Brian M.J. Cantwell

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response

SummaryAs 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 μg/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<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 drugs 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.

Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study.

To determine if the chemotherapy resistance of non-small cell lung cancer could be modified by oral verapamil, 72 patients were entered into a randomised trial of verapamil plus chemotherapy vs the same chemotherapy alone. Verapamil 480 mg day-1 was given for 3 days starting 24 h prior to chemotherapy which consisted of bolus vindesine 7 mg followed by ifosfamide/mesna 5 g m-2 over 24 h, followed by mesna alone for a further 8 h. Cycles were repeated every 3 weeks for up to six courses. Sixty-six patients were eligible for tumour response analysis and responses occurred in 41% of those randomised to chemotherapy plus verapamil and in 18% of those randomised to chemotherapy alone (P = 0.057). Median survival from start of treatment was significantly better in the verapamil arm (P = 0.02). Toxicity of the combination of chemotherapy plus verapamil was principally neurological and was manageable. Thus the addition of oral verapamil to vindesine/ifosfamide chemotherapy is feasible and in this study was associated with improved outcome. Further confirmation of these observations is required in non-small cell lung cancer, a tumour characterised by resistance to conventional chemotherapy.

Adriamycin alone or combined with vincristine in the treatment of advanced breast cancer

One hundred and nineteen women with advanced breast cancer treated previously by endocrine therapy but no prior chemotherapy were given adriamycin 70 mg/m2 i.v. on day 1 of a 3-weekly cycle for 8 courses, followed by a regimen of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) until relapse. They were allocated randomly to receive either no treatment (group A) or vincristine 1.4 mg/m2 i.v. on days 1 and 8 during treatment with adriamycin (group AV). In 107 evaluable patients objective responses were seen in 30/53 patients (57%) in group A and in 28/54 patients (52%) in group AV. The projected dose of adriamycin received was 78% in group A and 75% in group AV; and 60% for vincristine in group AV. The subjective and haematological toxicity for adriamycin was similar in both groups, but 65% of patients treated with vincristine developed neurotoxicity. The median duration of objective regressions was the same for both groups (7 months), and the median time to failure was 5 months for group A and 6 months for group AV respectively. The median survival of the responders tended to be longer in group AV (17.5 months) than in group A (13 months), but this difference was not statistically significant (P = 0.112). It is concluded that there is no advantage therapeutically in combining vincristine and adriamycin in patients with advanced breast cancer.

Intermittent high-dose tamoxifen as a potential modifier of multidrug resistance

In vitro tamoxifen reverses multidrug resistance (MDR). To evaluate the clinical potential of using tamoxifen in this way, intermittent high-dose tamoxifen was combined with oral etoposide in 86 patients. At 320 mg/day tamoxifen for 6 days, mean plasma levels of tamoxifen in 11 patients increased from 453 ng/ml (range 269-664) on day 2 to 984 ng/ml (578-1336) on day 6. Of 31 patients who had plasma tamoxifen measured during the time of etoposide administration (days 4-6), 13(43%) were over 1111 ng/ml (3 mumol/l), an active in vitro level. Potentially active levels of the principal metabolite, N-desmethyl tamoxifen, were also obtained but accumulation was slower. Emesis and thromboembolism were toxicities. Tamoxifen is a modifier of MDR, a role that warrants further clinical studies.

A comparison of the endocrine effects of low dose aminoglutethimide with and without hydrocortisone in postmenopausal breast cancer patients.

The endocrine effects of 125 mg (low dose) aminoglutethimide (AG) twice daily (b.d.) were compared with those of 125 mg AG + 20 mg hydrocortisone (HC) b.d. in 23 and 45 postmenopausal patients with advanced breast cancer, respectively. The patients in each group were drawn from two separate populations, but the mean age and weight of the groups were similar and there were no significant differences between the pretreatment serum levels of the hormones investigated. Serum oestrone and oestradiol levels were suppressed by both treatments, but there was a significantly greater suppression by AG + HC. This greater suppression is probably due to the observed increase in serum androstenedione (i.e. precursor) levels with AG alone, whilst with AG + HC these levels were found to be reduced. In terms of suppression of serum oestrogen levels it is of benefit to combine low dose AG with HC.

A phase 1 and pharmacokinetic study of didox: a ribonucleotide reductase inhibitor.

A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.

Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer

Fifty-two patients with progressive advanced breast cancer were treated with the novel antifolate CB 3717 (N10-propargyl-5,8-dideazofolic acid) which inhibits thymidylate synthetase. Forty-six patients were pretreated with hormones, 43 with cytotoxic chemotherapy and 39 patients with both treatments. Eight of 48 patients (16.6%) evaluable for response had partial responses (confidence limits 7.4-30.2%, 95% confidence level) following CB 3717 administration. Liver function abnormalities, reversible in most cases, were the most commonest toxicities and were frequently accompanied by malaise. Severe renal failure occurred in eight patients, five of whom had had partial responses to CB 3717. This study shows the importance of thymidylate synthetase as a target for therapy but the clinical value of CB 3717 is limited by its hepatic and renal toxicities.

Abnormally-fucosylated haptoglobin: a cancer marker for tumour burden but not gross liver metastasis.

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 level of FHp was related to patient response to therapy status, this latter index being an indirect determination of tumour burden. FHp levels did not correlate with gross liver metastasis (as shown by CT scans or the blood levels of liver enzymes). This conclusion was further supported by results from patients with hepatocellular cancer. FHp was elevated in most of these patients, but the pattern of change did not correlate with variations in the level of the hepatoma marker, alpha-foetoprotein. It seems likely that FHp is produced by the liver. Primary and secondary tumours could release substances, such as cytokines, which interfere with fucose metabolism in the liver.

The multidrug resistant phenotype in clinical practice; evaluation of cross resistance to ifosfamide and mesna after VP16–213, doxorubicin and vincristine (VPAV) for small cell lung cancer

Eight-eight previously untreated patients with small cell lung cancer were treated with a combination of VP16, adriamycin and vincristine (VPAV) for three courses. Resistance to these drugs is associated with the multidrug resistance (MDR) membrane glycoprotein in cell lines in vitro. The clinical relevance of this mechanism of resistance was assessed by using a second line treatment with intravenous infusions of ifosfamide/mesna 5 g/m2 every 3 weeks in patients with only partial responses or non-responders. Cross-resistance to alkylating agents is rare in the MDR. Ifosfamide produced partial responses in six (43%) of 14 patients unresponsive to prior therapy. Intravenously infused ifosfamide/mesna was also used in consolidation therapy with only minor bone marrow or urinary tract toxicity. This did not prevent CNS relapse. The overall response rate to VPAV was 69% and for all treatment modalities, 75%. Median survival for all patients ws 39.5 weeks and 59 weeks for all patients attaining complete response. The addition of large fraction chest irradiation given with the final course of induction chemotherapy to those with good chemotherapy responses produced a further response in 44% of assessable patients. Combined modality treatment resulted in moderate and reversible toxicity. The lack of improved survival with ifosfamide and the resistance of the majority of patients to salvage with ifosfamide/mesna suggested that the MDR is not the major mechanism of resistance in the clinic, since cross-resistance to alkylating agents of this type is not a feature of MDR cells.

A phase II trial of goserelin (Zoladex) in relapsed epithelial ovarian cancer

Thirty patients with advanced epithelial ovarian cancer were treated with the luteinising hormone releasing agonist, goserelin. There were two partial responses lasting 40 and 105 weeks respectively. In addition five patients had disease stabilisation lasting 25, 35, 40, 66 and 70 weeks respectively and 23 patients had progressive disease. No significant or unexpected toxicities occurred. This minimally toxic therapy halted disease progression for 6 months or more in 23% of patients, the majority of whom were heavily pretreated. There were five early deaths due to disease progression. The use of goserelin in patients with epithelial ovarian cancers resistant to or relapsing soon after first line platinum based chemotherapy needs to be further evaluated.