As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

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Twenty-one postmenopausal women with advanced breast cancer were treated with monthly 3.6-mg sc injections of the LHRH agonist goserelin [D-Ser-(But)6, Azgly10-LHRH] to determine whether the resultant endocrine changes could provide an explanation for the clinical responses that occur during therapy with this agent. After 4 weeks, serum gonadotropin levels were less than 10% of pretreatment levels, whereas serum PRL levels did not change. A significant decrease in serum testosterone occurred in 19 of 20 patients; this fall was associated with a 22% fall in serum estradiol levels. Serum androstenedione levels also decreased, but serum estrone and dehydroepiandrosterone sulfate (DHAS) levels did not. The lack of fall in serum DHAS levels indicates that the changes in androgen levels were a result of reduced ovarian secretion, and the reduced estradiol levels were a consequence of reduced precursor (i.e. testosterone) availability. The continued dependence of ovarian androgen secretion on gonadotropin stimulation after the menopause may explain the responses of some patients to LHRH agonists and some other therapeutic agents of unknown or uncertain modes of action.

Summary A previous study has shown that there are high levels of an abnormally-fucosylated form of haptoglobin (FHp) in the blood of cancer patients (Thompson & Turner, 1987b). In this study, we investigated the expression of this substance in serial blood specimens from women with ovarian or breast cancer who were undergoing cytotoxic chemotherapy. The The 27 women who had breast cancer had undergone either a lumpectomy or a mastectomy 6 months to 20 years previously (median 3.5 yr). Twenty-four women still had clinical signs of cancer when specimen collection was started. During the period of collection the major therapies were as follows: Mitoxanthrone (ten women); aminoglutethimide, hydrocortisone, disodium pamidronate (three); aminoglutethimide, hydrocortisone (three); Tamoxifen (two); Cyclophosphamide, 5-fluoruracil, prednisolone (two); Ifosphamide, Doxorubicin (one); Vincristine, prednisolone (one); Vincristine, mitomycin (one); LHRH agonist (one); radiotherapy (one) and two were untreated. Nineteen of the women were previously treated with radiotherapy; 17 of these received Tamoxifen and five had prior treatment with Mitoxanthrone.At least two blood specimens were collected from each ovarian and breast cancer patient (median number three; range two to six) over a period of time that varied (median time = 12 months; range 1-22 months). The time between collections also varied (median = 3 months; range 1-15 months). Seventy-seven and 73 specimens were collected from the ovarian and breast patients respectively. Only one or two specimens were collected from the hepatoma patients.Ovarian and breast cancer patients were assessed when specimens were collected; these assessments were made by clinical examination and appropriate radiological and ultrasound scanning techniques. The patient response to therapy was categorised into three groups; complete response, partial response or stable disease, and progressive disease. Complete response was defined as complete disappearance of all demonstrable disease for at least 4 weeks. Partial response was defined as a reduction (> 50% bidimensional or > 30% unidimensional) in total size of measurable disease, and stable disease was defined as < 50% change (bidimensional) or < 30% (unidimensional) in the total size of the measurable lesions. Progressive disease was defined as a >50% (bidimensional) or >30% (unidimensional) increase in the size of any measurable lesion.The hepatocellular cancers were diagnosed by physical examination combined with radiological and ultrasonic scanning techniques, and confirmed by the histological examination of biopsy material. No information was available for the clinical assessments of the hepatoma patients.

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