R.C. Coombes

PREVENTION OF EMESIS IN PATIENTS RECEIVING CYTOTOXIC DRUGS BY GR38032F, A SELECTIVE 5-HT3 RECEPTOR ANTAGONIST

15 patients receiving cytotoxic drugs (other than cisplatin) that had previously produced nausea and vomiting refractory to first-line antiemetics were given a selective 5-HT3 receptor antagonist (GR38032F), 4 mg intravenously and 4 mg orally, immediately before chemotherapy, the oral dose being repeated 5 and 10 h later. Nausea, vomiting, and side-effects were recorded for the ensuing 24 h. The 15 patients received a total of thirty-one courses of chemotherapy. Only 1 patient vomited. The only adverse events were dryness of the mouth in 1 patient, mild sedation in 1, and diarrhoea in 1, and these were not clearly drug related.

PROSPECTIVE RANDOMISED TRIAL OF TAMOXIFEN VERSUS SURGERY IN ELDERLY PATIENTS WITH BREAST CANCER

116 patients aged 70 or over who were judged to have surgically resectable cancer of the breast were prospectively randomised to tamoxifen 20 mg daily or surgical resection. At a median follow-up of three years, local relapse or progression was seen in 15 (25%) of 60 patients in the tamoxifen group and 21 (37.5%) of 56 in the surgical arm. Distant metastases occurred in 8 (13%) in the tamoxifen group and in 10 (18%) in the surgical arm. There were 13 deaths in the tamoxifen group and 11 in the surgical arm, of which 8 and 9, respectively, were attributable to breast cancer. Disease-free survival did not differ between the groups.

Topical calcipotriol treatment in advanced breast cancer

19 patients with locally advanced or cutaneous metastatic breast cancer were treated with the topical vitamin D analogue calcipotriol 100 micrograms daily. 14 patients completed 6 weeks treatment; 3 showed a 50% reduction in the bidimensional diameter of treated lesions and 1 other patient showed a minimal response. 2 patients became hypercalcaemic during treatment. In all patients who responded the tumours contained receptors for 1,25-dihydroxyvitamin D3, shown by immunocytochemistry.

POTENCY AND SELECTIVITY OF THE NON‐STEROIDAL AROMATASE INHIBITOR CGS 16949A IN POSTMENOPAUSAL BREAST CANCER PATIENTS

A selective inhibitor of aromatase is widely sought for the treatment of postmenopausal women with breast cancer. CGS 16949A has been shown to be a highly selective, potent inhibitor of aromatase in vitro. Its potency as an oestrogen suppressant and its selectivity were examined by treating 24 postmenopausal patients with advanced breast cancer for 4 weeks with doses of 0.3, 1‐0 and 2‐0 mg twice daily. The study was conducted in two parts which compared the two lower doses and the two higher doses separately in a cross‐over design protocol. All doses significantly suppressed serum oestradiol and oestrone levels below pretreatment levels. Cross‐over analysis indicated that the 2.0 mg twice daily dose achieved significantly greater suppression of oestradiol levels than 1‐0 mg twice daily but there was no significant difference between any of the doses in the suppression of oestrone. No significant effects were noted on serum levels of LH, FSH, SHBG, prolactin, testosterone, androstenedione, 17‐ hydroxyprogesterone or cortisol. For the four steroids this was true both for basal samples and those collected after Synacthen stimulation. However, serum aldosterone levels were significantly suppressed by 1‐0 mg twice daily CGS 16949A and further suppressed by 2‐0 mg twice daily. It is concluded that CGS 16949A is a potent oestrogen suppressant in postmenopausal patients but that its effect is not totally selective.

Aromatase inhibitors: basic and clinical studies.

Application of aromatase inhibitors to the treatment of conditions in which estrogen plays, a role is discussed. Studies in vitro demonstrate that 4-hydroxyandrostenedione (4-OHA) is a potent inhibitor of aromatase. The compound reduces ovariant estrogen production and causes regression of carcinogen (DMBA)-induced mammary tumors in the rat. In the rhesus monkey, 4-OHA was also shown to inhibit peripheral aromatization. To date 58 postmenopausal breast cancer patients with advanced metastatic disease have received 500 mg im weekly while 31 patients received 250 mg 4-OHA orally per day. Estradiol levels were significantly reduced in all patients from a mean of 7.2 + 0.8 pg/ml to 2.8 + 0.3 pg/ml. Of patients receiving 4-OHA im 27% had partial or complete responses and in 10% of patients the disease was stabilized. Similar responses occurred in the patients receiving 4-OHA orally. These results suggest that 4-OHA is effective and that this compound and other aromatase inhibitors could be valuable new additions to the treatment of breast cancer.

Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione

Summary4-Hydroxyandrostenedione (4-OHA), a new specific aromatase inhibitor, was used to treat 57 post-menopausal women with advanced breast cancer at a dose of 250 mg by i. m. injection every 2 weeks; 55 women were assessable for response. In all, 18 patients (33%) had objective evidence of a response to treatment, with a median duration of 12 months; the disease stabilised in 8 (14%) patients. Serum oestradiol levels, which were measured weekly in nine of the patients, were found to be suppressed to a mean of between 36% and 51% of pretreatment levels during the first 6 weeks of treatment. Three patients were withdrawn from treatment because of toxicity (pain at injection site, sterile abscess and rash). One patient had an isolated episode of anaphylaxis after 6 months of treatment. In comparison with our previous reports of 4-OHA treatment, a dose of 250 mg given i. m. fortnightly appears to be the optimal dose regimen. The efficacy of the drug seems to be similar to that of tamoxifen and aminoglutethimide.

Aromatase inhibitors and hormone-dependent cancers

Aromatase (estrogen synthetase) occurs in a variety of tissues. Using immunocytochemistry, we have recently located this enzyme in cellular compartments of several types of human tissue. Furthermore, we found the mRNA was located in the same structures where tested. As both gonadal and peripherally formed estrogen contribute to growth of hormone sensitive cancers, we have developed aromatase inhibitors to block synthesis of this hormone. We have determined that 4-hydroxyandrostenedione (4-OHA) selectively inhibits aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. 4-OHA was also found to inhibit gonadotropin levels and reduce estrogen and progesterone receptor levels in treated animals. The mechanism of these effects appear to be associated with the weak androgenic activity of the compound. These effects together with aromatase inhibition may result in a synergistic response reducing estrogen production and action. In postmenopausal women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either daily oral or parenteral weekly treatment with 4-OHA at doses that did not affect their gonadotropin levels, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occurred in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. These results indicate that 4-OHA is of benefit in postmenopausal patients with advanced disease who have relapsed from prior hormonal therapies, and that steroidal inhibitors may be of value in premenopausal patients.

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

SummaryThe pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 μg/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forCo (21.7±1.82 μg/ml),Km (2.66±0.68 μg/ml) and Vmax (0.86±0.06 μg ml−1 h−1). On subsequent repeated dosing with PyG, both theKm (4.31±0.48 μg/ml) and the Vmax (1.83±0.13 μg ml−1 h−1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.

The use of nasal calcitonin spray in the treatment of hypercalcaemia of malignancy

Hypercalcaemia is a frequent metabolic complication of advanced malignant disease. Calcitonin has been shown to be effective both in controlling malignant hypercalcaemia [10] and in reducing pain in patients with bone metastases [9]. A number of other treatments are also effective in reducing serum calcium levels in malignant disease, including mithramycin [5], intravenous phosphate infusions [2] and bisphosphonates [1]. All effective preparations currently used in managing acute malignant hypercalcaemia require parenteral administration. Synthetic salmon calcitonin has recently been formulated as a nasal spray, and we report on its use in the treatment o f hypercalcaemia of malignancy.

Experience with intermediate-dose (110–120 mg/m2) epirubicin

SummaryA total of 23 patients with advanced malignancies received escalating doses of epirubicin (100–120 mg/m2) i.v. at 3-week intervals; 15 had received previous chemotherapy. In all, 46 courses of chemotherapy were given. Mucositis (grade II or III) occurred in 47% of courses at 120 mg/m2, but in only 15% of courses at 115 mg/m2. Myelotoxicity was manifest as leucopenia, with a median white blood count nadir of 1.9 (range, 0.8–7.0)×109/l. Nausea and vomiting were generally well controlled by prophylactic antiemetic therapy. Alopecia was WHO grade 0 in 2 patients, grade I in 1, grade II in 5 and grade III in 14. No renal or hepatic toxicity was noted, and there were no episodes of congestive cardiac failure. One fatal coronary thrombosis (proven at post-mortem examination) occurred 48 h after a dose of 115 mg/m2. Four patients developed thrombophlebitis at the injection site that was not dose-related; it occurred at doses between 100 and 120 mg/m2. Two patients who had been given chemotherapy in the past had complete responses (one penile carcinoma, one gastric carcinoma). Six patients had partial responses, including two with breast cancer, one with gastric cancer and three with sarcoma. Intermediate-dose epirubicin was well tolerated up to 120 mg/m2, when mucositis became a significant clinical problem. Preliminary data suggest promising activity in gastric cancer, breast cancer and a variety of sarcomas.