A randomized phase II trial of aminoglutethimide and hydrocortisone versus combined aminoglutethimide, hydrocortisone and fluoxymesterone in advanced breast cancer

Radiotherapy and Oncology, 9 (1987) 217-220 Elsevier

217

RTO 00356

A randomized phase II trial of amino glutethimide and hydrocortisone versus combined aminoglutethimide, hydrocortisone and fluoxymesterone in advanced breast cancer Constantine S, Gennatas-, Angelos Kalovidouris-, George A. Paraskevas-, John Kouvaris-, Demetrios Trichopoulos" and Constantine PapavasiliouIChemolllerapy Service, 2nd Department of Surgery. Departments of 2 Radiology and t Surgery, University of Athens, Areteion Hospital, 115 28 Athens, Greece, and "Departmem of Health and Epidemiology. University of Athens Medical School, Goudi, Athens, Greece (Received 9 December 1985, revision received 21 January 1987, accepted 24 february 1987)

Key words: Aminoglulethimide; Androgen; Breast cancer

Summary Fifty postmenopausal women with advanced breast cancer were included in the following randomized phase

II trial: 25 patients received aminoglutethimide 1000 mg and hydrocortisone 40 mg daily. Twenty-five patients received amino glutethimide 1000 mg, hydrocortisone 40 mg and fluoxymesterone 20 mg daily, The two groups of patients were comparable in respect to the most important pretreatment characteristics. The majority of patients in both groups had bone lesions. There was a history of response to tamoxifen in all the cases and 17 patients had positive estrogen and progesterone receptors. The evaluation of response was based on the system adopted by the VICCo In the aminoglutethimide-hydrocortisone group, 16 (64%) patients obtained a partial remission, 3 (12%) remained stable and 6 (24%) had progressive disease. In the combination treatment group, 17 (68%) patients obtained a partial remission, 3 (12%) remained stable and 5 (20%) developed progressive disease. The median duration of partial remission and stabilization of the disease was 9 and 7 months respectively in both groups.

Introduction Several studies have proved the effectiveness of aminoglutethimide in the management of advanced Address for correspondence: Constantine S. Gennatas, 29 C. Varnali Street, 15233 Chalandri, Athens, Greece. 0167-8140(87/$03.50

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breast cancer [2,10]. The results of combination endocrine therapy are presented in two excellent reviews [4,12]. The combinations of aminoglutethimide with tamoxifen or progestins have not significantly changed the effectiveness of each treatment administered alone [1,5,6,8,9,11,12]. Generally, only a fewtypes of combined endo-

[987 Elsevier Science Publishers B,V, (Biomedical Division)

218 crine therapies have yielded even slight improvement in tumor response [4,12]. However, it is important to "ascertain whether a particular combination of hormones is superior to single hormonal agents. Each possible combination should be studied and even negative results are a positive contribution to the research for the optimal management of hormone-responsive breast cancer [9]. As the combination of aminoglutethimide and hydrocortisone with androgens had never been studied, we considered it worthwhile to undertake this phase II study [7].

Patients and methods Between February 1982 and January 1983, 50 women with advanced breast cancer were studied in a prospective randomized phase II trial. Sequential eligible patients were assigned to the groups on the basis of random number tables. No stratification was attempted. The criteria for eligibility were the following: (1) Biopsy proven breast carcinoma, stage IV according to the TNM classification. (2) A history of menopause for 5 years or more or a history of oophorectomy. (3) A history of response to tamoxifen. (4) Positive estrogen and/or progesterone receptors or unknown receptor status. (5) At least one lesion measurable by physical examination or radiography (irradiated lesions were excluded). (6) Objective evidence of disease progression. (7) Patients must be taken off tamoxifen for at least 4 weeks before randomization. (8) Patients with eNS metastases,

severe diabetes mellitus, renal, hepatic or cardiac insufficiency, leukopenia or thrombocytopenia and negative estrogen and progesterone receptors were excluded from this study. There were no age or performance status limitations. Details of patient characteristics are given in Table 1. The two groups of patients were comparable with respect to these characteristics. Hormone receptor status was known from the primary tumor. Only lytic bone lesions were considered evaluable. The 50 patients included in this report had a history of response to tamoxifen, which we use as firstline therapy in postmenopausal patients with soft tissue or bone metastases. They were placed on this protocol after initial response and subsequent failure of tamoxifen therapy. They had received no other hormonal or cytotoxic therapy. This was a second-line treatment for patients with a history of response to tamoxifen. In all cases, there was progressive disease. Patients were randomized to treatment either with amino glutethimide 1000 mg and hydrocortisone 40 mg daily or amino glutethimide 1000 mg, hydrocortisone 40 mg and fluoxymesterone 20 mg daily. All medication was administered orally, An informed consent was signed prior to randomization. Treatment was continued until there was objective evidence of disease progression, following that patients were taken off the study. History, physical examination, complete blood counts, urinalysis, electrolytes, serum calcium, liver profile and PBS were carried out prior to treatment and at regular intervals during this study. Also chest X-ray, skeletal X-rays and bone scan were

TABLE I Patients characteristics. Patients

AG+HC AG+HC+F

25 25

Median age (range in yrs)

61 (43-74) 60 (42-75)

Median disease-free interval from mastectomy (mths)

28 27

Estrogen and/or progesterone receptors positive

Karnofsky index (%)

<40

40-70 70-lO0

8

4

9

5

17 [8

Abbreviations: AG= aminoglutethimide; HC= hydrocortisone: F = f.uoxymesterone.

4 2

219 performed prior to therapy and repeated when clinically indicated. Other studies, e.g. computed tomography of the liver, were also carried out when clinically indicated. The evaluation of response was based on the system adopted by the VICC and its guidelines were strictly followed [3]. The minimum period of treatment to consider a case evaluable was 4 weeks. Duration of response was measured from the start of therapy.

Results All cases were followed to the end. The median follow-up period was 16 months. Sixteen (64%) of the 25 patients randomized to receive aminoglutethimide and hydrocortisone achieved a partial remission. Three (12%) showed stable disease and 6 (24 %) developed progressive disease. Seventeen (68%) of the 25 patients randomized to receive the combination with fluoxymesterone achieved a partial remission, 3 (12%) showed stable disease and 5 (20%) had progressive disease. The 95% confidence limits were 43-82% and 46-85% respectively. No detailed statistical analysis was attempted given the nature of the study, which falls into the realm of a phase II trial. Details of response by site of disease for each form of treatment are given in Table II. The median duration of partial remission and stabilization of the disease were 9 and 7 months respectively for both groups.

Aminoglutethimide side-effects consisted of drowsiness (20%), skin rash (12%), orthostatic hypotension (10%), and cramps (8%). In one case, hypotension was clinically significant and it was corrected with an increased dose of hydrocortisone. The addition of fludrocortisone was not considered indispensable. Toxicity was the same in the two groups. Hydrocortisone produced an increase of blood sugar in a patient with mild diabetes mellitus. It was corrected with an oral hypoglycemic agent. Fluoxymesterone caused hoarseness of the voice in one case.

Discussion This study confirms that the combination of aminoglutethimide and hydrocortisone is an effective endocrine therapy in properly selected postmenopausal women with advanced breast cancer. It seems to be particularly useful in patients with predominantly lytic bone metastases. The history of response to tamoxifen is a significant prognostic factor and the response rate in our study is in the same order of magnitude as that reported in the literature [10]. Special care was taken to avoid observer bias influencing interpretation of objective response, because of pain relief achieved in bone metastases [12]. Pain relief was noted soon after the beginning of treatment in those patients, who later obtained a partial remission. The opinion of a radiologist was asked whenever the evaluation of re-

TABLE II Responses by dominant site of involvement. No. of responses/no. of patients treated

Partial response No change Progressive disease

Viscera

Bone

Soft tissue

AG+HC AG+HC+F

AG+HC AG+HC+F

AG+HC

AG+HC+F

3/4

1/3

112

1/2 1/2

1/4

2/3

13/19 2/19 4/19

15/20 2/20 3/20

Abbreviations: AG == Aminoglutcthimide, HC = Hydrocortisone; F == Fluoxyrnesterone.

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220 sponse was based on X-ray findings. The period of 4 weeks between the discontinuation of tamoxifen and the beginning of the new therapy was considered long enough in the face of progressive disease and the rarity, in our experience, of withdrawal response to antiestrogens. The toxicity of both regimens was limited. In no case was treatment discontinued because of toxicity. In summary, this trial indicates that the combination of androgens with aminoglutethimide and hydrocortisone gives a response rate and a duration of response in the same order of magnitude than what we would expect from our experience with the administration of amino glutethimide and hydrocortisone alone.

References Blossey, H. C, Wander, H. E., Koebberling 1. and Nagel, G, A. Arninoglutethimide and medroxyprogesterone acetate in the therapy of metastatic breast cancer. First clinical and endocrinological results. Proceedings of a symposium held in Basel, Switzerland, December 11 and 12,1980. Basel: Ciba-Geigy: 181-186, 1982. 2 Gale, K. E. Treatment of advanced breast cancer with aminoglutethimide: a 14 year experience. Cancer Res. 42 (Suppl.): 3389s-3396s, 1982. 3 Hayward, J. L., Carbone, P.P., Heusen, J,C., Kumaoka, S., Segaloff, A. and Rubens, R.D. Assessment of response to therapy in advanced breast cancer. A project of the Programme on Clinical Oncology of the International Union Against Cancer, Geneva, Switzerland. Cancer 39: 12891294, 1977.

4 Kiang, D.T. Combined or sequential endocrine therapy in breast cancer. Rev. Endocrine Re!. Cancer: 11, 5, 1982. 5 Nagel, G,A., Wander, H.E. and Blossey, H.c. Phase 11 study of amino glutethimide and medroxyprogesterone acetate in the treatment of patients with advanced breast cancer, Cancer Res. 42 (Suppl.): 3442s-3444s, 1982. 6 Nagel, G.A., Wander, H,E., Blossey, C., Eggeling, 1., Essers, U" Gulzow, K., Hahn, D., Hiller, E., Sauer, H,J., Hoffman, L., Klasen, H., Kieeberg, U., Schwarze, B. and Weiss, J. Aminoglutethimide and medroxyprogesterone acetate in breast cancer. Clinical and endocrinological results. Proceedings of the 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2, 1982: SY 96, Part 218: 42-46. 7 Pocock, S.l Clinical Trials. A Practical Approach. John Wiley and Sons, Chichester, 1983. 8 Powles, T.J., Gordon. C. and Coombes, R.C. Clinical trial of multiple endocrine therapy for metastatic and locally advanced breast cancer with Tamoxifen, aminoglutethimidedanazol compared to Tamoxifen used alone. Cancer Res. 42 (Suppl.): 3458s-34608, 1982. 9 Ragaz, J. Combination of hormones for metastatic carcinoma of the breast: aminoglutethimide plus tamoxifen in combination versus aminoglutethirnide alone versus tam oxifen alone. Rev. Endorcine Rel. Cancer (Suppl, a): 547-562. 1981. 10 Santen, R.1. Aminoglutethirnide, Scientific profile. In: A Comprehensive Guide to the Therapeutic Use of Arninoglutethimide, 2nd edn., pp, 101-160, Editors: RJ, Santen and I.C. Henderson. Karger, Basel, 1982. 11 Smith, I.E., Harris, AL., Morgan, M., Grazet, J.L. and McKinna lA. Tamoxifen versus aminoglutethimide versus combined tamoxifen and aminoglutethimide in the treatment of advanced breast carcinoma. Cancer Res. 42 (Suppl.): 34308-3433s, 1982. 12 Stoll, B.A. Combination or sequential endocrine therapy in breast cancer. Eur. J. Cancer Clin. OneoL 21: 413-416, 1985.