Clinical Trial of Multiple Endocrine Therapy For

Home , Aminoglutethimide

[CANCER RESEARCH (SUPPL.) 42, 3458s-3460s, August 1982] 0008-5472/82/0042-OOOOS02.00 Clinical Trial of Multiple Endocrine Therapy for Metastatic and Locally Advanced Breast Cancer with Tamoxifen-Aminoglutethimide- Danazol Compared to Tamoxifen Used Alone1

Trevor J. Powles, C. Gordon, and R. C. Coombes

Medical Breast Unit, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, England

Abstract

Multiple-endocrine therapy with combinations of various This paper reports a controlled randomized clinical trial types of treatment has not been evaluated properly in spite of which compared treatment of advanced breast cancer with the success of individual types of hormone treatment. This tamoxifen to treatment with a combination of TAD.2 paper reports the early results of a randomized controlled clinical trial comparing tamoxifen (10 mg 2 times/day)-amino- Patients and Methods glutethimide (250 mg 3 times/day)-danazol (100 mg 3 times/ Between September 1979 and April 1981, 122 patients with as day)-hydrocortisone (20 mg 2 times/day) (TAD) with tamoxifen sessable metastatic or locally advanced breast cancer have been (10 mg 2 times/day). randomized to receive either tamoxifen (10 mg twice/day) or a com Analysis of the first 107 assessable patients indicates objec bination of tamoxifen (10 mg twice/day), aminoglutethimide (250 mg tive response (criteria of the International Union Against Can 3 times/day), danazol (100 mg 3 times/day), and hydrocortisone (20 cer) in 33% of patients receiving tamoxifen versus 50% of mg twice/day). All patients were at least 1 year postmenopausal, with patients receiving TAD. Duration of response to TAD is identical histologically confirmed breast cancer and with a life expectancy of at to duration of response to tamoxifen alone. TAD is well toler least 3 months. None had been treated previously with tamoxifen, ated, and toxicity, although greater than for tamoxifen, is aminoglutethimide, danazol, or corticosteroids. Ten patients had had alternative endocrine therapy previously but none for 6 weeks prior to acceptable. inclusion in this trial. An additional 12 patients had been treated previously with cytotoxic chemotherapy but none for at least 3 weeks Introduction prior to randomization for this trial. Although all patients were assessable for toxicity, only 107 patients Although various types of endocrine therapy have been used (57 tamoxifen versus 50 TAD) were assessable for tumor response at successfully to cause remissions of metastatic or locally ad 3 months, either because of early death, intolerable toxicity, life- vanced breast cancer, there have been few reports on treat threatening progression of disease, or disease considered inassessa- ment with combinations of more than one kind of endocrine ble for response on subsequent review. Assessment of response has therapy. Combinations of androgen with estrogen (6), cortico- been defined for all patients according to criteria of the International Union Against Cancer (4). steroids with radiation menopause (1, 14), androgen with cas Prior to the start of treatment, all patients were assessed for extent tration (3,5), estrogen with progesterone (7,12), and tamoxifen and distribution of disease, including full clinical investigation, photog with androgen (20) have been reported with varying degrees raphy of visible lesions, biopsy if possible for steroid receptor assays, of success. Generally, the results, mostly based on noncon- full blood count, iliac crest bone marrow aspirate, liver function tests, trolled clinical studies, have been inconclusive and difficult to serum calcium, bone scan, chest X-ray, radiological skeletal survey, interpret. and tomography or computer-assisted tomographic scan if indicated. The variations in distribution of steroid receptors and other All patients were clinically assessed at monthly intervals and contin prognostic indications of response, together with the dissimi ued treatment for at least 3 months. Treatment was stopped if patients larities in pharmacology and toxicity of each type of treatment, had progressive disease, either through failure to respond or at relapse after response or stabilization of disease. All investigations were re indicate a need for further searching for more successful peated at 3 months and subsequently at 6-month intervals while on combinations of endocrine therapy. treatment. Tamoxifen will induce remissions in 30 to 40% of patients with advanced breast cancer with a mean duration of response Results of 9 to 20 months (8,11) apparently by a direct antiestrogenic effect on breast cancer cells (9). Similarly, approximately 30% Of the 122 patients who had been randomized by April 1981, of patients respond to aminoglutethimide (17, 19), an agent sixty were allocated to receive TAD and 62, tamoxifen. The which inhibits steroid, particularly estrogen, synthesis by the mean age, the duration from first relapse to start of tamoxifen adrenal and other tissues (10, 13, 18). Another endocrine or TAD, the proportion estrogen receptor positive, and the agent used for treatment of metastatic breast cancer is danazol number who had received previous systemic treatment were (2), a synthetic progestin with impeded androgenic properties the same for both groups (Table 1). Of the patients who (15). received TAD, 7 achieved CR, 13 had stabilization of disease, and 12 had progressive disease in spite of treatment. Of those 1 Presented at the Conference ' Aromatase: New Perspectives for Breast Cancer." December 6 to 9, 1981, Key Biscayne, Fla. receiving tamoxifen, 5 achieved CR, 14 had PR, 13 had sta * The abbreviations used are: TAD. tamoxifen-aminoglutethimide-danazol-hy- bilization of disease, and 25 had progressive disease (Table drocortisone; CR. complete response; PR, partial response. 2).

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This gives an overall response rate for all randomized pa Table 3 tients of 42% for TAD compared to 31 % for tamoxifen, and for Time from start of tamoxifen or TAD to achievement of overall PR or CR for those patients who responded to treatment assessable patients, 50% for TAD compared to 33% for ta Time (wk) to response moxifen. An additional 26% of the TAD patients and 23% of tamoxifen patients had stabilization of their disease for at least PR CR 18.24 Â±15.1s (2-52)" 3 months, giving an overall success for TAD treatment of 76% TAD 21.6 Â±12.6 (8-49) 21.4 Â± 9.1 (12-37) compared to 56% for tamoxifen. Tamoxifen 20.5 Â±17.7 (5-81) The time taken to achieve remission was the same in both a Mean Â±S.E. b Numbers in parentheses, range. groups (Table 3). Remission in bone took longer to achieve (median, 41.5 weeks) than in viscera (CR, 27.5 weeks; PR, 22.5 weeks) or soft-tissue disease (CR, 17.1 weeks; PR, 15.0 weeks). The duration of remission was the same for both groups (Chart 1), although median duration of remission has i - not yet been achieved. Survival for the 2 groups of patients at the present time is similar. Twenty-one patients have died in each group, and actuarial life table analysis shows no difference in predicted survival (Chart 2), although the median survival has not been reached. Both treatments were well tolerated, and treatment was stopped because of intolerance in only one patient receiving TAD and in none receiving tamoxifen. Lethargy, skin rash and Cushingoid symptoms, mild hypercalcemia, and edema were the main problems (Table 4) and generally resolved with dose modification. 10 20 30 40 50 Weeks Discussion Chart 1. Duration of response predicted by actuarial life table analysis for patients who responded to tamoxifen (â€¢ â€¢¿)comparedto those who re sponded to TAD (â€¢ â€¢¿). These results indicate that patients can be treated effectively with TAD multiple-endocrine therapy with an increased re 100 sponse rate compared to that achieved with tamoxifen alone. The duration of response is similar for both types of treatment, 90 but further follow-up is required in order to identify possible 80 benefit for most patients in remission. Similarly, although ac tuarial life table analysis indicates no difference in survival 1 7Â° between the 2 groups, the patients who have died so far are 60- nonresponders to treatment. Whether there is any survival benefit for the increased number of responding patients on 40- Table 1 Characteristics of patients receiving either tamoxifen or TAD 30 20 ~ p =0. 86 first re lapse to 10 start of tamoxi receptor fen or positiveNo. endo 10 20 30 40 50 60 70 age TAD crine chemo no.60 (yr)64 (mos.)7.5 %9/16 therapy7 therapy84 Weeks Chart 2. Survival from start of treatment as predicted by actuarial life table TAD 56 analysis for patients who received tamoxifen (â€¢ â€¢¿)comparedto those who TamoxifenTotal 62Mean 66(from 6.7Estrogen12/19 63Previous11Previous received TAD (

Table 2 Objective response (criteria of the international Union Against Cancer) for patients receiving either tamoxifen or TAD of re sponse of re (CR + sponse(CRPR)andstabiliza of re +PR) as sponse(CRofassessa tionofassessa no.of sessablefor +PR) pa re sive dis ofallpatients4231%ble pa ble pa tients6062No.sponse5057CR75PR1814Stabilization1313Progresease1225% tients50a33%tients76a56 TADTamoxifenTotal

ap<0.05.

AUGUST 1982 3459s

Table 4 Number of patients having morbidity including toxicity to tamoxifen or TAD

oidsymp

toms90Mascu-linization.hirsutism50Hotflushes62 TAD(60)aTamoxifen (62)Lethargy234Skinrash90Nausea109Hyper-calcemia41Edema161Cushing- Numbers in parentheses, total number receiving treatment.

TAD compared to tamoxifen remains to be seen with longer 7. Kennedy, B. J., and Kiang, D. T. Hypophysectomy in the treatment of follow-up. advanced cancer of the breast. Cancer (Phila.). 29. 1606-1611.1972. 8. Legha, S. S., Davis. H. L.. and Muggia, F. M. Hormonal therapy for breast With the relative failure of cytotoxic drugs for treatment of cancer = new approaches and concepts. Ann. Intern. Med., 88. 69-77, metastatic breast cancer (16), emphasis is again being directed 1978. 9. Lippman, M., BolÃ¡n, G., and Huff, K. The effects of estrogens and antiestro- towards endocrine therapy. gens on hormone-responsive human breast cancer in long-term tissue With the variations in types of endocrine therapy available culture. Cancer Res.. 36: 4595-4601. 1976. for treatment of metastatic breast cancer, it is surprising that 10. Lipton, A., and Santen, R. J. Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer (Phila.), 33. 503- more effort has not been made to evaluate the efficacy of 511, 1974. multiple-endocrine therapy. Treatment benefit will probably 11. Mouridsen, H., Palshof, T., Patterson. J., and Battersby. L. Tamoxifen in only be identified by properly controlled clinical trials, and advanced breast cancer. Cancer Treat. Rev.. 5: 131-141, 1978. 12. Muggia, F. M., Lippman, M., and Hinson, J. C. Reports from the workshop aminoglutethimide with its unique mechanism of action asso on the use of steroids as carriers of cytotoxic agents in breast cancer. ciated with high response rate should be considered for inclu Cancer Treat. Rep.. 62: 1239-1241. 1978. sion in future combinations. 13. Newsome, H. H.. Brown, P. W., Terz, J. J., and Lawrence. W. Medical adrenalectomy and plasma steroids in advanced breast carcinoma. Surgery (St. Louis), 83. 83-89, 1978. 14. Nissen Meyer, R.. and Vogy, J. H. Cortisone treatment of metastatic breast cancer. Acta Union Int. Contra Cancrum. 75: 1140-1144, 1959. References 15. Potts. G. O. Pharmacology of danazol. J. Int. Med. Res., 5 (Suppl. 3): 1-14, 1977. 1. Brinkley. D. M., and Kingsley-Pillars, E. Treatment of advanced carcinoma 16. Powles. T. J., Coombes, R. C.. Smith. I. E., Jones, J. M.. Ford, H. T., and of the breast by bilateral oophorectomy and prednisolone. Lancet, / 123- Gazet, J-C. Failure of chemotherapy to prolong survival in a group of patients 127, 1960. with metastatic breast cancer. Lancet, T: 580-582, 1980. 2. Coombes. R. C., Dearnaley, D., Humphreys, J., Gazet, J-C., Ford, H. T., 17. Santen, T. J., Samojlik. E., Lipton, A., Harvey, H., Ruby, E. B., Wells, S. A., Nash, A. G., and Powles, T. J. Danazol treatment of advanced breast cancer. and Kendall, S. A. Genetic hormonal and clinical studies with aminogluteth Cancer Treat. Rep., 64. 1073-1076, 1980. imide in breast cancer. Cancer (Phila.), 39: 2948-2958, 1977. 3. Donegan, W. L. Endocrine therapy of breast cancer. In: J. S. Spratt, Jr., and 18. Santen, T. J., Santner. S., Davis, B., Veldhuis, J., Samojhk, E., and Ruby. E. W. L. Donegan (eds.). Cancer of the Breast, pp. 44-64. Philadelphia: W. B. Aminoglutethimide inhibits extraglandular estrogen production in postmen- Saunders Co.. 1967. opausal women with breast carcinoma. J. Clin. Endocrinol. Metab., 47: 4. Hayward, J. L., and Rubens, R. D. Assessment of response to therapy in 1257-1273, 1978. advanced breast cancer. Br. J. Cancer, 35: 292-298, 1977. 19. Smith, l. E., Fitzharris, B. M., McKinna, J. A., Fahmy. D. R., Nash, A. G., 5. Hortung. H.. Malmio, K., Hiisi-Brummert, and Bjorkensten. G. A. Endocrine Neville, A. M., Gazet, J-C., Ford. H. T., and Powles. T. J. Aminoglutethimide treatment of metastasizing breast cancer. Acta Med. Scand.. i 72 (Suppl. in treatment of metastatic breast carcinoma. Lancet, 2. 646-649, 1978. 385). 1-37, 1962. 20. Tormey, D. C., Simon, R. M.. Lippman. M. E.. Bull, J. M., and Myers. C. E. 6. Kennedy, and Brown, Combined oestrogenic and androgenic hormonal Evaluation of tamoxifen dose in advanced breast cancerâ€”a progress report. therapy in advanced breast cancer. Cancer (Phila.). 18: 431-435, 1965. Cancer Treat. Rep., 60: 1451, 1976.

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1982 American Association for Cancer Research. Clinical Trial of Multiple Endocrine Therapy for Metastatic and Locally Advanced Breast Cancer with Tamoxifen-Aminoglutethimide-Danazol Compared to Tamoxifen Used Alone

Trevor J. Powles, C. Gordon and R. C. Coombes

Cancer Res 1982;42:3458s-3460s.

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