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Estrogen replacement therapy following treatment for stage I endometrial carcinoma
GYNECOLOGIC ONCOLOGY 36,
189-191(1990)
Estrogen Replacement Therapy following Treatment for Stage I Endometrial Carcinoma’** ROGER
B.
LEE,
M.D.,*F3 THOMAS W.
BURKE,
M.D.,?
AND ROBERT
C.
PARK,
M.D.+
Departments of Obstetrics and Gynecology, *Madigan Army Medical Center, TBrooke Army Medical Center, and $Walter Reed Army Medical Center Received January 3, 1989
One hundred forty-four patients with clinical stage I endometrial adenocarcinoma were treated over an 11-year period at Mad&an Army Medical Center and Brooke Army MedicalCenter. Following surgical staging, 44 selected patients were placed on oral estrogen replacement for a median duration of 64 months. In the estrogen user group, there were no recurrent endometrial cancer and no intercurrent death. Of the 99 nonestrogenusers, there were 8 recurrences (8%) and 8 intercurrent deaths. Patients placed on estrogen replacement had low-risk factors for recurrence, namely, low tumor grade (grades 1 and 2), less than % myometrlal invasion, and no me&bases to lymph nodes or other organs. Postoperative estrogen replacement appears to be safe in academic prrsr,I~C. selected low&k patients. o 1990 INTRODUCTION
Estrogen replacement for patients previously treated for endometrial carcinoma has been controversial. Although there is a lack of scientific data to support or condemn its use, reports of increased incidence of endometrial cancer related to the use of exogenous estrogens have influenced many physicians in not prescribing estrogen to this group of patients. Many cancer patients have poor quality of life secondary to estrogen depletion. Hot flushes, irritability, insomnia, vaginal dryness, unstable bladder syndrome, and increased fractures have been of great concern to these patients. Patients with postmenopausal symptoms not alleviated by nonestrogen medication may be considered for hormone therapy when the chance of cure ’ This paper was presented at the Annual Meeting of Western Association of Gynecologic Oncologists, Jackson Hole, WY, June 1988. * The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of Department of Army or the Department of Defense. 3 To whom correspondence should be addressed at Assistant Professor, UW, Director, Division of Gynecologic Oncology at Tacoma General Hospital, 315 South K Street, Tacoma, WA 98405.
following primary therapy is very high. The following retrospective study is the authors’ 11 years experience in prescribing oral estrogens to patients with low recurrence risk following surgical therapy for stage I endometrial cancer. MATERIALS
AND METHODS
Included in this study were all patients with clinical stage I adenocarcinoma of the endometrium who were treated at Madigan Army Medical Center and Brooke Army Medical Center. These patients had received all or part of their initial therapy at one of the above institutions between January 1, 1975 and December 31, 1985. To be evaluable for the study, each patient had to have a minimum of 2 years follow-up or until death. Patients were considered as lost to follow-up if they did not have the required 2 years of follow-up post primary therapy. Only patients considered at low risk for recurrence were offered estrogen replacement therapy. The factors considered low risk were low tumor grade (grades 1 and 2), less than YZmyometrial invasion, and no metastases to lymph nodes or other organs. Information regarding hormone therapy and other data were obtained from each hospital’s Tumor Registry, outpatient records, and/or personal communications. Patients were considered to be estrogen users if they had received at least 2 months of oral estrogens. The usual dosages of oral conjugated estrogens were 0.625 or 1.25 mg taken every day for 25 days each month. Users of only vaginal estrogen creams were not included in this study. RESULTS
One hundred forty-four patients were treated for stage I endometrial carcinoma over the 11-year period. One
189 00!30-8258190 $1.50 Copyright 0 1990 by Academic Press, Inc. AU rights of reproduction in any form reserved.
190
LEE. BURKE. AND PARK
patient was lost to follow-up, leaving 143 evaluable patients who were followed for at least 2 years after primary therapy or until death. Of the 143 patients 44 were oral estrogen users. The mean and median ages at diagnosis of the estrogen users were 55.7 and 57 years old, respectively (range 28-67) with a median follow-up time of 87 months (range 25150). All 44 patients had total abdominal hysterectomy and bilateral salpingo-oophorectomy; 33 had additional pelvic and/or paraaortic lymph node sampling. Three of the estrogen users (7%) had either pre- or postoperative pelvic radiotherapy plus vaginal Cesium application. The majority of these patients started taking hormone therapy within the first postoperative year and had been on estrogen for more than 5 years (Tables 1 and 2). Fifteen patients (34%) took a progestin with the estrogen replacement either initially or later on when addition of progesterone was popularized. Seventy-five percent of patients on estrogen were either stage IA or IB grade 1. The rest were grade 2. None of the estrogen users had grade 3 cancer (Table 3). In terms of myometrial invasion, all of the patients taking estrogen had either no myometrial invasion or less than one-half myometrial invasion (Table 4). There were no recurrence and no intercurrent death. The only side effect of estrogen therapy was breast tenderness in 3 patients. There were 99 nonestrogen users. The mean and median ages at diagnosis were 60.1 and 61, respectively (range 32-84). The median follow-up time was 63 months (range 24-154). All patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy and 51 had additional pelvic and para-aortic lymph node sampling. Forty-five patients (45%) had either pre- or postoperative radiotherapy with vaginal Cesium application. When analyzing stage, grade, and myometrial invasion, the grade 3 cancers with deep myometrial invasion were found in the nonestrogen users (Tables 3 and 4). There were 8 recurrences (8%) among the 99 nonestrogen users. The nonestrogen users consisted of a group of 37 patients with high-risk factors and 62 with low-risk factors. Seven recurrences occurred in 37 nonestrogen patients with high-risk factors and 1 recurrence occurred in 62 patients with low-risk factors. No significant difference in recurrence rate was found between low-risk estrogen and low-risk nonestrogen users (Fisher’s Exact Test, P > 0.05). All patients with
TABLE Number of Months
1
Time (years): Number of patients:
2
l-2 1(2%)
13-24 4(9%)
25-60 9(21%)
X0 6(13%)
>5 23(55%)
DISCUSSION Patients who have been surgically treated for endometrial cancer and are at low risk for recurrence could be considered for estrogen replacement therapy. Patients who have surgical stage I, grade 1 or 2 with less than Y2myometrial invasion, negative lymph nodes, and negative peritoneal cytology have a O-3% recurrence rate [1,2]. In our series, there was one local recurrence in 62 low-risk nonestrogen patients and none in 44 low-risk estrogen patients; thus the total recurrence rate was 0.09%. The one patient with recurrence had a grade 2 cancer and had received whole pelvic irradiation; she is the only recurrent patient who is alive without disease at 73 months post-therapy. Our study is in agreement with the study of Creasman et at. [3]. Their recurrence rate for the 47 estrogen users was 2%. However, only 12 patients (25%) had taken oral estrogen; the remainder had used vaginal estrogen cream. Fifty-seven percent of our patients with low recurrence risk were prescribed hormone replacement within the first year of primary treatment and approximately onethird of patients had their hormone replacement started after a delay of 2 to 5 years after primary therapy. The TABLE 3 of Cancer with Estrogenand NonestrogenUsers
after Primary Therapy That Estrogen 1-12 25(57%)
>2 and ~5 14(32%)
recurrences have died of disease except one who is alive without disease at 73 months of follow-up time. In addition, 5 of 8 patients dying of intercurrent disease died from myocardial infarction. The other 3 patients died from a second primary cancer (colon, breast, lung). The higher number of patients dying of intercurrent disease in the nonestrogen group was significantly different from that of the estrogen group (P < 0.05). However, when analyzing only deaths from myocardial infarction, no significance difference was found between the two low-risk groups (Table 5). There was no difference in mean age between low-risk estrogen and nonestrogen users.
Stages
Was Started Months post-therapy: Number of patients:
TABLE
Duration of EstrogenTherapy
Stage: Grade: Estrogen: Nonestrogen:
IA 3 2 1 16(36%) 8(18%) 0 40(40%) 23(23%) 9(9%)
IB 2 3 1 17(39%) 3(7%) 0 lS(lS%) 6(6%) 3(3%)
ESTROGEN REPLACEMENT
TABLE 5 Deaths from Myocardial Infarction
TABLE 4 Myometrial Invasion in Estrogen and Nonestrogen Users Depth of invasion: Estrogen: Nonestrogen:
None 2 1(48%) 24(24%)
< ‘$5 23(52%) 43(44%)
3 55 0 31(31%)
Unknown 0 l(l%)
191
THERAPY
Estrogen users: Nonestrogen:
Low risk
High risk
o/43 l/36
o/o 4163
Note. Fisher’s Exact Test P > 0.05.
reasons for the delay in hormone replacement varied. Some patients worried about adverse side effects of estrogen tried various nonestrogen therapies and switched to oral estrogen when postmenopausal symptoms persisted. Other patients had waited 2 years post primary treatment presumably because 80% of recurrences occur within the first 2 years [4]. Thirteen percent of low-risk patients did not start taking hormones until 5 years posttherapy, a time when patients were considered cured of their cancer. In retrospect, none of these patients needed to wait to start oral estrogens; the delayed hormone therapy may have limited the health benefits from estrogen usage. Once osteoporosis is present, delayed estrogen replacement prevents further bone loss, but any gain in bone mass is minimal unless a higher dosage of estrogen is prescribed [5]. The incidence of osteoporosis and cardiovascular disease as well as a sense of well-being should be improved as shown by previous reports although not specifically studied in this series [6-lo]. In our study the estrogenusers group had no deaths from myocardial infarction and the nonestrogen group had five deaths, but this difference was not significant because of our small number of patients. The incidence of thromboembolism among patients on low dose estrogen replacement is not increased [lo] and there was not any thromboembolism in our small selected group. Large prospective studies need to be done, but estrogen replacement would appear relatively safe for patients with low-risk early stage endometrial carcinoma following complete surgical resection.
REFERENCES 1. Fanning, J., Evans, M. C., Peters, A. J., Samuel, M., Harmon, E. R., and Bates, J. S. Adjuvant radiotherapy for stage IG2 endometrial adenocarcinoma and adenoacanthoma with limited myometrial invasion, Obster. Gynecol. 70, 920-922 (1987). 2. DiSaia, P. J., and Creasman, W. T. Management of endometrial adenocarcinoma stage I with surgical staging followed by tailored adjuvant radiation therapy, Clin. O&et. Gynecol. 13(4), 751-765 (1986). 3. Creasman, W. T., Henderson, D., Hinshaw, W., and Clarke-Pearson, D. L. Estrogen replacement therapy in the patient treated for endometrial cancer, Obsret. Gynecol. 67, 326-330 (1986). 4. Nori, D. Principles of radiation therapy in the management of carcinoma of the endometrium, in Radiation therapy of gynecologic cancer (D. Nori and B. B. S. Hilaris, Eds.), Alan R. Liss, New York, pp. 115-146 (1987). 5. Cann, C. E., Genant, H. K., Ettinger, B., and Gordan, G. S. Spinal mineral loss in oophorectomized women, J. Amer. Med. Assoc. 244, 2056-2058 (1980). 6. Stampfer, M. J., Willett, W. C., Colditz, G. A., Rosner, B., Speizer, F. E., and Hennekens, C. H. A prospective study of postmenopausal estrogen therapy and coronary heart disease, N. Engl. /. Med. 313, 1044-1049 (1985). 7. Stampfer, M. J., Willett, W. C., Colditz, G. A., Rosner, B., Speizer, F. E., and Hennekens, C. H. Postmenopausal estrogen use and heart disease, N. Engl. J. Med. 315, 135-136 (1986). 8. Colditz, G. A., Willett, W. C., Stampfer, M. J., Rosner, B., Speizer, F. E., and Hennekens, C. H. Menopause and the risk of coronary heart disease in women, N. Engl. J. Med. 316, 11051110 (1987). 9. Campbell,S., and Whitehead, M. Estrogen therapy and the menopausal syndrome, Clin. O&et. Gynecol. 4, 31-39 (1977). 10. Bush, T. L., and Barrett-Connor, E. Noncontraceptive estrogen use and cardiovascular disease, Epidemiol. Rev. 7, 89-104 (1985).
189-191(1990)
Estrogen Replacement Therapy following Treatment for Stage I Endometrial Carcinoma’** ROGER
B.
LEE,
M.D.,*F3 THOMAS W.
BURKE,
M.D.,?
AND ROBERT
C.
PARK,
M.D.+
Departments of Obstetrics and Gynecology, *Madigan Army Medical Center, TBrooke Army Medical Center, and $Walter Reed Army Medical Center Received January 3, 1989
One hundred forty-four patients with clinical stage I endometrial adenocarcinoma were treated over an 11-year period at Mad&an Army Medical Center and Brooke Army MedicalCenter. Following surgical staging, 44 selected patients were placed on oral estrogen replacement for a median duration of 64 months. In the estrogen user group, there were no recurrent endometrial cancer and no intercurrent death. Of the 99 nonestrogenusers, there were 8 recurrences (8%) and 8 intercurrent deaths. Patients placed on estrogen replacement had low-risk factors for recurrence, namely, low tumor grade (grades 1 and 2), less than % myometrlal invasion, and no me&bases to lymph nodes or other organs. Postoperative estrogen replacement appears to be safe in academic prrsr,I~C. selected low&k patients. o 1990 INTRODUCTION
Estrogen replacement for patients previously treated for endometrial carcinoma has been controversial. Although there is a lack of scientific data to support or condemn its use, reports of increased incidence of endometrial cancer related to the use of exogenous estrogens have influenced many physicians in not prescribing estrogen to this group of patients. Many cancer patients have poor quality of life secondary to estrogen depletion. Hot flushes, irritability, insomnia, vaginal dryness, unstable bladder syndrome, and increased fractures have been of great concern to these patients. Patients with postmenopausal symptoms not alleviated by nonestrogen medication may be considered for hormone therapy when the chance of cure ’ This paper was presented at the Annual Meeting of Western Association of Gynecologic Oncologists, Jackson Hole, WY, June 1988. * The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of Department of Army or the Department of Defense. 3 To whom correspondence should be addressed at Assistant Professor, UW, Director, Division of Gynecologic Oncology at Tacoma General Hospital, 315 South K Street, Tacoma, WA 98405.
following primary therapy is very high. The following retrospective study is the authors’ 11 years experience in prescribing oral estrogens to patients with low recurrence risk following surgical therapy for stage I endometrial cancer. MATERIALS
AND METHODS
Included in this study were all patients with clinical stage I adenocarcinoma of the endometrium who were treated at Madigan Army Medical Center and Brooke Army Medical Center. These patients had received all or part of their initial therapy at one of the above institutions between January 1, 1975 and December 31, 1985. To be evaluable for the study, each patient had to have a minimum of 2 years follow-up or until death. Patients were considered as lost to follow-up if they did not have the required 2 years of follow-up post primary therapy. Only patients considered at low risk for recurrence were offered estrogen replacement therapy. The factors considered low risk were low tumor grade (grades 1 and 2), less than YZmyometrial invasion, and no metastases to lymph nodes or other organs. Information regarding hormone therapy and other data were obtained from each hospital’s Tumor Registry, outpatient records, and/or personal communications. Patients were considered to be estrogen users if they had received at least 2 months of oral estrogens. The usual dosages of oral conjugated estrogens were 0.625 or 1.25 mg taken every day for 25 days each month. Users of only vaginal estrogen creams were not included in this study. RESULTS
One hundred forty-four patients were treated for stage I endometrial carcinoma over the 11-year period. One
189 00!30-8258190 $1.50 Copyright 0 1990 by Academic Press, Inc. AU rights of reproduction in any form reserved.
190
LEE. BURKE. AND PARK
patient was lost to follow-up, leaving 143 evaluable patients who were followed for at least 2 years after primary therapy or until death. Of the 143 patients 44 were oral estrogen users. The mean and median ages at diagnosis of the estrogen users were 55.7 and 57 years old, respectively (range 28-67) with a median follow-up time of 87 months (range 25150). All 44 patients had total abdominal hysterectomy and bilateral salpingo-oophorectomy; 33 had additional pelvic and/or paraaortic lymph node sampling. Three of the estrogen users (7%) had either pre- or postoperative pelvic radiotherapy plus vaginal Cesium application. The majority of these patients started taking hormone therapy within the first postoperative year and had been on estrogen for more than 5 years (Tables 1 and 2). Fifteen patients (34%) took a progestin with the estrogen replacement either initially or later on when addition of progesterone was popularized. Seventy-five percent of patients on estrogen were either stage IA or IB grade 1. The rest were grade 2. None of the estrogen users had grade 3 cancer (Table 3). In terms of myometrial invasion, all of the patients taking estrogen had either no myometrial invasion or less than one-half myometrial invasion (Table 4). There were no recurrence and no intercurrent death. The only side effect of estrogen therapy was breast tenderness in 3 patients. There were 99 nonestrogen users. The mean and median ages at diagnosis were 60.1 and 61, respectively (range 32-84). The median follow-up time was 63 months (range 24-154). All patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy and 51 had additional pelvic and para-aortic lymph node sampling. Forty-five patients (45%) had either pre- or postoperative radiotherapy with vaginal Cesium application. When analyzing stage, grade, and myometrial invasion, the grade 3 cancers with deep myometrial invasion were found in the nonestrogen users (Tables 3 and 4). There were 8 recurrences (8%) among the 99 nonestrogen users. The nonestrogen users consisted of a group of 37 patients with high-risk factors and 62 with low-risk factors. Seven recurrences occurred in 37 nonestrogen patients with high-risk factors and 1 recurrence occurred in 62 patients with low-risk factors. No significant difference in recurrence rate was found between low-risk estrogen and low-risk nonestrogen users (Fisher’s Exact Test, P > 0.05). All patients with
TABLE Number of Months
1
Time (years): Number of patients:
2
l-2 1(2%)
13-24 4(9%)
25-60 9(21%)
X0 6(13%)
>5 23(55%)
DISCUSSION Patients who have been surgically treated for endometrial cancer and are at low risk for recurrence could be considered for estrogen replacement therapy. Patients who have surgical stage I, grade 1 or 2 with less than Y2myometrial invasion, negative lymph nodes, and negative peritoneal cytology have a O-3% recurrence rate [1,2]. In our series, there was one local recurrence in 62 low-risk nonestrogen patients and none in 44 low-risk estrogen patients; thus the total recurrence rate was 0.09%. The one patient with recurrence had a grade 2 cancer and had received whole pelvic irradiation; she is the only recurrent patient who is alive without disease at 73 months post-therapy. Our study is in agreement with the study of Creasman et at. [3]. Their recurrence rate for the 47 estrogen users was 2%. However, only 12 patients (25%) had taken oral estrogen; the remainder had used vaginal estrogen cream. Fifty-seven percent of our patients with low recurrence risk were prescribed hormone replacement within the first year of primary treatment and approximately onethird of patients had their hormone replacement started after a delay of 2 to 5 years after primary therapy. The TABLE 3 of Cancer with Estrogenand NonestrogenUsers
after Primary Therapy That Estrogen 1-12 25(57%)
>2 and ~5 14(32%)
recurrences have died of disease except one who is alive without disease at 73 months of follow-up time. In addition, 5 of 8 patients dying of intercurrent disease died from myocardial infarction. The other 3 patients died from a second primary cancer (colon, breast, lung). The higher number of patients dying of intercurrent disease in the nonestrogen group was significantly different from that of the estrogen group (P < 0.05). However, when analyzing only deaths from myocardial infarction, no significance difference was found between the two low-risk groups (Table 5). There was no difference in mean age between low-risk estrogen and nonestrogen users.
Stages
Was Started Months post-therapy: Number of patients:
TABLE
Duration of EstrogenTherapy
Stage: Grade: Estrogen: Nonestrogen:
IA 3 2 1 16(36%) 8(18%) 0 40(40%) 23(23%) 9(9%)
IB 2 3 1 17(39%) 3(7%) 0 lS(lS%) 6(6%) 3(3%)
ESTROGEN REPLACEMENT
TABLE 5 Deaths from Myocardial Infarction
TABLE 4 Myometrial Invasion in Estrogen and Nonestrogen Users Depth of invasion: Estrogen: Nonestrogen:
None 2 1(48%) 24(24%)
< ‘$5 23(52%) 43(44%)
3 55 0 31(31%)
Unknown 0 l(l%)
191
THERAPY
Estrogen users: Nonestrogen:
Low risk
High risk
o/43 l/36
o/o 4163
Note. Fisher’s Exact Test P > 0.05.
reasons for the delay in hormone replacement varied. Some patients worried about adverse side effects of estrogen tried various nonestrogen therapies and switched to oral estrogen when postmenopausal symptoms persisted. Other patients had waited 2 years post primary treatment presumably because 80% of recurrences occur within the first 2 years [4]. Thirteen percent of low-risk patients did not start taking hormones until 5 years posttherapy, a time when patients were considered cured of their cancer. In retrospect, none of these patients needed to wait to start oral estrogens; the delayed hormone therapy may have limited the health benefits from estrogen usage. Once osteoporosis is present, delayed estrogen replacement prevents further bone loss, but any gain in bone mass is minimal unless a higher dosage of estrogen is prescribed [5]. The incidence of osteoporosis and cardiovascular disease as well as a sense of well-being should be improved as shown by previous reports although not specifically studied in this series [6-lo]. In our study the estrogenusers group had no deaths from myocardial infarction and the nonestrogen group had five deaths, but this difference was not significant because of our small number of patients. The incidence of thromboembolism among patients on low dose estrogen replacement is not increased [lo] and there was not any thromboembolism in our small selected group. Large prospective studies need to be done, but estrogen replacement would appear relatively safe for patients with low-risk early stage endometrial carcinoma following complete surgical resection.
REFERENCES 1. Fanning, J., Evans, M. C., Peters, A. J., Samuel, M., Harmon, E. R., and Bates, J. S. Adjuvant radiotherapy for stage IG2 endometrial adenocarcinoma and adenoacanthoma with limited myometrial invasion, Obster. Gynecol. 70, 920-922 (1987). 2. DiSaia, P. J., and Creasman, W. T. Management of endometrial adenocarcinoma stage I with surgical staging followed by tailored adjuvant radiation therapy, Clin. O&et. Gynecol. 13(4), 751-765 (1986). 3. Creasman, W. T., Henderson, D., Hinshaw, W., and Clarke-Pearson, D. L. Estrogen replacement therapy in the patient treated for endometrial cancer, Obsret. Gynecol. 67, 326-330 (1986). 4. Nori, D. Principles of radiation therapy in the management of carcinoma of the endometrium, in Radiation therapy of gynecologic cancer (D. Nori and B. B. S. Hilaris, Eds.), Alan R. Liss, New York, pp. 115-146 (1987). 5. Cann, C. E., Genant, H. K., Ettinger, B., and Gordan, G. S. Spinal mineral loss in oophorectomized women, J. Amer. Med. Assoc. 244, 2056-2058 (1980). 6. Stampfer, M. J., Willett, W. C., Colditz, G. A., Rosner, B., Speizer, F. E., and Hennekens, C. H. A prospective study of postmenopausal estrogen therapy and coronary heart disease, N. Engl. /. Med. 313, 1044-1049 (1985). 7. Stampfer, M. J., Willett, W. C., Colditz, G. A., Rosner, B., Speizer, F. E., and Hennekens, C. H. Postmenopausal estrogen use and heart disease, N. Engl. J. Med. 315, 135-136 (1986). 8. Colditz, G. A., Willett, W. C., Stampfer, M. J., Rosner, B., Speizer, F. E., and Hennekens, C. H. Menopause and the risk of coronary heart disease in women, N. Engl. J. Med. 316, 11051110 (1987). 9. Campbell,S., and Whitehead, M. Estrogen therapy and the menopausal syndrome, Clin. O&et. Gynecol. 4, 31-39 (1977). 10. Bush, T. L., and Barrett-Connor, E. Noncontraceptive estrogen use and cardiovascular disease, Epidemiol. Rev. 7, 89-104 (1985).