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Home , Aminoglutethimide, Aromatase inhibitor, Megestrol acetate

Endocrine-Related (1999) 6 265-269 Combination hormonal therapy involving inhibitors in the management of women with

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 , but there is no evidence for any superiority of this approach over single-agent therapy alone. The advent of new aromatase inhibitors with greater , selectivity, and better 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 (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 levels and thus allowing TAM to act more agents are in clinical use today including , effectively as a competitive inhibitor with . progestins, , , luteinizing - 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 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 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 . 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

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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/ 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, ; MPA, 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- 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 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 (50 mg alone. twice a day for 2 weeks and 25 mg twice a day thereafter).

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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 , levels of TAM, progestin. The largest study compared 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 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. The other two studies close to zero for most of the determinations. There was no compared medroxy acetate (MPA) with AG evidence for a substantial detrimental impact of letrozole or the combination of MPA plus AG (Wander et al. 1987 on TAM or the two metabolites as had been observed with Samonis et al. 1994). There was no significant advantage AG (Lien et al. 1990). identified for the combination in terms of response rate in In addition, in our study estrogen suppression induced either study. Potentially relevant to these findings are by letrozole was substantial despite concomitant reports that AG will substantially reduce levels of both administration of TAM. All patients experienced a MA and MPA. When MPA was administered orally, AG substantial reduction in estradiol after the addition of was found to reduce mean plasma levels of MPA by 50% letrozole for 6 weeks with a median decrease of 88.5% (Van Deijk et al. 1985) and mean serum levels by 60% (range 73.7-95.2%). (Lundgren et al. 1990). Likewise, AG was found to reduce In the complementary study by Dowsett et al. (1997a), serum MA levels by 79% (Lundgren et al. 1990). patients received letrozole 2.5 mg daily for 6 weeks followed by the addition of TAM at a dose of 20 mg daily. Evaluation of letrozole in combination Letrozole pharmacokinetics were based on plasma with TAM samples taken 1 day before the addition of TAM and after 6 weeks of receiving both agents. Letrozole AUC The availability of a new generation of aromatase decreased by a mean±S.D of 30.6±17.9%, with the inhibitors which are orally active, potent, specific, and reduction being seen in 9 of the 10 patients. The range of well-tolerated raises the issue of readdressing the value of the AUC reduction was from –5% to +59.4% and was combination hormonal therapy. The agents of most greater than 30% in seven patients. The authors noted that interest are letrozole (Dombernowsky et al. 1998) and the reduced plasma levels of letrozole corresponded to (Buzdar et al. 1996) as these have been estimated daily doses of 1.5-2 mg. approved by the US Food and Drug Administration (FDA). Because of prior experience with letrozole (Ingle et al. 1997), we studied this agent in combination with Future considerations TAM. Recent preclinical data raise concerns regarding the Lessons were learned from studies by Lien et al. concept of combining aromatase inhibitors with TAM. (1990), which showed the adverse impact of AG on levels Brodie et al. (1998) have utilized MCF-7 cells which are of TAM and its major metabolites, and Dowsett et al. stably transfected with the aromatase gene in

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Downloaded from Bioscientifica.com at 10/03/2021 04:23:38PM via free access Ingle et al.: Combination hormonal therapy with aromatase inhibitors ovariectomized nude mice to study the antitumor effect of between letrozole and tamoxifen in postmenopausal patients TAM and two aromatase inhibitors, letrozole and with advanced breast cancer. Breast 6 245. anastrozole. The pertinent finding relative to the topic Dowsett M, Welch H, Blackman GM, King N, Howell A, Tobias under discussion was that there was no additional benefit J & Baum M 1997b A randomised, double blind, parallel- from adding TAM to aromatase inhibitors over the group trial to evaluate the effect of ‘Arimidex’ (anastrozole) aromatase inhibitors alone. Whereas the combination of on the pharmacokinetics of tamoxifen in postmenopausal TAM plus letrozole was significantly more efficacious breast cancer patients. Breast 6 245. than TAM alone, it appeared that letrozole alone was Goss PE & Gwyn KMEH 1994 Current perspectives on superior to the combination of TAM plus letrozole. aromatase inhibitors in breast cancer. Journal of Clinical Oncology 12 2460-2470. The concept of combining aromatase inhibitor with Hisamatsu K, Nomura Y & Tashiro H 1992 Aminoglutethimide antiestrogens such as TAM remains attractive but further and aminoglutethimide+tamoxifen. Gan to Kagaku Ryoho 19 preclinical and clinical research with these agents is 2017-2023. necessary. The value of combining aromatase inhibitors Ingle JN, Green SJ, Ahmann DL, Long HJ, Edmonson JH, Rubin with other hormonal agents remains to be established. J, Chang MN & Creagan ET 1986 Randomized trial of tamoxifen alone or combined with aminoglutethimide and Acknowledgements in women with metastatic breast cancer. Journal of Clinical Oncology 4 958-964. The authors acknowledge Mrs Gail Prechel for her Ingle JN, Johnson PA, Suman VJ, Gerstner JB, Mailliard JA, assistance in manuscript preparation. Camoriano JK, Gesme DH Jr, Loprinzi CL, Hatfield AK & Hartmann LC 1997 A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women References with metastatic breast carcinoma. Cancer 80 218-224. Alonso-Muñoz MC, Ojeda-Gonzalez MB, Beltran-Fabregat M, Lien EA, Anker G, Lonning PE, Solheim E & Ueland PM 1990 Dorca-Ribugent J, Lopez-Lopez L, Borras-Balada J, Decreased serum concentrations of tamoxifen and its Cardenal-Alemany F, Gomez-Bastiste X, Fabregat-Mayol J & metabolites induced by aminoglutethimide. Cancer Research Viladiu-Quemada P 1988 Randomized trial of tamoxifen 50 5851-5857. versus aminoglutethimide and versus combined tamoxifen Lipton A, Santner SJ, Santen RJ, Harvey HA, Feil PD, and aminoglutethimide in advanced postmenopausal breast White-Hersey D, Bartholomew MJ & Antle CE 1987 cancer. Oncology 45 350-353. Aromatase activity in primary and metastatic human breast Brodie A, Lu Q, Liu Y, Long B, Wang J-P & Yue W 1998 cancer. Cancer 59 779-782. Preclinical studies using the intratumoral aromatase model for Lundgren S, Lonning PE, Aakvaag S & Kvinnsland S 1990 postmenopausal breast cancer. Oncology 12 (Suppl 5) 36-40. Influence of aminoglutethimide on the metabolism of Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, medroxyprogesterone acetate and megestrol acetate in Eiermann W, Wolter JM, Azab M, Webster A & Plourde PV postmenopausal patients with advanced breast cancer. Cancer 1996 Anastrozole, a potent and selective aromatase inhibitor, and 27 101-105. versus megestrol acetate in postmenopausal women with Milsted R, Habeshaw T, Kaye S, Sangster G, Macbeth F, advanced breast cancer: results of overview analysis of two Campbell-Ferguson J, Smith D & Calman K 1985 A phase III trials. Journal of Clinical Oncology 14 2000-2011. randomised trial of tamoxifen versus tamoxifen with Corkery J, Leonard RCF, Henderson IC, Gelman RS, Hourihan aminoglutethimide in post-menopausal women with advanced J, Ascoli DM & Salhanick HA 1982 Tamoxifen and amino- breast cancer. Cancer Chemotherapy and Pharmacology 14 in advanced breast cancer. Cancer Research 42 272-273. 3409s-3414s. Powles TJ, Ashley S, Ford HT, Gazet JC, Nash AG, Neville AM Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, & Coombes RC 1984 Treatment of disseminated breast cancer Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, with tamoxifen, aminoglutethimide, hydrocortisone, and Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, danazol, used in combination or sequentially. Lancet 1 1369- Chaudri HA, Hornberger U & Trunet PF 1998 Letrozole, a 1372. new oral aromatase inhibitor for advanced breast cancer: Rose C, Kamby C, Mouridsen HT, Bastholt L, Brincker H, double-blind randomized trial showing a dose effect and Skovgaard-Poulsen H, Andersen AP, Loft H, Dombernowsky improved and tolerability compared with megestrol P & Andersen KW 1986 Combined endocrine treatment of acetate. Journal of Clinical Oncology 16 453-461. postmenopausal patients with advanced breast cancer. Breast Dowsett M, Murray RML, Pitt P & Jeffcoate SL 1986 Cancer Research and Treatment 7 45-50. Biochemical basis for the antagonism between amino- Russell CA, Green SJ, O’Sullivan J, Hynes HE, Budd GT, glutethimide and danazol in the endocrine treatment of breast Congdon JE, Martino S & Osborne CK 1997 Megestrol cancer. Annals of Clinical Biochemistry 23 277-284. acetate and aminoglutethimide/hydrocortisone in sequence or Dowsett M, Pfister CU, Johnson SRD, Houston SJ, Miles DW, in combination as second-line endocrine therapy of estrogen Verbeek JA & Smith IE. 1997a Pharmacokinetic interaction receptor-positive metastatic breast cancer: a Southwest

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Oncology Group phase III trial. Journal of Clinical Oncology of medroxyprogesterone acetate: its correlation with serum 15 2494-2501. . Cancer Treatment Reports 69 85-90. Wander HE, Kleeberg UR, Essers U, Blossey HC & Nagel GA Samonis G, Margioris AN, Bafaloukos D & Razis DV 1994 1987 Aminoglutethimid plus hochdosiertes Medroxy- Prospective randomized study of aminoglutethimide (AG) progesteronazetat versus Aminogluethimid plus Kortison in versus medroxyprogesterone acetate (MPA) versus AG+MPA der Therapie des metastasierenden Mammakarzinoms. in generalized breast cancer. Oncology 51 411-415. Onkologie 10 321-323. Van Deijk WA, Blijham GH, Mellink WAM & Meulenberg PMM 1985 Influence of aminoglutethimide on plasma levels

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