Paula Pitt

Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors: A Phase II Trial

PURPOSE To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

Aromatase inhibition with 4-OHAndrostenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer

SummaryOne hundred and twelve post menopausal or post oophorectomy women with advanced breast cancer (BC) who had all previously had aminoglutethimide (AG) were treated with the potent aromatase inhibitor 4-hydroxy androstenedione (4-OHA).Twenty three women (21%) had a partial response to 4-OHA while another twenty five patients (22%) had stabilization of previously progressing disease. Patients responded to 4-OHA both after previously responding to then relapsing on, and after failing to respond to aminoglutethimide. Toxicity was minimal. This study shows that potent aromatase inhibition with 4-OHA is effective in women with advanced BC who have already been treated with a less potent aromatase inhibitor, and suggests that relative changes in oestrogen levels may be more important than absolute levels.

Low-dose aminoglutethimide without steroid replacement in the treatment of postmenopausal women with advanced breast cancer

Fifty-seven patients with actively progressing advanced breast cancer have been assessed for their response to low-dose aminoglutethimide (125 mg bd) without steroid replacement. Eleven women (19%) had an objective response while a further eight had stabilization of disease. However, one patient died with apparent adrenal insufficiency and another developed low plasma cortisol and serum sodium. Furthermore, 4/17 patients who had failed to respond to low-dose A/G subsequently responded when changed to conventional-dose A/G + steroid replacement, while three patients had stabilization of previously progressing disease. These results indicate that low-dose A/G without steroid replacement is potentially hazardous and that low-dose and conventional-dose A/G + steroids do not produce identical results.

Treatment of advanced prostatic cancer, resistant to conventional therapy with aminoglutethimide

Fifty-eight patients with advanced, progressing prostatic cancer resistant to conventional therapy have been assessed for their response to treatment with aminoglutethimide (A/G). Eleven men (19%) had objective regression of their disease while in a further eight (14%) progression of the disease was arrested. Median survival in the objective remitters (15 months) and in the group in whom stabilization of disease occurred (9.3 months) was significantly longer than in the non-remitting patients (4.7 months). The drug was well tolerated and no serious side-effects occurred. A/G appears to be a useful treatment in patients with advanced prostatic cancer resistant to conventional therapy.

Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer*

SummaryToremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites,N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1–3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.

Medical adrenalectomy in patients with advanced breast cancer resistant to anti-oestrogen treatment

Fifty-three women with actively progressing advanced breast cancer, who had all previously received tamoxifen, were treated with aminoglutethimide to induce medical adrenalectomy. Sixty-nine percent of the patients who had previously responded to tamoxifen subsequently responded to aminoglutethimide, while thirty-five percent of the nonresponders to tamoxifen subsequently responded to aminoglutethimide. The median duration of remission to aminoglutethimide was 12 months with a range from 4 to 22 + months. The drug was well tolerated and would appear to be the treatment of choice in tamoxifen responsive cases of advanced breast cancer.SummaryFifty-three women with actively progressing advanced breast cancer, who had all previously received tamoxifen, were treated with aminoglutethimide to induce medical adrenalectomy. Sixty-nine percent of the patients who had previously responded to tamoxifen subsequently responded to aminoglutethimide, while thirty-five percent of the nonresponders to tamoxifen subsequently responded to aminoglutethimide. The median duration of remission to aminoglutethimide was 12 months with a range from 4 to 22 + months. The drug was well tolerated and would appear to be the treatment of choice in tamoxifen responsive cases of advanced breast cancer.

Antagonism of amignoglutethimide and danazol in the suppression of serum free oestradiol in breast cancer patients

Abstract The response rate of advanced postmenopausal breast cancer patients to treatment with aminoglutethimide (AG) + danazol was significantly worse than that with AG alone. The suppression of serum oestradiol levels by AG + danazol was similar to that by AG alone, but the combination treatment also suppressed sex hormone binding globulin (SHBG) levels and increased the % free oestradiol, whilst these parameters were unaffected by AG alone. The degree of suppression by AG + danazol of free oestradiol concentrations was less than the suppression of total oestradiol level and in some patients the concentration of the free fraction was increased above pretreatment levels. These effects on the presumed biologically active unbound fraction of oestradiol may explain the poort clinical response rate to AG + danazol.

The effect of danazol on tumour control and weight loss in patients on tamoxifen therapy for advanced breast cancer: A randomised double-blind placebo controlled trial

To assess the effect of danazol in advanced breast cancer 183 patients were randomised to receive either tamoxifen plus danazol or tamoxifen plus placebo. Patients underwent systemic work-up pretreatment then every 12 weeks or sooner if they clinically progressed. There were no differences in objective response rates with tamoxifen plus danazol vs. tamoxifen plus placebo (27% vs. 24%), time to progression (median 6.4 vs. 6.2 months) or survival (median 22.6 vs. 23.5 months) when the two arms were compared (all P > 0.5). The addition of danazol to tamoxifen had no effect on time to progression when adjusted for significant prognostic factors in a multivariate analysis. However, it was found incidentally that weight was stable on tamoxifen plus danazol (average gain 0.6 kg, S.E. 0.6 kg) compared with a significant loss on tamoxifen plus placebo (average loss 2.0 kg, S.E. 0.6 kg, P = 0.003). The average weight was maintained on tamoxifen plus danazol even in patients who did not respond to treatment.

Biochemical Basis for the Antagonism between Aminoglutethimide and Danazol in the Endocrine Treatment of Breast Cancer

Only 13% of postmenopausal advanced breast cancer patients responded to endocrine treatment with aminoglutethimide plus danazol whilst 33% responded to aminoglutethimide alone, despite a similar suppression of serum oestradiol levels in the two groups. The patients on aminoglutethimide and danazol showed a marked suppression of sex hormone binding-globulin binding capacity and a consequent rise in percent-free oestradiol. This led to the concentration of free oestradiol being less well suppressed than that of total oestradiol and in some patients free oestradiol concentrations were higher on treatment than before. Patients on aminoglutethimide alone showed no change in the binding of oestradiol and the percentage suppression of the free oestradiol concentration was similar to that of total oestradiol. The opposing effects of danazol and aminoglutethimide on the concentration of the free, biologically active fraction of oestradiol in the circulation may explain the poor therapeutic efficacy of this combination in breast cancer patients.