Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists.

In 1983, Coates conducted a survey that ranked the side-effects perceived by patients receiving chemotherapy in the order of their severity. Vomiting and nausea were found to be the two most distressing side-effects. They have an impact on quality of life and compliance with treatment. The development of 5HT3 antagonists has been a major step forward in the prevention and treatment of chemotherapy-induced nausea and vomiting. Presently, these antiemetics are routinely used as concomitant therapy in emetogenic chemotherapy regimens. The purpose of this study was to evaluate the impact of 5HT3 antagonists on patient perceptions of the side-effects of chemotherapy. Coates' survey was replicated in patients who received 5HT3 antagonists for acute nausea and vomiting resulting from emetogenic chemotherapy. Patients received the survey to identify those physical and non-physical side-effects that they attributed to chemotherapy and were asked to rank the five most distressing side-effects. Of the 197 patients who consented to take part in the study, 181 were evaluable. Nausea, hair loss and vomiting were described as the three most distressing side-effects of chemotherapy. Eighty per cent of all the patients actually experienced nausea and 57% experienced vomiting. Hair loss appeared to be more distressing to women (P < 0.001) but, in other aspects, gender, age and marital status did not influence the ranking of the three most distressing side-effects. Constipation was ranked as 6th and was not identified as a distressing side-effect in 1983. Nausea and vomiting remain to be the first and third most distressing side-effects of chemotherapy, even though the incidence and severity of acute nausea and vomiting are now significantly reduced

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic colorectal cancer.

In a phase I study of weekly administered cisplatin combined with oral etoposide, we observed a partial response in 4 out of 11 patients with metastatic colorectal cancer. Subsequently, we performed a phase II study to investigate the activity of this combination as first-line treatment in this disease. Fourteen patients with metastatic colorectal cancer were enrolled in this study. Treatment consisted of cisplatin, administered in 3% sodium chloride, at a dose of 70 mg m-2 on days 1, 8 and 15 and days 29, 36 and 43 combined with oral etoposide 50 mg absolute dose daily on days 1-15 of both courses. Patients with stable disease or better continued treatment with etoposide 50 mg m-2 orally on days 1-21 every 28 days. A partial response was observed in two patients with liver metastases (14%; 95% confidence limits 2-42%) for 30 and 32 weeks. Five patients had stable disease. Toxicity consisted mainly of anaemia, leucocytopenia, nausea and vomiting. Tinnitus was reported by six patients. The activity of the combination cisplatin-oral etoposide in the schedule is only minimal in metastatic colorectal cancer

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ringopened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic, study as part of a phase I study in patients with various types of soli