The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2–4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri‐phosphate (TNTP) (p = 0.02) over 3 (±1) weeks were significantly associated with response, as were the levels of PME (p < 0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (±1). PME at week 3 (±1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was −6%) compared with those measured on the same day (difference in TP was −29%). © 1998 John Wiley & Sons, Ltd.

Sinry The role of chemotherapy m the palliation of patients with advanced st (IIB and non-small-cel (Souquet et al., 1993), and chemotherapy remains very much a palliative approach.No single chemotherapy regimen has been shown superior to others in the treatment of NSCLC, but best response rates have consistently been achieved with cisplatin-based regimens (Veronesi et al., 1988;Luedke et al., 1990). The combination of isplatin with mitomycin C and vinblasti has been shown in randomised trials to be one of the most effective regimens (Ruckdeschel et al., 1986), and this has the advantage over most other combinations of very rarely causing signiicant alopecia (an important consideration for palliative treatment). There is a tendency to use cisplatin in high dosage (100-120mgm-) in many of these regimens, but this is associated with significnt toxicity, including emesis, peripheral neuropathy, nephrotoxicity and high-frequency hearing loss. These problems disappear or are at least very markedly reduced with moderate-dose cisplatin (50mgm-2) and probably without significant reduction in efficacy (Hardy et al., 1989).We have therefore developed a moderate-dose cisplatin (P) regimen in combination with mitomycin C (M) and vinblastine (V) (MVP) which is well tolerated with few side-effects (Hardy et al., 1989

Summary The site of action of aminoglutethimide (AG) has been investigated. An Aminoglutethimide (AG) in combination with hydrocortisone (HC) is an effective endocrine therapy in advanced postmenopausal breast cancer, producing a response rate and duration similar to tamoxifen (Smith et al., 1981). AG was introduced into the treatment of breast cancer as an inhibitor of adrenal steroid production. One site of action is the earliest step in the adrenal conversion of cholesterol to pregnenolone (20,22 desmolase) (Dexter et al., 1967). AG treatment regimes are currently designed to inhibit this step and HC is added in replacement doses to prevent a reflex rise in ACTH secretion (Santen et al., 1974). However, AG has another site of action, the inhibition of the conversion of androgens to oestrogens in peripheral tissues tissues (Figure 1), which is the main source of oestrogen in the postmenopausal woman . AG can also inhibit 1 1-fJ-hydroxylase (Faglia et al., 1971).One of the factors limiting the use of AG is the side effects that occur at conventional dose levels (250mg 4 times a day). In one series of 190 patients, 58% had transient side effects, 9.5% needed to reduce the dose and 5% discontinued the drug (1977). Graves & Salhanick (1979) showed that aromatisation in vitro is at least 10 times more sensitive than desmolase to inhibition by AG. We have therefore studied the site of action of AG in postmenopausal patients with advanced breast cancer receiving AG and HC therapy in conventional doses and investigated the endocrine effects of low doses of AG alone. Patients and methods Synacthen testsTen postmonopausal patients with advanced breast cancer, who were taking AG 250mg 4 x daily and hydrocortisone 20mg b.d. (8am, 8pm), were studied after 3 months of therapy. Tetracosactrin (250,pg; Synacthen, Ciba) was given i.m. in the gluteus maximus. The patient was resting before the injection and for 30min afterwards. Blood samples were taken before and 30min after the injection.These tests were performed to assess the need for cortisol replacement during stress, but oestrone, dehydroepiandrosterone sulphate (DHA-S), A4 androstenedione and 17 OH progesterone were also measured.A normal cortisol response was considered to be an initial cortisol level > 138 nM I-1 and a rise of 2 200 nM 1-, with a plasma level of 2 500 nM 1 at 30 min, irrespective of initial levels.

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