Endocrine-Related Cancer (1999) 6 265-269 Combination hormonal therapy involving aromatase inhibitors in the management of women with breast cancer J N Ingle, V J Suman, V C Jordan1 and M Dowsett2 Mayo Clinic, Rochester, Minnesota 55905, USA 1Northwestern University, Chicago, Illinois 60611, USA 2Royal Marsden Hospital, London SW3 6JJ, UK (Requests for offprints should be addressed to J N Ingle, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA) Abstract Numerous comparative clinical trials have been conducted evaluating combination hormonal therapy involving the aromatase inhibitor aminoglutethimide, but there is no evidence for any superiority of this approach over single-agent therapy alone. The advent of new aromatase inhibitors with greater potency, selectivity, and better tolerability has prompted a reconsideration of the combined therapy approach, with attention being focused on pharmacologic and endocrinologic clinical research. The value of combining newer aromatase inhibitors with other hormonal agents remains to be established. Endocrine-Related Cancer (1999) 6 265-269 Introduction hormonal agents from other classes. In the case of combining aromatase inhibitors with tamoxifen (TAM), it Hormonal therapy remains an integral part of the is possible that the different mechanisms of action would management of most women with breast cancer both in the be complementary, with the aromatase inhibitor decreas- adjuvant and metastatic settings. A variety of hormonal ing estrogen levels and thus allowing TAM to act more agents are in clinical use today including antiestrogens, effectively as a competitive inhibitor with estradiol. progestins, androgens, estrogens, luteinizing hormone- releasing hormone analogs, and aromatase inhibitors. Numerous reports have been published evaluating Despite the availability of multiple agents and multiple aromatase inhibitors in combination with other hormonal classes of agents, a sizeable proportion of tumors will not agents but the most informative are those of a comparative respond to treatment and those tumors that do respond nature. This report will review the experience of will, in all likelihood, become resistant to treatment. The randomized trials evaluating combination hormonal desirability of finding more efficacious hormonal therapy therapy involving aromatase inhibitors and discuss pre- regimens is indisputable. The existence of multiple classes liminary studies utilizing letrozole plus TAM. of agents with different mechanisms of action and excellent tolerability which can be given at full therapeutic Randomized clinical trials evaluating doses in combination has formed the basis for the interest combination hormonal therapy in studying combination hormonal therapy. involving aromatase inhibitors The mechanism of action of the aromatase inhibitors is well defined in terms of reduction of circulating The randomized trials evaluating combination hormonal estrogens. The existence of aromatase activity in a therapy involving aromatase inhibitors are given in substantial proportion of breast carcinomas (Lipton et al. Table 1. The aromatase inhibitor utilized in all these 1987) is an additional incentive for their study. Recent studies was aminoglutethimide (AG) along with hydro- advances in aromatase inhibitor research has led to the cortisone. Five trials evaluated TAM alone or combined introduction of new more potent, more specific, and more with AG (Corkery et al. 1982, Milsted et al. 1985, Ingle et tolerable agents (Goss & Gwyn 1994). The aromatase al. 1986, Rose et al. 1986, Alonso-Muñoz et al. 1988). The inhibitors are particularly attractive for combining with trial with the largest sample size was that of Rose et al. Endocrine-Related Cancer (1999) 6 265-269 Online version via http://www.endocrinology.org 1351-0088/99/006-265 © 1999 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 09:28:45AM via free access Ingle et al.: Combination hormonal therapy with aromatase inhibitors Table 1 Randomized clinical trials of combination hormonal therapy involving aminoglutethimide No of Objective Median duration Time to treatment Median evaluable response of response failureA or survival Regimen patients rate (%) (months) progressionB (months) (months) Reference TAM 97 34 ~24 10A NA Rose et al. vs (1986) TAM + AG 82 28 ~24 8 NA TAM 49 43 15 7.2B 21.9 Ingle et al. vs (1986) TAM + AG 51 49 15 7.6 27.6 TAM 34 53 NA 15B NA Alonso-Munoz vs et al. (1988) AG 29 48 NA 13 NA vs TAM + AG 31 38 NA 14 NA TAM 26 19 86 NA NA Milsted et al. vs (1985) TAM + AG 26 23 56 NA NA TAM 9 33 NA 6A NA Corkery et al. vs (1982) TAM + AG 11 36 NA 6 NA TAM 99 30.6 ~22.5 NA NA Powles et al. vs (P=0.05) (1984) TAM/AG/Danazol 99 43.2 ~17.5 NA NA AG 25 20 NA NA NA Hisamatsu et al. vs (1992) AG + TAM 21 19 NA NA NA MA 75 6* NA 5A 26 Russell et al. vs (1997) AG 80 24 NA 4 27 vs MA + AG 80 23 NA 7 26 AG 62 32 NA NA NA Wander et al. vs (1987) MPA + AG 69 32 NA NA NA MPA 29 31 9 NA NA Samonis et al. vs (1994) AG 28 36 9 NA NA vs MPA + AG 28 43 10 NA NA NA, not available; TAM, tamoxifen; AG, aminoglutethimide; MA, megestrol acetate; MPA, medroxyprogesterone acetate. *Response determined in total of 122 patients. (1986) which involved 179 patients evaluable for time AG was found to be associated with a significant analysis and 166 patients evaluable for response. There (P=0.032) decrease in the area under the curve (AUC) for was no indication of a therapeutic advantage, and the TAM, with the mean reduction being 73% (range: 56- toxicity was greater with the addition of AG. The other 80%), which corresponded to a mean increase in TAM four randomized trials (Corkery et al. 1982, Ingle et al. clearance of 222%. The impact of AG on five metabolites 1986, Milsted et al. 1985, Alonso-Muñoz et al. 1988) of TAM, including N-desmethyl-TAM and 4-hydroxy- contained smaller sample sizes but had similar results. TAM, was also examined, and the AUC for most After the completion of these studies of TAM plus AG, metabolites was also reduced, with a mean reduction of Lien et al. (1990) reported a study of pharmacokinetic about 50%. The authors concluded that their data were interactions between these two agents. They studied six most consistent with induction of TAM metabolism by postmenopausal women treated for more than 6 months AG. This reduction of TAM and its metabolites provided with TAM as a single agent. AG was then added, using a potential explanation for the failure of the studies noted 250 mg four times a day in five patients and three times a above to show superiority for TAM plus AG over TAM day in one patient, along with cortisone acetate (50 mg alone. twice a day for 2 weeks and 25 mg twice a day thereafter). 266 Downloaded from Bioscientifica.com at 09/25/2021 09:28:45AM via free access Endocrine-Related Cancer (1999) 6 265-269 In a variation on the TAM plus AG theme, Powles (1986), which demonstrated the antagonistic affect of AG et al. (1984) compared TAM plus AG plus danazol (a and danazol on estradiol levels. Before considering a synthetic progestin) with TAM alone. The combination phase III trial, it was considered necessary to evaluate regimen produced a higher response rate (43 vs 31%, patients for any pharmacokinetic interactions between P=0.05) but no advantage in terms of duration of TAM and letrozole. In order to examine the effects of response. The authors concluded that the trial did not show letrozole on TAM, we performed a pilot study in which a therapeutic advantage for the combination. Of note with patients received TAM (20 mg daily) for 6 weeks followed respect to the reported higher response rate for the three- by the addition of letrozole (2.5 mg daily) (JN Ingle, VJ agent combination is that it was subsequently Suman, PA Johnson, JE Krook, JA Mailliard, RH demonstrated that AG and danazol have opposing effects Wheeler, CL Loprinzi, EA Perez, VC Jordan & on the concentration of the free biologically active fraction M Dowsett, unpublished work). Dowsett et al. (1997a) of estradiol (Dowsett et al. 1986). Thus, the use of danazol concurrently performed the complementary study in combination with AG would be expected to be evaluating the effect of TAM on letrozole levels. counterproductive. In the former study which evaluated the impact of Three studies have evaluated the addition of AG to a letrozole on TAM pharmacokinetics, levels of TAM, progestin. The largest study compared megestrol acetate N-desmethyl-TAM, and 4-hydroxy-TAM were measured (MA) with AG or the combination of MA plus AG at 6 week intervals up to 18 weeks after the addition of (Russell et al. 1997). They studied a select group of letrozole. Seventeen patients were assessed with respect to women who were required to have estrogen receptor week 6 levels (before addition of letrozole) and week 24 positive tumors and prior treatment with TAM in the levels (18 weeks after addition of letrozole). There was no advanced disease setting with achievement of a partial indication of a systematic decrease in TAM, N-desmethyl response or stability for at least six months. The objective TAM or 4-hydroxy TAM following the addition of response rates were 6% (MA), 24% (AG), and 23% (MA letrozole. The variability in the percent change in TAM plus AG), with no significant difference being identified and that of the two metabolites was substantial but (χ2, 2 df, P=0.01). In addition, there was no difference in generally consistent and the median percent changes were time to treatment failure or survival.