Medical and Pediatric Oncology 18:317-320 (1990)
Diethylstilbestrol Revisited in Advanced Breast Cancer Management Michael I. Boyer, ME, BS and Martin H.N. Tattersall, MD, FRACP
Prior to the introduction of tamoxifen, diethylstilbestrol (DES) was widely used as the first-line endocrine therapy in postmenopausal women with advanced breast cancer. Since randomized trials reported that tamoxifen has a similar response rate but fewer side effects than DES, its use has declined markedly. We administered DES in a dose of 10-20 mg daily to 11 postmenopausal women with advanced breast cancer, all of whom had received previous endocrine and some cytotoxic therapy also. Four women showed tumour responses to DES (1 complete and 3 partial), 5 had stable dis-
I
ease, and 2 progressive disease. Amongst the patients who responded, 2 had previously been unresponsive to other endocrine treatments. Of the women with stable disease, 3 had prolonged relief of symptoms. No withdrawal responses were noted. The major side effects were nausea (severe in 2 patients, mild in 1) and cardiac failure (2 patients). We conclude that DES remains a useful, active agent in the management of advanced breast cancer in postmenopausal women, even in patients with tumours unresponsive to other endocrine therapy.
Key words: metastatic breast cancer, endocrine therapy, estrogen
clined markedly, although even in 1986 Gockerman et al. felt that DES was the preferable agent on the basis of Since late last century hormonal manipulation has cost effectiveness [7]. The introduction of newer endobeen used to treat women with advanced breast cancer crine agents such as aminoglutethimide and the increased [I]. In premenopausal women, oophorectomy was the use of progestational agents such as medroxyprogesterfirst procedure to be used extensively and later adrena- one acetate in patients failing tamoxifen have resulted in lectomy or hypophysectomy were also shown to benefit a further decrease in use of DES, to the point where its some patients. In the 1940s additive endocrine therapy role in advanced breast cancer management now is with estrogens or androgens began being used widely, thought to be small. Recently, estrogen recruitment of and in older, post-menopausal women they were found tumour cells into cycle prior to cytotoxic chemotherapy to be effective [2,3]. In approximately one third of pa- has been advocated [8] but its place in management has tients estrogens caused a tumour response and a slightly not been determined. smaller proportion responded to androgens. Patients After observing an impressive response to DES in a whose tumours responded had a survival advantage over patient with pulmonary metastases resistant to several the nonresponders [4,5]. During the 1960s, estrogens, other endocrine therapies, we administered DES to a specifically diethylstilbestrol (DES), became the fa- further 10 women with disseminated breast cancer. The voured endocrine treatment for post-menopausal patients results are reported here, and we discuss the current stabecause of apparently greater efficacy and fewer side tus of estrogen therapy in advanced breast cancer. effects than androgens [4,5]. The introduction in the 1970s of the anti-estrogenic agent tamoxifen significantly changed the use of exogenous estrogens in the management of advanced breast cancer. Randomised trials comparing DES and tamoxifen in post-menopausal women with advanced breast From the Department of Cancer Medicine, University o f Sydney cancer revealed a slightly higher, though not statistically (M.H.N.T.), and the Department of Clinical Oncology, Royal Prince significant, regression rate with DES. However, tamox- Alfred Hospital (M.J.B., M.H.N.T.), Sydney, Australia. ifen treatment was associated with fewer side effects Address reprint requests to Prof. M.H.N. Tattersall, Dept. of Cancer [6,7]. Following these reports the use of DES has de- Medicine, University of Sydney, NSW, 2006, Australia. INTRODUCTION
0 1990 Wiley-Liss, Inc.
318
Boyer and Tattersall
TABLE I. Details of Prior Theram. Reswnse to DES. Time to Proeression. and Survival* Patient
Age
Disease sites
DFI 65 49
Previous therapy
Best response
Response to DES
Time to progression
Survival
Nodes T, M, A SD CR 8 27 Lung T, M, A, H PD PR 6 9 Nodes Skin T Lung 60 3 68 PR PR 4 5 Skin 10 T, M Lung 4 66 PR PR 5 21 Bone 120 T,M 5 63 SD SD 5 I3 + Skin 6 80 Breast 48 T, M, A, H PR SD 2 10 Nodes Bone 24 T, M 7 71 SD SD 3 14 Lung Skin 8 56 Lung 156 T, M SD SD 7 16+ Bone SD SD 5 18 + Bone 42 T, M, A, H 9 46 T, M, A SD PD 1 4 Nodes 62 10 56 120 T. M. A. H PR PD 1 13 Nodes 11 67 *Abbreviations: DFI, disease-free interval in months; previous therapy, T = tamoxifen, M = medroxyprogesterone acetate, A = aminoglutethimide, H = halotestin; best response = best response to previous therapy; time to progression in months from time of commencement of DES; survival in months from commencement of DES; CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease. 1
2
58 63
+
+
+
PATIENTS A N D METHODS
Eleven women with previously treated, advanced breast cancer were given DES. Their ages ranged from 46 to 80 years (median 63) and the time between initial diagnosis and relapse ranged from 9 months to 13 years (median 5 years). Six patients received 20 mg DES daily, 3 patients 15 mg daily, and 2 patients 10 mg daily. All patients were post-menopausal at the time of starting treatment with DES, although 4, premonopausal at the time of diagnosis, had received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (2), had undergone bilateral oophorectomy ( l ) , or had a radiation-induced menopause (1). None of the post-menopausal patients had received any adjuvant therapy. The estrogen receptor status was known in 5 women, from the primary tumour in 4 patients, in whom it was positive, and from metastatic disease in 1 other patient (positive). All patients had histologically confirmed locally recurrent or metastatic breast cancer which had been treated previously with endocrine therapy, cytotoxic chemotherapy, or both. Sites of metastatic disease included lung, skin, and bone (5 patients each) and regional or distant lymph node (3 patients). One patient had a locally advanced breast cancer that had been previously irradiated. Prior to the commencement of DES, no patient had evidence of cardiac failure or other cardiovascular disease.
Criteria for response were those traditionally employed and previously reported [9].
RESULTS
Of the 11 patients treated, 4 showed a tumour response to DES treatment, 5 had stable disease, and 2 patients had progressive disease. Clinical details of the patients together with their prior therapy are shown in Table I. Of particular note was the finding that 2 women whose tumours had previously been unresponsive to several endocrine treatments showed a response to DES . Two of the responders received 20 mg of DES daily, and 1 each received 15 mg and 10 mg daily. One patient, with nodal metastases only, had a complete response; the remainder had partial responses. Details of the time to disease progression and survival are shown in Table I. Tumour responses were seen in metastatic sites in lung, skin, lymph nodes, and breast, but no responses were documented in patients with bony metastases. In 3 responding patients progressive disease occurred at some metastatic sites whilst other sites of metastatic disease continued to show a response. No tumour responses were seen following withdrawal of DES. Five patients had stable disease for several weeks during treatment with DES. Three of these had prolonged (5, 6, and 7 months) relief of bone pain despite the lack of acceptable objective evidence of regression of bony
Diethylstilbestrol in Breast Cancer
319
metastases. The 2 remaining patients, although having receiving 1.5 or 15 mg daily. The basis of the dose no evidence of disease progression, commenced new response relationship of DES is not clear but may well treatment because of continued symptoms. relate to blood or tissue levels of the drug. The precise The major toxicity of stilbestrol treatment was nausea, levels of DES required for response have not been dewhich was severe in 2 patients and mild in 1 other pa- fined but cell culture studies indicate that concentrations tient. Two patients developed cardiac failure during greater than 10-7M inhibit breast cancer growth in vitro stilbestrol therapy. One of these developed mild right [ 111. The speed with which blood or tissue levels of the ventricular failure which was controlled with diuretics, agent reach pharmacological levels could account for the and DES was continued. The other developed biventric- rapidity of response to DES when compared with tamoxular failure after 20 weeks of treatment and DES was ifen. ceased. Hypercalcemia was not observed in patients reToxicity attributable to DES was mild in our patients, ceiving DES, and there were no episodes of venous although it was the reason for stopping treatment in one. thromboses. Previous reports have documented a noncompliance rate of up to 10% due to the side effects of therapy [12], suggesting that adverse effects are a significant issue in DISCUSSION the use of DES. In their randomised trial of different Four of 11 women with advanced breast cancer treated doses of DES, Carter et al. [ 101 found that the incidence with DES showed objective tumour response. All of of adverse effects, particularly gastrointestinal effects these patients had been extensively treated previously such as nausea and vomiting, was also dose related. In with endocrine and some with cytotoxic therapy also. the context of patients with advanced breast cancer howTwo of the patients showing tumour response had not ever, where an alternative treatment might be cytotoxic responded previously to several other endocrine agents. chemotherapy, the toxicity of DES may be more acceptThese responses are surprising, since failure of 1 endo- able. Other advantages of DES are the lack of need for crine manipulation is commonly predictive of resistance regular haematological monitoring and the relatively low to other hormonal treatment, and this dogma is 1 basis cost of this agent. for introducing cytotoxic treatment as preferred secondRecently, attention has been drawn to the cost of treatline therapy in women after lack of tumour response to ment of patients with cancer and the need to consider first-line endocrine manipulation. However, Ingle et al. these costs when planning therapy [13,14]. DES is a reported tumour responses in 4 of 22 women treated with cheap drug particularly in comparison to tamoxifen. In DES following no response to tamoxifen therapy [ 6 ] .In Australia, in February 1988, the cost of treatment with the same study, 3 of 25 women treated with tamoxifen DES (15 mg/day) was approximately 5% of the cost of showed tumour response after not responding to DES. treatment with tamoxifen (20 mglday). This difference in These results support our observation that response to cost is of importance given that both drugs have similar DES occurs in women who have shown no response to efficacy. other endocrine therapies, as well as in those patients When to introduce cytotoxic therapy in women with who have initially responded to previous endocrine treat- disseminated breast cancer, especially in elderly paments. Larger studies are required to define the proba- tients, is the subject of debate. It is in these elderly bility of these responses and to identify patients more women, above the age of 70 years, that DES is reported likely to respond. to have its highest tumour response rates [4], but as All our patients treated with DES were post-meno- demonstrated in the present series, regression is also seen pausal but the tumour responses all occurred in women in the younger postmenopausal patient. Although the tuunder the age of 70 years. Previous reports have stressed mour response rate with endocrine therapy may be lower that responses to DES occur most commonly in the older than that seen with cytotoxic agents [13], the adverse post-menopausal woman [2,3]. effects, cost, and complexity of this latter form of therThe tumour response rate seen in our group of patients apy make its use unattractive in the elderly patient. DES is similar to that reported by Ingle et al. [6], who ob- may be of particular use in these patients by delaying the served complete responses in 11 percent and partial re- need for cytotoxic treatment. sponses in 30 percent of patients who had not previously Just what place DES should take amongst the other received additive endocrine therapy. The dose of DES endocrine agents is a difficult issue. The activity of DES taken by our patients was similar to that study. However, is equal to other agents [2-4,6,7], and whilst side effects a dose response in the action of DES in advanced breast occur they are comparable to those experienced with cancer is probable, and Carter et al. [lo] reported sig- aminoglutethimide. This would suggest that DES has a nificantly higher response rates in patients treated with place as an alternative second- or third-line endocrine doses of DES of 1,500 or 150 mg per day than in those agent.
320
Boyer and Tattersall
CONCLUSIONS
The status of DES in advanced breast cancer has changed dramatically in the last decade, moving from a first-line endocrine agent to being rarely used at all. Despite this, it remains a drug that has equivalent efficacy to the currently preferred agent (tamoxifen), and perhaps greater efficacy than current second-line treatments such as medroxyprogesterone acetate or aminoglutethimide [15]. In our series the toxicity of DES has not been so marked as to preclude its use over these drugs. Responses were seen in 4 of our 11 patients, and notably, in 2 patients who had previously not responded to other endocrine treatment. The molecular basis for DES action in these circumstances requires investigation. We conclude that DES remains a useful, cheap drug, which is simple to administer in advanced carcinoma of the breast, despite the advent of several newer endocrine agents. In view of the finding that response to DES occurs even in patients who have not previously responded to endocrine manipulation, a therapeutic trial should be considered prior to proceeding to cytotoxic chemotherapy. REFERENCES 1. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet ii:104-162, 1896. 2. Stilbestrol for advanced breast cancer: A combined investigation. Royal Society of Medicine. Br Med J 2:20-21, 1944. 3. Nathanson IT: The effect of stilbestrol on advanced carcinoma of the breast. Cancer Res 6:484, 1946.
4. Androgens and estrogens in the treatment of disseminated mammary carcinoma. Retrospective study of 1944 patients. Council on drugs. JAMA 172:1271-1283, 1960. 5 . Cooperative Breast Cancer Group: Results of studies of the cooperative breast cancer group 1961-1963. Cancer Chemother Rep 41:l-24, 1964. 6. Ingle JN, Ahman DL, Green SJ, et al.: Randomized clinical trial of DES versus tamoxifen in post-menopausal women with advanced breast cancer. N Engl J Med 304:16-21, 1981. 7. Gockerman JP, Spremulli EN, Raney M, Logan T: Randomized comparison of tamoxifen versus DES in estrogen receptor positive or unknown metastatic breast cancer. A Southeastern Cancer Study Group trial. Cancer Treat Rep 70:1199-1203, 1986. 8. Lippman ME: Hormone stimulation and chemotherapy for breast cancer. J Clin Oncol5:331-332, 1987. 9. Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981. 10. Carter AC, Sedransk N, Kelly RM, et al.: Diethylstilbestrol: Recommended dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group. JAMA 237~2079-2085, 1977. 11. Lippman M, Bolan G, Huff K: The effect of estrogens and antiestrogens on hormone-responsive human breast cancer in longterm tissue culture. Cancer Res 36:4595-4601, 1976. 12. Kennedy BJ: Systemic effects of androgenic and estrogenic hormones in advanced breast cancer. J Am Geriatr SOC13:230-235, 1965. 13. Holli K, Hakama M: Treatment of the terminal stages of breast cancer. Br Med J 298:13-14, 1989. 14. Timothy AR: Cost versus benefit in the non-surgical management of breast cancer. Br Med J 297:471-472, 1988. 15. Legha SS, Davis HL, Muggia FM: Hormonal therapy of breast cancer: New approaches and concepts. Ann Intern Med 88:6977, 1978.
Diethylstilbestrol Revisited in Advanced Breast Cancer Management Michael I. Boyer, ME, BS and Martin H.N. Tattersall, MD, FRACP
Prior to the introduction of tamoxifen, diethylstilbestrol (DES) was widely used as the first-line endocrine therapy in postmenopausal women with advanced breast cancer. Since randomized trials reported that tamoxifen has a similar response rate but fewer side effects than DES, its use has declined markedly. We administered DES in a dose of 10-20 mg daily to 11 postmenopausal women with advanced breast cancer, all of whom had received previous endocrine and some cytotoxic therapy also. Four women showed tumour responses to DES (1 complete and 3 partial), 5 had stable dis-
I
ease, and 2 progressive disease. Amongst the patients who responded, 2 had previously been unresponsive to other endocrine treatments. Of the women with stable disease, 3 had prolonged relief of symptoms. No withdrawal responses were noted. The major side effects were nausea (severe in 2 patients, mild in 1) and cardiac failure (2 patients). We conclude that DES remains a useful, active agent in the management of advanced breast cancer in postmenopausal women, even in patients with tumours unresponsive to other endocrine therapy.
Key words: metastatic breast cancer, endocrine therapy, estrogen
clined markedly, although even in 1986 Gockerman et al. felt that DES was the preferable agent on the basis of Since late last century hormonal manipulation has cost effectiveness [7]. The introduction of newer endobeen used to treat women with advanced breast cancer crine agents such as aminoglutethimide and the increased [I]. In premenopausal women, oophorectomy was the use of progestational agents such as medroxyprogesterfirst procedure to be used extensively and later adrena- one acetate in patients failing tamoxifen have resulted in lectomy or hypophysectomy were also shown to benefit a further decrease in use of DES, to the point where its some patients. In the 1940s additive endocrine therapy role in advanced breast cancer management now is with estrogens or androgens began being used widely, thought to be small. Recently, estrogen recruitment of and in older, post-menopausal women they were found tumour cells into cycle prior to cytotoxic chemotherapy to be effective [2,3]. In approximately one third of pa- has been advocated [8] but its place in management has tients estrogens caused a tumour response and a slightly not been determined. smaller proportion responded to androgens. Patients After observing an impressive response to DES in a whose tumours responded had a survival advantage over patient with pulmonary metastases resistant to several the nonresponders [4,5]. During the 1960s, estrogens, other endocrine therapies, we administered DES to a specifically diethylstilbestrol (DES), became the fa- further 10 women with disseminated breast cancer. The voured endocrine treatment for post-menopausal patients results are reported here, and we discuss the current stabecause of apparently greater efficacy and fewer side tus of estrogen therapy in advanced breast cancer. effects than androgens [4,5]. The introduction in the 1970s of the anti-estrogenic agent tamoxifen significantly changed the use of exogenous estrogens in the management of advanced breast cancer. Randomised trials comparing DES and tamoxifen in post-menopausal women with advanced breast From the Department of Cancer Medicine, University o f Sydney cancer revealed a slightly higher, though not statistically (M.H.N.T.), and the Department of Clinical Oncology, Royal Prince significant, regression rate with DES. However, tamox- Alfred Hospital (M.J.B., M.H.N.T.), Sydney, Australia. ifen treatment was associated with fewer side effects Address reprint requests to Prof. M.H.N. Tattersall, Dept. of Cancer [6,7]. Following these reports the use of DES has de- Medicine, University of Sydney, NSW, 2006, Australia. INTRODUCTION
0 1990 Wiley-Liss, Inc.
318
Boyer and Tattersall
TABLE I. Details of Prior Theram. Reswnse to DES. Time to Proeression. and Survival* Patient
Age
Disease sites
DFI 65 49
Previous therapy
Best response
Response to DES
Time to progression
Survival
Nodes T, M, A SD CR 8 27 Lung T, M, A, H PD PR 6 9 Nodes Skin T Lung 60 3 68 PR PR 4 5 Skin 10 T, M Lung 4 66 PR PR 5 21 Bone 120 T,M 5 63 SD SD 5 I3 + Skin 6 80 Breast 48 T, M, A, H PR SD 2 10 Nodes Bone 24 T, M 7 71 SD SD 3 14 Lung Skin 8 56 Lung 156 T, M SD SD 7 16+ Bone SD SD 5 18 + Bone 42 T, M, A, H 9 46 T, M, A SD PD 1 4 Nodes 62 10 56 120 T. M. A. H PR PD 1 13 Nodes 11 67 *Abbreviations: DFI, disease-free interval in months; previous therapy, T = tamoxifen, M = medroxyprogesterone acetate, A = aminoglutethimide, H = halotestin; best response = best response to previous therapy; time to progression in months from time of commencement of DES; survival in months from commencement of DES; CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease. 1
2
58 63
+
+
+
PATIENTS A N D METHODS
Eleven women with previously treated, advanced breast cancer were given DES. Their ages ranged from 46 to 80 years (median 63) and the time between initial diagnosis and relapse ranged from 9 months to 13 years (median 5 years). Six patients received 20 mg DES daily, 3 patients 15 mg daily, and 2 patients 10 mg daily. All patients were post-menopausal at the time of starting treatment with DES, although 4, premonopausal at the time of diagnosis, had received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (2), had undergone bilateral oophorectomy ( l ) , or had a radiation-induced menopause (1). None of the post-menopausal patients had received any adjuvant therapy. The estrogen receptor status was known in 5 women, from the primary tumour in 4 patients, in whom it was positive, and from metastatic disease in 1 other patient (positive). All patients had histologically confirmed locally recurrent or metastatic breast cancer which had been treated previously with endocrine therapy, cytotoxic chemotherapy, or both. Sites of metastatic disease included lung, skin, and bone (5 patients each) and regional or distant lymph node (3 patients). One patient had a locally advanced breast cancer that had been previously irradiated. Prior to the commencement of DES, no patient had evidence of cardiac failure or other cardiovascular disease.
Criteria for response were those traditionally employed and previously reported [9].
RESULTS
Of the 11 patients treated, 4 showed a tumour response to DES treatment, 5 had stable disease, and 2 patients had progressive disease. Clinical details of the patients together with their prior therapy are shown in Table I. Of particular note was the finding that 2 women whose tumours had previously been unresponsive to several endocrine treatments showed a response to DES . Two of the responders received 20 mg of DES daily, and 1 each received 15 mg and 10 mg daily. One patient, with nodal metastases only, had a complete response; the remainder had partial responses. Details of the time to disease progression and survival are shown in Table I. Tumour responses were seen in metastatic sites in lung, skin, lymph nodes, and breast, but no responses were documented in patients with bony metastases. In 3 responding patients progressive disease occurred at some metastatic sites whilst other sites of metastatic disease continued to show a response. No tumour responses were seen following withdrawal of DES. Five patients had stable disease for several weeks during treatment with DES. Three of these had prolonged (5, 6, and 7 months) relief of bone pain despite the lack of acceptable objective evidence of regression of bony
Diethylstilbestrol in Breast Cancer
319
metastases. The 2 remaining patients, although having receiving 1.5 or 15 mg daily. The basis of the dose no evidence of disease progression, commenced new response relationship of DES is not clear but may well treatment because of continued symptoms. relate to blood or tissue levels of the drug. The precise The major toxicity of stilbestrol treatment was nausea, levels of DES required for response have not been dewhich was severe in 2 patients and mild in 1 other pa- fined but cell culture studies indicate that concentrations tient. Two patients developed cardiac failure during greater than 10-7M inhibit breast cancer growth in vitro stilbestrol therapy. One of these developed mild right [ 111. The speed with which blood or tissue levels of the ventricular failure which was controlled with diuretics, agent reach pharmacological levels could account for the and DES was continued. The other developed biventric- rapidity of response to DES when compared with tamoxular failure after 20 weeks of treatment and DES was ifen. ceased. Hypercalcemia was not observed in patients reToxicity attributable to DES was mild in our patients, ceiving DES, and there were no episodes of venous although it was the reason for stopping treatment in one. thromboses. Previous reports have documented a noncompliance rate of up to 10% due to the side effects of therapy [12], suggesting that adverse effects are a significant issue in DISCUSSION the use of DES. In their randomised trial of different Four of 11 women with advanced breast cancer treated doses of DES, Carter et al. [ 101 found that the incidence with DES showed objective tumour response. All of of adverse effects, particularly gastrointestinal effects these patients had been extensively treated previously such as nausea and vomiting, was also dose related. In with endocrine and some with cytotoxic therapy also. the context of patients with advanced breast cancer howTwo of the patients showing tumour response had not ever, where an alternative treatment might be cytotoxic responded previously to several other endocrine agents. chemotherapy, the toxicity of DES may be more acceptThese responses are surprising, since failure of 1 endo- able. Other advantages of DES are the lack of need for crine manipulation is commonly predictive of resistance regular haematological monitoring and the relatively low to other hormonal treatment, and this dogma is 1 basis cost of this agent. for introducing cytotoxic treatment as preferred secondRecently, attention has been drawn to the cost of treatline therapy in women after lack of tumour response to ment of patients with cancer and the need to consider first-line endocrine manipulation. However, Ingle et al. these costs when planning therapy [13,14]. DES is a reported tumour responses in 4 of 22 women treated with cheap drug particularly in comparison to tamoxifen. In DES following no response to tamoxifen therapy [ 6 ] .In Australia, in February 1988, the cost of treatment with the same study, 3 of 25 women treated with tamoxifen DES (15 mg/day) was approximately 5% of the cost of showed tumour response after not responding to DES. treatment with tamoxifen (20 mglday). This difference in These results support our observation that response to cost is of importance given that both drugs have similar DES occurs in women who have shown no response to efficacy. other endocrine therapies, as well as in those patients When to introduce cytotoxic therapy in women with who have initially responded to previous endocrine treat- disseminated breast cancer, especially in elderly paments. Larger studies are required to define the proba- tients, is the subject of debate. It is in these elderly bility of these responses and to identify patients more women, above the age of 70 years, that DES is reported likely to respond. to have its highest tumour response rates [4], but as All our patients treated with DES were post-meno- demonstrated in the present series, regression is also seen pausal but the tumour responses all occurred in women in the younger postmenopausal patient. Although the tuunder the age of 70 years. Previous reports have stressed mour response rate with endocrine therapy may be lower that responses to DES occur most commonly in the older than that seen with cytotoxic agents [13], the adverse post-menopausal woman [2,3]. effects, cost, and complexity of this latter form of therThe tumour response rate seen in our group of patients apy make its use unattractive in the elderly patient. DES is similar to that reported by Ingle et al. [6], who ob- may be of particular use in these patients by delaying the served complete responses in 11 percent and partial re- need for cytotoxic treatment. sponses in 30 percent of patients who had not previously Just what place DES should take amongst the other received additive endocrine therapy. The dose of DES endocrine agents is a difficult issue. The activity of DES taken by our patients was similar to that study. However, is equal to other agents [2-4,6,7], and whilst side effects a dose response in the action of DES in advanced breast occur they are comparable to those experienced with cancer is probable, and Carter et al. [lo] reported sig- aminoglutethimide. This would suggest that DES has a nificantly higher response rates in patients treated with place as an alternative second- or third-line endocrine doses of DES of 1,500 or 150 mg per day than in those agent.
320
Boyer and Tattersall
CONCLUSIONS
The status of DES in advanced breast cancer has changed dramatically in the last decade, moving from a first-line endocrine agent to being rarely used at all. Despite this, it remains a drug that has equivalent efficacy to the currently preferred agent (tamoxifen), and perhaps greater efficacy than current second-line treatments such as medroxyprogesterone acetate or aminoglutethimide [15]. In our series the toxicity of DES has not been so marked as to preclude its use over these drugs. Responses were seen in 4 of our 11 patients, and notably, in 2 patients who had previously not responded to other endocrine treatment. The molecular basis for DES action in these circumstances requires investigation. We conclude that DES remains a useful, cheap drug, which is simple to administer in advanced carcinoma of the breast, despite the advent of several newer endocrine agents. In view of the finding that response to DES occurs even in patients who have not previously responded to endocrine manipulation, a therapeutic trial should be considered prior to proceeding to cytotoxic chemotherapy. REFERENCES 1. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet ii:104-162, 1896. 2. Stilbestrol for advanced breast cancer: A combined investigation. Royal Society of Medicine. Br Med J 2:20-21, 1944. 3. Nathanson IT: The effect of stilbestrol on advanced carcinoma of the breast. Cancer Res 6:484, 1946.
4. Androgens and estrogens in the treatment of disseminated mammary carcinoma. Retrospective study of 1944 patients. Council on drugs. JAMA 172:1271-1283, 1960. 5 . Cooperative Breast Cancer Group: Results of studies of the cooperative breast cancer group 1961-1963. Cancer Chemother Rep 41:l-24, 1964. 6. Ingle JN, Ahman DL, Green SJ, et al.: Randomized clinical trial of DES versus tamoxifen in post-menopausal women with advanced breast cancer. N Engl J Med 304:16-21, 1981. 7. Gockerman JP, Spremulli EN, Raney M, Logan T: Randomized comparison of tamoxifen versus DES in estrogen receptor positive or unknown metastatic breast cancer. A Southeastern Cancer Study Group trial. Cancer Treat Rep 70:1199-1203, 1986. 8. Lippman ME: Hormone stimulation and chemotherapy for breast cancer. J Clin Oncol5:331-332, 1987. 9. Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981. 10. Carter AC, Sedransk N, Kelly RM, et al.: Diethylstilbestrol: Recommended dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group. JAMA 237~2079-2085, 1977. 11. Lippman M, Bolan G, Huff K: The effect of estrogens and antiestrogens on hormone-responsive human breast cancer in longterm tissue culture. Cancer Res 36:4595-4601, 1976. 12. Kennedy BJ: Systemic effects of androgenic and estrogenic hormones in advanced breast cancer. J Am Geriatr SOC13:230-235, 1965. 13. Holli K, Hakama M: Treatment of the terminal stages of breast cancer. Br Med J 298:13-14, 1989. 14. Timothy AR: Cost versus benefit in the non-surgical management of breast cancer. Br Med J 297:471-472, 1988. 15. Legha SS, Davis HL, Muggia FM: Hormonal therapy of breast cancer: New approaches and concepts. Ann Intern Med 88:6977, 1978.
