• Are aromatase inhibitors superior to antiestrogens?

      Howell, Anthony; Buzdar, Aman; CRUK Department of Medical Oncology, University of Manchester, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK. anthony.howell@christie-tr.nwest.nhs.uk (2005-02)
      Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2-3 years of tamoxifen, followed by 2-3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?
    • Blood and neoplastic diseases. Rational approach to the chemotherapy of human malignant disease-II.

      Crowther, Derek; Christie Hospital and Holt Radium Institute, Manchester (1974-10-26)
    • Does desensitization to hexarelin occur?

      Rahim, Asad; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (1998-04)
      Hexarelin, a potent growth hormone (GH)-releasing peptide, is capable of causing profound GH release in normal individuals. If the GH response to hexarelin in humans becomes appreciably attenuated following long-term administration, this would seriously limit the potential therapeutic use of hexarelin and similar agents. The effect of twice-daily subcutaneous injections of hexarelin on GH release was therefore investigated over a period of 16 weeks in 12 healthy elderly individuals. The mean (+/- SEM) areas under the GH curve (AUCGH) at weeks 0, 1, 4 and 16 were 19.1 +/- 2.4, 13.1 +/- 2.3, 12.3 +/- 2.4 and 10.5 +/- 1.8 microg/l/hour, respectively. There was a significant change in AUCGH over the study period (P = 0.0003). Further analysis showed that the decreases in AUCGH at weeks 4 and 16 were significant (P < 0.05 and P < 0.01, respectively) compared with baseline values. Four weeks after completion of the 16-week study period, hexarelin was again administered. On this occasion, AUCGH increased significantly compared with that at week 16 (from 10.5 +/- 1.8 to 19.4 +/- 3.7 microg/l/hour; P < 0.05) and was not significantly different compared with that at week 0. These results show that attenuation of the GH response after long-term hexarelin therapy is partial and reversible.
    • The effects of CV205-502 in patients with hyperprolactinaemia intolerant and/or resistant to bromocriptine.

      Razzaq, R; O'Halloran, Domhnall J; Beardwell, Colin G; Shalet, Stephen M; Department of Clinical Endocrinology, Christie Hospital, Manchester, UK. (1993)
      CV205-502 is a new non-ergot dopamine agonist currently being studied for the treatment of hyperprolactinaemia. We have assessed the effects of CV205-502 on prolactin secretion and the clinical consequences of hyperprolactinaemia in 16 patients with hyperprolactinaemia who had previously been unsuccessfully treated with bromocriptine. These patients had been either intolerant of and/or resistant to the effects of bromocriptine. Sixteen patients, all women in an age range between 20 and 49 years (mean 31.5 years), were treated for periods of between 8 and 52 weeks with doses of CV205-502 ranging from 0.075 to 0.3 mg taken once daily at night. Seven out of 10 of the patients, who were intolerant of bromocriptine, tolerated CV205-502 better with fewer side effects although the nature of the side effects was similar to that associated with bromocriptine. Only 1 patient from this group stopped taking CV205-502 due to side effects. Six of 11 patients exhibiting bromocriptine resistance showed a significant reduction in the degree of hyperprolactinaemia but normoprolactinaemia was achieved in only 1. Galactorrhoea ceased in 2 of 6 patients, menstruation resumed in 6 of 11 patients presenting with amenorrhoea, and 2 patients conceived. In patients with bromocriptine intolerance and/or resistance, CV205-502 is useful as a second line treatment.
    • Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer.

      Howell, Anthony; DeFriend, D; Robertson, J; Blamey, R; Walton, P; CRC Department of Medical Oncology, University of Manchester, Christie Hospital, UK. (1995-01-07)
      We treated 19 patients with advanced breast cancer resistant to tamoxifen with a new specific antioestrogen (ICI 182780) which, in animal studies, has no agonist activity. 13 (69%) patients responded (7 had partial responses and 6 showed no change) to monthly intramuscular injections of ICI 182780 after progression on tamoxifen, for a median duration of 18 months with minimum side effects. Preliminary evidence suggests that the agent is without effects on the liver or the hypothalamic-pituitary axis. ICI 182780 appears to be a promising new agent for treatment of advanced and early breast cancer.