per 100,000 population among 31,716 gastric cancers registered between 1957 and 1981 in the United Kingdom (Allum et al., 1989a). There is an apparent increase in the proportion of proximal lesions and a decrease in the proportion of distal antral cancers (Allum et al., 1989a; Cady et al., 1989). For the majority of the patients the diagnosis means a strong likelihood of death. The 5-year survival rates were only 7% to 10% and there has been relatively little improvement in this outlook over the past 30

Measurements of response to chemotherapy using ultrasound in metastatic liver involvement

The liver is a frequent site of metastases and in several cases the only available target for assessing the activity of chemotherapeutic agents. A standard procedure for liver measurements by ultrasound was investigated. One hundred and twenty-three chemotherapy cycles were evaluated. This study shows that metastatic involvement of the liver can be measured by several ultrasound parameters which represent different features of the same process: the number and the surface of the nodules, the volume of the organ. Ultrasound parameters were correlated with liver function tests, CEA, hepatomegaly and measurements of other metastatic sites. The surface of metastases still appeared to be the most reliable criterion of response. Our results suggest that several liver ultrasound parameters may help to definitely assess the type of response to chemotherapy.

Clinical and Pharmacokinetic Phase I Trial with the Diethylaminoester of Flavone Acetic Acid (LM985, NSC 293015)*

The diethylaminoester of flavone acetic acid (LM985) is a new anticancer agent with curative effects against slow growing murine tumors. Thirty-one adult patients with solid tumors received a total of 57 courses of LM985 given on days 1 and 8 every 4 weeks. The drug was given as a short infusion (1-2 hr) at doses ranging from 120 to 1900 mg/sq.m/day. The dose-limiting toxicity consisted of acute expressive aphasia; this neurotoxicity usually appeared at the end of the infusion and resolved spontaneously within a few minutes to 1 hr after the end of the infusion. In some patients, neurotoxicity was avoided by reducing the infusion rate. Neurotoxicity was observed in 5 out of 6 patients receiving 960 mg/sq.m over 1 hr and in 3 out of 3 patients receiving 1900 mg/sq.m over 2 hr. The drug did not induce any significant myelosuppression. Other side-effects were very mild and consisted mainly of occasional nausea and/or vomiting at all dose levels. One patient with breast cancer resistant to several hormonal and chemotherapy regimens had stable disease for 6 months. LM985 was detected in plasma in very small concentrations (0-2.5 micrograms/ml) but there was extensive formation of flavone acetic acid (peak concentration ranging between 8.3 and 64 micrograms/ml). A dose of 1500 mg/sq.m on days 1 and 8 every 4 weeks could be recommended for phase II studies with LM985; however, since LM985 is a prodrug of flavone acetic acid, phase II studies with LM985 should not be activated prior to the completion of the ongoing phase I trials with flavone acetic acid, which may be devoid of the acute toxicity of LM985.