Gynecologic effects of tamoxifen and the association with endometrial carcinoma

InternationalJournal of Gynecology& Obstetrics49 (I 995) 241-257

Review article

Gynecologic effects of tamoxifen and the association with endometrial carcinoma V.J. Assikis, V.C. Jordan* Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago. IL. USA Received 5 January 1995; revision received 1 March 1995; accepted 16 March 1995

Abstract Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades.The benefits of adjuvant tamoxifen therapy in prolonging disease-freeand overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggeststhat tamoxifen causesa 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty casesof endometrial carcinoma are reported, but only one caseis identified in a premenopausal woman. When documented, 77% (n = 127)of the casesare good-grade (grade 1 or 2) and 80% (n = 125) are stage-1disease.Since the distribution of good grade (7Y/o)and stageI (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressiveor late-stagediseaseappear to be unwarranted. The modest increasein the incidenceof early-stage,good-grade endometrial carcinoma describedduring tamoxifen therapy suggeststhat it would be unreasonable to institute an aggressivedetection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination. Keywork

Tamoxifen; Endometrial cancer; Uterus; Carcinoma

1. Introduction Tamoxifen is the endocrine treatment of choice for selected patients with all stages of breast cancer. Several million women are currently taking it, and treatment schedules now extend for many * Correspondingauthor, Tel.: +I 3129084162;Fax: +l 312 9081378. 0020-7292/95/$09.50 0 1995 International SSDI 0020-7292(95)02387-R

years [l]. Tamoxifen is believed to produce its antitumor actions as an antiestrogen, but the drug also exhibits an unusual mixture of estrogenic and antiestrogenic effects in different tissues around the body. The use of tamoxifen in both pre- and postmenopausal patients [l] can present the gynecologist with an apparently aberrant set of endocrine and histopathologic changes in the female reproductive tract. Therefore it is essential

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Journal of Gynecology & Obstetrics 49 (1995) 241-257

that the physician be aware of the spectrum of changes that might otherwise cause concern for patient care. In the laboratory, tamoxifen can not only stimulate growth of endometrial cancer but can also block growth of breast cancer [2,3]. These disparate observations have raised the possibility that long-term tamoxifen therapy could increase the incidence of endometrial cancer as a side effect of breast cancer treatment [3]. Ultimately the Stockholm clinical trial of long-term adjuvant tamoxifen therapy for breast cancer confirmed this concept, as tamoxifen was found to reduce contralateral breast cancer but increase the risk of endometrial carcinoma [4]. This finding set the scenefor clinical investigations of the associations between tamoxifen and the development of endometrial cancer. Our review of all published data on gynecologic complications and the link between tamoxifen and endometrial cancer was prompted by the following: (1) the importance of tamoxifen throughout the world as a successfulbreast cancer therapy; (2) the emerging concern within the medical community about potential side effects; and (3) the need for clinicians to have reliable information to impart to patients and their families. The review begins with a description of the actions of tamoxifen on the reproductive tract because, while malignancy is rare, benign endocrine changes are seenin the majority of patients treated with tamoxifen. We then will addressseveral specific questions about tamoxifen and endometrial cancer: (1) What information is available on the incidence of endometrial carcinoma among tamoxifen users? (2) Is tamoxifen associated with late-stage, highgrade disease?(3) Is long-term tamoxifen therapy associatedwith endometrial carcinoma? (4) How long did the tamoxifen patients who died from endometrial carcinoma take tamoxifen? (5) What would be a reasonable strategy for evaluating women during tamoxifen therapy? The review concludeswith a strategy for the evaluation and monitoring of patients during tamoxifen therapy 2. Tamoxifen and the reproductive tract Tamoxifen increasesovarian steroidogenesisin premenopausal patients [5], although FSH and

LH tend to remain unchanged or are only slightly increased [6,7]. This is compatible with a direct action of tamoxifen on ovarian steroidogenesis, although a balance of its estrogenic and antiestrogenic properties maintains pituitary gonadotropin secretion at near-normal levels. It is unclear, however, whether ovarian hyperstimulation ultimately results in increased pathology, but ovarian cysts have been reported during tamoxifen therapy [8,9]. The formation of such cysts may cause complications such as torsion [9] and may pose a serious diagnostic dilemma regarding whether or not the ovarian changesin the ovaries resulted from the metastatic spread of the primary breast cancer. One review describesa decreasedincidence of ovarian cancer in postmenopausal women taking tamoxifen [lo]. Despite this, a case of ovarian granulosa cell tumor in a premenopausal patient receiving tamoxifen has been reported [ 111.The authors hypothesized that ‘impaired hepatic metabolism caused by tamoxifen led to an enhanced sensitivity of the drug’s estrogenic effects on the ovary’. Whether this explanation is entirely adequate as a causeof ovarian pathogenesis remains open to debate. Whereas oral contraceptives produce a reduced risk for the development of ovarian cancer [12], probably by reducing the frequency of ovulation, it is conceivable that an agent like tamoxifen, which may stimulate the ovaries, may ultimately increase the risk of ovarian cancer in those women with elevated risk. At present no data exist to suggest that tamoxifen administration to premenopausal women elevatesthe risk for postmenopausal ovarian cancer. In contrast, clomiphene, a structurally related triphenylethylene used to induce ovulation in subfertile women, has been shown in one report to elevate the subsequent risk for ovarian carcinoma [13]. Theoretically, women who take a combination of chemotherapy and tamoxifen should be at lower risk for ovarian cancer because chemotherapy causesovarian function to ceaseprematurely [ 141. Up to 25% of premenopausal women become amenorrheic during tamoxifen therapy [ 151.However the remainder who continue to menstruate remain at risk for pregnancy, and clinicians should advise these women to use barrier contraception during tamoxifen therapy. No clear-cut laboratory

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evidence of tamoxifen teratogenicity exists, and only one caseof genetic abnormalities in offspring has been reported [16]. In this case, the mother was 35 years old and had a history of cocaine abuse as well as radiation exposure. She received tamoxifen throughout pregnancy and gave birth to an infant with Goldenhar’s syndrome (oculoauriculovertebral dysplasia). This is a rare finding (l/3500-26 500 births) and certainly can not be used to imply causation by tamoxifen becauseof the patient’s exposure to other known teratogens. In contrast, a successful pregnancy has recently been reported in a patient who had been treated with tamoxifen and progestins for endometrial carcinoma [ 171.This should not be surprising in view of the fact that many successfulpregnancies have occurred with the use of tamoxifen as a profertility agent [ 181. 3. Tamoxifen, the vagina and the uterus

Tamoxifen causes estrogen-like changes in the vaginal epithelium of some patients [ 19,201.Becausethe uterus is also a target tissue for estrogen action, it is logical to expect a responseto tamoxifen. However the situation is more complex in the uterus because epithelial, myometrial and endometrial stromal tissues may respond differently to the estrogenic and antiestrogenic properties of the drug. Tamoxifen treatment may causeproliferation of the endometrium in some, but not all women, and can produce various histologic types of endometrial hyperplasia [21-241. One recent study [24] in healthy postmenopausal women who participated in a prevention trial illustrates the effects of tamoxifen (20 mgdaily) on the uterus. One hundred eleven women were randomized to receive tamoxifen or placebo. The patients then underwent an ultrasound examination and suction curettage approximately 22 months after randomization. The averageendometrial thickness was 9.1 mm for the tamoxifen-treated group and 4.8 mm for the control group (P < 0.001). A diagnosis of atrophic endometrium was made in 61% of tamoxifen-treated women compared with 90% of the control women. As would be expected, proliferative endometrium was twice as common in the tamoxifen-treated group, moreover 16% of these

of Gyneco1og.p & Obstetrics

49 / 1995) 241-257

243

women had atypical hyperplasia. This diagnosis was absent in the control group. Table 1 reviews four studies in postmenopausal women, divided into tamoxifen-treated (n = 235) and control patients (n = 151). Proliferative endometrium is twice as common in the tamoxifentreated women. Endometrial hyperplasia is 10 times more common in women treated with tamoxifen. This finding is in agreement with ultrasonographic studies demonstrating an increase in endometrial thickening and a larger uterine volume [25,26] in tamoxifen-treated patients. Table 2 summarizes the results of three studies comparing the thickness of endometrium in tamoxifen-treated and control breast cancer patients. Thesereports show that tamoxifen increases the thickness of the endometrium, a factor that is considered to be indicative of a proliferative endometrium. Another approach to assessing the effect of tamoxifen therapy on the endometrium has been to screen a pretreatment group and record the uterine changesduring tamoxifen therapy. Neven et al. [27] reported 16 breast cancer patients who had an atrophic baseline endometrial biopsy before starting tamoxifen therapy. A second biopsy performed 6-36 months later showed that nine patients had developed a proliferative endometrium and one a uterine adenocarcinoma. A similar approach was taken by Gal et al. [23], who showed that 3 out of 11 patients developed endometrial hyperplasia 6 months after starting tamoxifen therapy. Despite the interest of these findings, these initial studies are small and merit confirmation. Overall it would appear that tamoxifen may enhance endometrial proliferation in 30-40% of postmenopausal women, but it is unclear which patients will respond to tamoxifen as a weak estrogen and which will not. This paradox is paralleled by contradictory reports that tamoxifen worsens the symptoms of endometriosis [28,29] or treats it successfully [30]. Interestingly tamoxifen also has been associated with an endometrial carcinoma arising from an ovarian endometriotic focus [3 11. Finally tamoxifen has also been reported to enhance the development [32] and growth of uterine leiomyomas [33] and to increase

C = 29 T = 30 c = 20 T = 93 C = 52 T=51 c = 50 T=61 c= 151 T = 235

Neven et al. [22]

(%) 85 36%

37

31

0

17

111 73%

45

41

0

25

46 20%

8

3

23

12

15 10%

3

4

4

4

4 3%

I

5 25 11%

2

0

1

8

5

7

15 6%

10

2

2

1

1 0.6%

0

1

0

0

C

T

C

T

C

T

T

C

Hyperplastic

Polyps

Proliferative

Atrophic

co.001

co.001


< 0.05

P-value

postmenopausal

women

Hysteroscopy, breast patients Endometrial biopsy, cancer patients Endometrial biopsy, cancer patients Endometrial biopsy, high-risk women

Comment

healthy

breast

breast

cancer

Most studies were conducted with breast cancer patients, however the study by Kedar et al. [24] was conducted with postmenopausal women recruited from the Royal Marsden Prevention Trial in London. UK.

Distribution

Kedar et al. [24]

Lahti et al. [26]

Cohen et al. [25]

n

of endometria from either control (C = no treatment) or tamoxifen (T)-treated

Reference

Table 1 The histologic classification

V.J. Assikis. V.C. Jordan /International

Journal of Gynecology & Obstetrics 49 (1995) 241-257

Table 2 The ultrasound determination of endometrial thickness in either control (C = no treatment) or tamoxifen (T)-treated postmenopausal women n

Reference

Cohen et al. [25] Lahti et al. (261 Kedar et al. 1241 Distribution

(‘h)

c = 20 T=93 c= 52 T=51 c = 50 T = 61 C= 122 T = 205

Endometrial

thickness

<5 mm

>5 mm

T

T

C

C

5

12

88

8

8

42

43

10

33

44

28

6

46 22%

98 80%

159 24 78% 20%

significantly the detection of endometrial polyps [21,26,34-361. 4. Tamoxifen and other gynecologic malignancies A very small number of reports of gynecologic malignancies, other than endometrial carcinoma, have been reported in association with tamoxifen therapy during the past decade. Unfortunately these reports are too few to derive any conclusion about an association with tamoxifen therapy. Severalreports describeother uterine malignancies observed during tamoxifen therapy. Stewart and Knight first reported three uterine sarcomasin the tamoxifen-treated arm of a Scottish trial [37]; one sarcomawas detectedin the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial [38]. In total seven casesof uterine sarcoma have been reported in patients treated with tamoxifen [39-411. Thirteen mixed miillerian tumors (MMT) also have been described [39,41-461. The tumors might potentially arise from the estrogenic properties of tamoxifen because endometrial stromal sarcomas have been reported to be estrogen- and/or progesterone receptor-positive [47] and there are two reports of such cases in patients with a milieu of estrogen excess [48,49]. Finally a single caseof a fallopian tube carcinoma has been reported after tamoxifen therapy [39].

245

5. Tamoxifen and endometrial carcinoma Among non-tamoxifen patients, breast cancer and endometrial cancer naturally share common risk factors, such as obesity and high endogenous estrogen levels [50,51]. A Swedish national study [52] documented that breast cancer patients had a relative risk (RR) of 1.72 of developing a uterine malignancy. Furthermore this risk was agedependent and rose to 2.4 if the patient was above 70 years of age. A Russian study calculated this risk to be even higher (RR = 6) [53]. Since 1985, when Killackey et al. [54] reported three casesof endometrial carcinoma in patients treated for a few months with tamoxifen, numerous case reports associating tamoxifen therapy and endometrial cancer have appeared. Table 3 lists 250 casesreported in the literature during the past decade. Unfortunately, information on patient characteristics, diseasestage,drug dosesand duration of therapy often has been incomplete or not reported. Most of these citations represent noncontrolled casereports and many are retrospective in design. Although these observations suggest a possible association between tamoxifen and endometrial carcinoma, no definite causal relationship can be derived from the data presentedin Table 3. It is common practice to include tumors of mesenchymal origin (sarcomasand MMT) in reports of endometrial cancer casesrelated to adjuvant tamoxifen therapy. It is prudent to point out that the inclusion of such tumors not only confusesefforts to detect the true relationship between tamoxifen and endometrial carcinoma but also adds a bias to these efforts. Accordingly we have excluded from our analysis any tumor that is not an endometrial carcinoma. Other gynecologic tumors have been documented in the previous section. The literature associating tamoxifen and endometrial carcinoma records significantly variable daily dosesof tamoxifen and duration of therapy. Of the 250 patients listed in Table 3 the daily dose was not reported in 19%;53% received 20 mg daily and 20% received 40 mg daily. Given these circumstances,there appears to be little basis for the suggestion that patients receiving higher doses of tamoxifen are more likely to develop endometrial cancer. Severalclinical trials that include a control

246

V.J. Ass&is, V.C. Jorah /IntenrationaI Journal of Gynecology & Obstetrics 49 (1995) 241-257

Table 3 A literature survey of the casesof endometrial carcinoma noted during tamoxifen treatment Reference

Killackey et al. [54] Hakes et al. [55] Hardell [56] Fomander et al. [43] Stewart [57] Sunderland & Osborne (151 Dauplat et al. [58]

n

Tamoxifen dose (mg/day)

Length of tamoxifen therapy (months)

Tamoxifen < 24 months

> 24 months

11 (S.D. 3.6) 12 (S.D. 0) 53.4 (SD. 31) 25.8 (S.D. IS) NS 12 (SD. 0) 21 (S.D. 18)

3 2 4 I2

7 4

28.2 (S.D. 10) 78 (S.D. 24)

4

3 5

1

3

I

2 2

Malfetano [59] Mathew et al. [60]

7 5

Le Bouedec et al. [61,62] Atlante et al. [63]

7 4

Rasmussen& Nielsen [a41 Spinelli et al. [65] Neven et al. 122,271 Andersson et al. [66] Lang-Averous et al. [67] De Muylder et al. 1211 Ribeiro & Swindell [68] O’Neill & Rodriguez-Mojica F91 Deprest et al. [70] Segna et al. [71]

2 3 2 7 3 2 1 I 1 II

Capurro et al. [72] Mignotte et al. 144) Hulka & Hall [34] Seoud et al. [39] Cohen et al. [25] Uziely et al. [73] Lahti et al. [26] Magriples et al. [45] Krause & Gerber (741 Ciatto et al. [75] Hopkins & Tasker [76] Ismail [77]

1 23 I 3 3 3 1 13 1 I 1 5

Fisher et al. [38] van Leeuwen et al. [78]

23 23

20 40 40 40 20 20 20 in 1 patient 30 in I patient 20 20 in 3 patients NS in 2 patients NS 40 in 2 patients 60 in 2 patients NS 40 20 30 NS NS 20 20 40 20 in 9 patients 10 in 2 patients 40 20 NS 20 20-30 20 NS 40 NS 20 NS 20 in 3 patients 40 in 2 patients 20 20-40

Silva et al. [41] Barakat et al. [46]

12 27

20 20

3 2 11 16 1 4 2

NS 48 (S.D. 19) NS 39 (S.D. 28) 36 12 (S.D. 0) NS NS I2 60 96 38.2 (SD. 20) 96 46.7 (SD. 20) NS NS NS NS NS 48 (S.D. 44) 48 NS NS 60 (S.D. 18) 35.3 (SD. 22) c 12 months, 6 patients 13-24 months, 7 patients 25-60 months, 7 patients > 60 months, 3 patients 23.2 46.7

4 2

7

4

18

6

5 8 13

15 IO

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241

Journal of Gynecology & Obstetrics 49 (1995) 241-257

Table 3 (continued) Reference

Dallenbach-Hellweg & Hahn [79]

Lahti et al. [80] Cohen et al. 1311

n

10

3 I

Tamoxifen dose (m&W

Length of tamoxifen therapy (months)

30 in 7 patients 20 in 2 patients 10 in I patient 20 20

54

Total = 250

53.7 (SD. 17.6) 12 Average = 41 months

Tamoxifen < 24 months

> 24 months

3 I 80

100

When available, the daily dose (me/day) and the duration of tamoxifen therapy in months are given. NS, not stated. - -

arm can be used to assessthe increased incidence of endometrial carcinoma produced by adjuvant tamoxifen therapy. In spite of this, the results reported are not consistent. The reasons for these inconsistencies may include detection biases as concerns are increased, the efficiency or lack thereof of national reporting systems,and the need to useprospective as well as retrospective data collection instruments. The first large-scale prospective clinical trial that offered clinical evidence of a possible association between tamoxifen and endometrial carcinoma was the Stockholm study [4]. Only postmenopausal breast cancer patients were randomized to 40 mglday tamoxifen adjuvant therapy or the control group. Thirteen endometrial cancers were initially reported in the treatment arm (931 patients) vs. two in the control arm (915 patients). In a recent update [43], four additional tumors were described in the treatment group and one in the control group. One of the four tumors in the treatment group was an MMT; the reported relative risk was 6.4 (P < 0.01). The authors concluded that the cumulative frequency of endometrial cancer was significantly greater in patients who received tamoxifen for more than 2 years. Theseresults were not confirmed by the Scottish trial [37], in which patients received 20 mg tamoxifen daily for 5 years or until relapse. Not a single case of endometrial carcinoma (but three sarcomas) was reported initially in the treatment group (n = 539), whereas two cases appeared in the control group (n = 531). The more recent up-

date [57] of this study added one casein each arm of the trial. Finally, the NSABP conducted the most recent evaluation of the potential link betweentamoxifen therapy and endometrial carcinoma in their nodenegative breast cancer trial B-14 [38]. In this study 20 mg tamoxifen daily was administered to 1419of 2834 randomly assigned breast cancer patients who were followed up for an averageof 8 years. In addition another 1220patients were prescribed the samedose of tamoxifen and were followed for at least 5 years. This latter group was not part of the randomized 2834 patients cited above. Fifteen casesof endometrial carcinoma were reported in the group which received tamoxifen as part of the randomized trial; one of thesewomen never received the drug. Two casesoccurred in patients in the placebo group (n = 1420) whose medical status (recurrence of breast cancer in one and colon cancer in the other) ultimately led to tamoxifen treatment. Eight casesoccurred in the group for which tamoxifen had been prescribed; one was a sarcoma. The relative risk was determined to be 7.5 (95% C.I. 1.7-32.7) and the annual hazard rate of endometrial cancer was 1.2/1000. The three clinical studies discussedso far used 5 years of adjuvant tamoxifen therapy. However studies of 1 year of adjuvant tamoxifen provide conflicting data. The Christie Hospital trial [68], in which patients received 20 mg daily for 1 year and were followed for 13 years, detected the sameincidence (one tumor) in both treated (289 patients) and untreated (306 patients) groups. In contrast,

248

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Journal of Gynecology

the Danish trial [66] used 30 mg tamoxifen daily for 48 weeks and reported two endometrial carcinomas in patients receiving radiotherapy (RT) alone (n = 846), but sevenendometrial carcinomas in patients who had both RT and tamoxifen (n = 864). The standardized incidence ratio for endometrial cancer was 1.9 (95% C.I. 0.8-3.9) for tamoxifen-treated patients and the cumulative incidence after 5 years was 0.27% for the control group and 1% for the tamoxifen-treated group. It is worth mentioning that unlike the Stockholm study [4], no decrease in the incidence of contralateral breast cancer was noted in the Danish study, probably becausethe duration of tamoxifen therapy (1 year) was too short. Overall, clinical trial data provide an important insight into the complexities of developing a valid reporting mechanism because endometrial sampling biases may skew the results. Another approach would be to study tumor registries to discover a relationship between tamoxifen use and an increased incidence of endometrial cancer. 6. Tamoxifen and the tumor registry Magriples et al. [45] conducted a retrospective search of the archives of the Yale New Haven Tumor Registry for the decade 1980- 1990.A total of 3457 patient records were screened and 53 women were identified who developed endometrial cancerafter a diagnosis of breast cancer. Fifteen of these patients received tamoxifen and 38 did not. The tamoxifen dose prescribed for the 15 patients who developed endometrial cancer was 40 mg daily, twice the recommended dose. There was a significant difference between tamoxifen-treated and tamoxifen non-treated patients in the interval between the diagnosis of breast cancer and the subsequent diagnosis of endometrial carcinoma: the tamoxifen-treated patients had an interval of 5 years,whereasthe patients not receiving tamoxifen had an interval of 12 years. Of the 15 patients treated with tamoxifen who developed a uterine malignancy, 13 were diagnosed with endometrial carcinomas and two with MMT. Magriples et al. [45] raised the issue that tamoxifen might be associated with so-called high-grade endometrial carcinoma becauseeight patients (61%) had poorly

di Obstetrics

49 (1995)

241-257

differentiated diseasesand four (31%) died of endometrial rather than breast cancer. In contrast, 2.6% of the women in the group who did not receive tamoxifen died of endometrial carcinoma. The authors interpreted their data to suggestthat radical screening measuresbe widely used (we do not agree \irith their proposals). They also advocated a thorough re-examination of the role of tamoxifen in endometrial carcinogenesis. A second study took a different approach and employed a retrospective case-control methodology. van Leeuwen et al. [78] used the Netherlands National Cancer Registry to calculate the relative risk of developing endometrial carcinoma for patients who took tamoxifen. The relative risk of endometrial cancer was calculated to be 1.3 for ever-tamoxifen users vs. controls, but this rose to 2.3 if the duration of therapy was more than 2 years, and up to 3.0 if a woman had taken tamoxifen for more than 5 years. The authors noticed a barely significant trend (P = 0.049) of increasing relative risk of endometrial carcinoma with increasing duration of therapy. The main problem with establishing the significance of the findings was the modest number of endometrial carcinomas noted in their study. Only 23 tumors were documented for the tamoxifen-treated women out of the total survey population. 7. An evaluation of the link betweentamoxifen and endometrial carcinoma Up to this point we have described the available evidencesuggestinga connection between tamoxifen and an increasein the detection of endometrial cancer. It is now pertinent to evaluate these data and their interpretation so that we can answer the questions raised in the introduction. The Stockholm study [4] was key to demonstrating the target site-specific effect of tamoxifen. Breast cancer was controlled, but there was an increase in the incidence of endometrial cancer. The initial report concluded that patients who received 5 years of adjuvant tamoxifen therapy were at a much higher risk of developing endometrial carcinoma than patients who only received 2 years of adjuvant tamoxifen therapy. After 7 years of follow-up, the cumulative incidence of

249

V.J. Assikis, V, C. Jordan / Inrernational Journal of Gynecology & Obstetrics 49 (19951 241-257 STOPTAFIOXIFEN

STOP T/+MOXlFEN

70 -

in

60 -

q

50 Months of Tamoxifen

40 -

0 q

30 20,IO-

c

n

im I

l

I

;

0 0

j , -

2 Yeals of Tamoxifen I

I

2

1

10 8 4 5 6 Detection of Endometrial Cancer after Breast Cancer (years)

12

piq [

TAMOXIFEN

1

Fig. 1. Endometrial cancers reported in the Stockholm study 1431plotted as duration of tamoxifen therapy vs. time to detection of endometrial cancer after breast cancer. Nine hundred thirty-one patients received at least 2 years of tamoxifen (40 mgidaily) and patients who were disease-free after 2 years were randomized either to stop tamoxifen or continue for 3 more years.

endometrial tumors was 0.4% for the control group, 0.9% for the patients treated with tamoxifen for up to 2 years and 5.5% for those treated for 5 years. Unfortunately no information was available at that time to assessthe actual duration of tamoxifen that each patient received at the time her endometrial tumor was detected. The recent publication by Fornander et al. [43] partially remedies this deficiency by describing the stage, time of detection after breast cancer and the duration of tamoxifen therapy for 16 endometrial tumors detected in the Stockholm study. One tumor was excluded from our analysis as it was an MMT. In Fig. 1 we plotted the duration of tamoxifen therapy vs. the time of detection of endometrial carcinoma after breast cancer surgery; 12 out of 16 patients received 2 years of tamoxifen therapy or less. Indeed seven patients developed endometrial cancer after stopping tamoxifen, but only two developed endometrial cancer if the drug was continued for a further 3 years. The fact that patients developed endometrial cancer after only short coursesof tamoxifen therapy is dramatically

illustrated in Fig. 2 where patients are classified based upon their duration of tamoxifen therapy. Using the data as presentedin thesetwo figures we believe it is unreasonable and inappropriate to conclude, basedon the Stockholm data, that longterm therapy produces a higher incidence of endometrial carcinoma. Rather it appears that the original conclusion might have been derived from an analysis of groups based upon an intention to treat rather than a straightforward analysis of individual patient data. Similarly the manner in which the data for the risk of endometrial carcinoma were presented in the Danish study [66] of 1 year of tamoxifen can bias the perception of tamoxifen’s role in the development of endometrial carcinoma. The authors compared endometrial carcinoma for two treatment groups: radiotherapy (RT) (2 cases in 846 patients = 2.36/1000)vs. RT plus tamoxifen (7 casesin 864 patients = 8.1/1000)as a breast cancer treatment. There was clearly a 3.5-fold increase in endometrial cancer incidence when tamoxifen was added to RT. However the control group (11 cases

250

V.J. As&is.

V. C. Jo&n

/International

Journal of Gynecology & Obsterrics 49 (1995) 241-257

Cases Endometrial Carcinoma n=l2

n=2

upto

upto

uptoe

Years of Tamoxifen Fig. 2. Casesof endometrial carcinoma in the Stockholm study [43] classified according to the duration of tamoxifen therapy.

in 1828 patients = 6/1000), who received no further therapy, had a much higher incidence of endometrial cancer compared with the RT group alone. The increased incidence of endometrial cancer for RT plus tamoxifen vs. control was only 1.35-fold. If one were to look at the statistics another way and were interested in the effect of RT alone, one could be misled into concluding that RT to the breast protects against endometrial cancer but the effect is negated by tamoxifen! The issueraised by the Yale group [45], i.e. that tamoxifen promotes the development of highgrade endometrial cancer, is clearly of major concern. The percentageof caseswith poorly differentiated disease(66%) reported in the survey of the Yale New Haven Tumor Registry is somewhat disconcerting; however this number only represents8 out of 13 casesobserved in a total of 3457patients in the registry. The actual number of patients receiving tamoxifen was not reported. To addressconcerns about tumor grade we reanalyzed all available data on stage and grade of endometrial tumors discovered following or during tamoxifen treatment (Table 4). Stagewas reported

in 156casesand tumor grade in 165 cases.Eighty percent of the reported cases were classified as stage I and 77% were of low grade (1 or 2). In Table 5 we compared the data for stageand grade obtained from the Yale study with our survey (excluding the Yale cases) and the Surveillance, Epidemiology and End Results (SEER) data (1983-1987) [81] derived from 12 717 endometrial cancer patients. The tumor grades reported for the tamoxifen-treated patients in our survey are almost identical to the SEER data but the Yale data are clearly different. If long-term tamoxifen therapy indeed were to causethe development of endometrial cancer with a poor prognosis, this clinical association would have enormous implications. However, careful consideration of the available data does not support this proposition. Table 6 lists each of the patients reported to have died of endometrial carcinoma in the NSABP B-14 study. The correlation between extended tamoxifen use and deaths from endometrial carcinoma is tenuous at best. Three NSABP patients were excluded from Table 7 and Fig. 3: patient 1 never took tamoxifen,

V.J. Assikis. V.C. Jordan /International

Journal of Gynecology & Obstetrics 49 (1995) 241-257

251

Table 4 The staging and grade of endometrial carcinoma reported in the literature No. of events

Reference

Malfetano [59] Fomander et al. [43] Segna et al. [7l] Magriples et al. [45] Fisher et al. (NSABP) [38] Mignotte et al. [44] van Leeuwen et al. [78] Silva et al. (411 Barakat et al. [46] Dallenbach-Hellweg & Hahn

Stage

Grade

I

II-IV

Good

Poor

I 16 11 13 23 23 23 I2 27 10

2 13 II 7 20 8 17 8 I8 10

5 3 0 2 3 2 3 3 9 0

6 15 9 5 17 I6 12” 3 16 10

0 0 2 8 5 2 11” 0 5 0

26

11

I

I8

5

Total = 191

Total staged = I56

[791 Others [21,31,39,54,58,60,63,65,80]

Total graded = 165

Good grade: 1271165 (77%) Poor grade: 38/165 (23%) Stage I: 125/156 (80%) Stages II-IV:31/156 (20%) aCalculated from a statement made by the authors in the discussion of the paper

patient 2 did not have endometrial carcinoma confirmed by the NSABP pathologist and patient 13 did not have endometrial carcinoma as the cause of death. In Table 7 we summarized the 10 deaths in the literature that are attributed to endometrial carcinoma in patients who received tamoxifen therapy. Five of the ten patients had less than 13 months of therapy and seven had 2 years or less. Clearly, ‘longer tamoxifen is worse’ did not apply in these cases.Finally, Fig. 3 depicts the duration of tamoxifen vs. the detection of endometrial cancer in patients who ultimately died of en-

dometrial cancer in the Stockholm and NSABP trials. Five out of six patients developed their endometrial carcinoma after 2 years or lessof tamoxifen therapy. Overall it appears that patients who have pre-existing endometrial carcinoma are not helped by tamoxifen therapy. This is not surprising, as endometrial carcinoma is often hormoneindependent and would be expectedto continue to grow during tamoxifen therapy. At present, no evidence exists to support the proposition that tamoxifen encourages the development of poor prognosis diseaseduring long-term therapy, but it

Table 5 A comparison of the stage and grade of endometrial carcinoma in the Yale series [45] with the current review (minus the Yale data). The SEER data are used as the standard comparison of stage and grade distribution Yale Stage I II-IV Grade Good (grades I or 2) Poor (grade 3)

Review

SEER

II9 219

78% 22%

118/147 291147

80% 20%

14% 26%

5/13 8/13

38% 62%

1221152 30/l 52

80% 200/u

79% 21%

252

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Journal of Gynecology & Obstetrics 49 (1995) 241-257

Table 6 The duration of therapy with tamoxifen and the reported causesof death (associated with endometrial carcinoma) for patients in the NSABP B-14 study [38] Patient no.

Duration of therapy (months)

Cause of death

2 5

0 5 22

9 13

42 65

3

9

Endometrial cancer Cardiovascular disease Most likely endometrial cancer Endometrial cancer Endometrial cancer, pulmonary embolus after hysterectomy Endometrial cancer

I

All patients, referred to by patient number in ref. [38], were randomized to receive tamoxifen except the last patient, patient 3, who was registered to receive tamoxifen treatment.

may increase the incidence of endometrial carcinoma through early detection. The estrogenic actions of tamoxifen could produce a detection bias through increased sampling; the level of occult diseasein the uteri of healthy women is five times the incidence of clinical disease 1821. 8. Overall assessmentof current knowledge In the light of our review of the literature, we

now can address the questions posed in the introduction: (1) What information is available on the incidence of endometrial carcinoma? We found 250 casesof endometrial carcinoma in patients treated with tamoxifen but not all reports present data on duration of therapy or dose. Given the fact that approximately 6 million woman-years of experience have been recorded with tamoxifen therapy worldwide, the reporting of endometrial carcinoma seemsto be infinitesimal. Each year about 80 000 US women with a diagnosis of breast cancer begin a course of long-term adjuvant tamoxifen therapy. This treatment strategy has only been in use for the 5 past years and thus perhaps as many 0.5 million women are currently receiving tamoxifen. The exact rate of endometrial carcinoma in tamoxifen-treated patients is almost impossible to determine. However, based on the incidence reported in the clinical trials and in our database, we estimate that the incidence is 2-3/1000 women per year compared with l/l000 control women based on the SEER data. (2) Does tamoxifen produce late-stage, highgrade disease? Only 165 of the 250 cases in our

survey had data on tumor grade and 156had staging data. The study by Magriples et al. 1451 documented 13 patients with endometrial carcinoma and 62% of thesehad poor grade (grade 3).

Table I The duration of tamoxifen therapy for patients in the Stockholm [43], Yale [45] and NSABP [38] studies who died of endometrial carcinoma. The patient and diseasecharacteristics are given where available Study

Patient

Age (years)

Survival after endometrial cancer diagnosis (months)

Duration of tamoxifen (months)

Endometrial histology

Grade

Stage

Stockholm

1 2 3 4 5 6 7 8 9 10

68 69 70 60 71 85 87 54 58 63

1 I 18 NS NS NS NS 5 11 28

24 13 11 12 120 96 3 42 22 9

NS NS NS Endometrioid Adenosquamous Endometrioid Papillary serous Carcinosarcoma Papillary Endometrioid

I 2 2 3 3 3 NS 3 3 2

I I IV NS NS IIIC NS IIb Ib Ib

Yale New Haven

NSABP

NS. not stated.

V.J. Assikis, V. C. Jordan /International

Journal of G.ynecology & Obstetrics 49 (1995) 24 I-257

so Months of Tamoxifen

[‘p’.)

40 --

e

30 -20 --

‘0 -0

253

2 years tamoxifen

4

1

n

=Stockholm

.

=NSABP

0 piq

# I I 2

I 1 6

I I 4

I I 8

t 10

Years Detection

of Endometrial

Carcinoma

after Breast Cancer Surgery Fig. 3. Deaths from endometrial cancer in the Stockholm [43] and NSABP B-14 study [38]. The detection of endometrial carcinomas is plotted against the duration of tamoxifen treatment for those women who eventually died of endometrial carcinoma in the two clinical trials.

Excluding these data our survey determined only 20% with grade-3 disease, virtually equal to the SEER data of 21%. Moreover the late-stage disease percentage was comparable between Magriples et al. (22%), our review (20%) and the SEER data (26%) (see Tables 4 and 5).

six patients received 2 years of tamoxifen or less (Fig. 3).

(3) Is long-term ramoxifen therapy associated with endometrial carcinoma? A reanalysis of the

Women who develop breast cancer are at elevated risk for endometrial carcinoma. Since several women have died of endometrial cancer after receiving but a few months of tamoxifen therapy, it is important to evaluate all breast cancer patients for pre-existing endometrial carcinoma before starting tamoxifen. Although some hormone-dependent endometrial disease can be controlled by tamoxifen [83] the majority of metastatic disease is hormone-independent and tamoxifen will not be beneficial. Becausethe incidence of endometrial carcinoma is very low (2-311000women per year) during or after tamoxifen therapy and the staging and grading of the disease at presentation is no different than that seenin the general population, no requirement for an aggressivedetection strategy presently exists. In the long term, aggressive detection strategies would be neither cost-effective nor, most importantly, acceptable to patients.

Stockholm data [43] shows that most women in the study developed endometrial carcinoma after only a 2-year course of tamoxifen (Figs. 1 and 2). In our literature review, 80 patients developed endometrial carcinoma with 2 years or lessof tamoxifen and 100 developed endometrial carcinoma with more than 2 years of tamoxifen (Table 3) (4) How long did the patients who are reported to have diedfrom endometrial carcinoma take tamoxi-

fen? In the Yale New Haven study two of the four patients receiving tamoxifen died after 3 and 12 months of therapy, respectively (Table 7). It is highly unlikely that tamoxifen was the causeof endometrial carcinoma in these women. Moreover a plot of the months of tamoxifen therapy received by women in the NSABP B-14 study or the Stockholm study who ultimately developed and died of endometrial cancer shows that five of the

9. A reasonable strategy to evaluate and monitor women during tamoxifen therapy

254

V.J. Assikis. V. C. Jorahn /International

Journal of Gynecology & Obstetrics 49 (1995) 241-257

A policy of patient education directed towards early reporting of the signs and symptoms of endometrial carcinoma should be instituted for all tamoxifen patients. Suspicious signs should initiate a request for a thorough gynecologic examination. The increasing use of ultrasonography to define thickened endometrium or polyp growth may ultimately lead to an excessof unnecessary endometrial biopsies and causeconcern to the patient. Although a dramatic increase in the diagnosis of endometrial cancer has not been observed during the past 10 years of tamoxifen use, the ultrasound endometrial changes observed recently during tamoxifen therapy almost certainly have been present in the past decadebut have not been described. Finally, it has been proposed that endometrial carcinoma growth be controlled by the cyclical use of progestins. The reasoning behind this proposal is that it has been successful in reducing endometrial cancer stimulated by the use of unopposed estrogen therapy [84]. We are currently unaware of whether progestins will blunt the effective antitumor effects of tamoxifen in hundreds of thousands of breast cancer patients, for the sakeof preventing one or two early-stageendometrial carcinomas per 1000women. In animal models, progestins reversethe antitumor actions of tamoxifen [85,86] and at least one randomized clinical study [87] demonstrates that tamoxifen plus medroxyprogesteroneacetate is not as effective as tamoxifen alone in controlling the growth of advanced breast cancer in postmenopausal women. Clearly additional studies are neededto define the value of local-release progestin devices during tamoxifen therapy; the use of systemic progestins should be discouraged in the absence of clinical data demonstrating that the patient will not be placed at a disadvantage for breast cancer recurrence. References [I] Jordan VC, editor. Long term tamoxifen treatment for breast cancer. Madison, WI: University of Wisconsin Press, 1994. [2] Satyaswaroop PG, Zaino RJ, Mortel R. Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res 1984; 44: 4006-4010.

[31 Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan

VC. Contrasting action of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 1988;48: 812-815. 141 Fomander T, Cedermark B, Mattsson A, Skoog L, Theve T, et al. Adjuvant tamoxifen in early breast cancer: occurrenceof new primary cancers.Lancet 1989;i(8630): 117-120, [51 Jordan VC, Fritz NF, Langan-Fahey S, Thompson M, Tormey DC. Alteration of endocrine parameters in premenopausal women with breast cancer during long term adjuvant tamoxifen therapy. J Natl Cancer Inst 1991;83: 1488-1491. 161Sawka CA, Pritchard KI, Paterson DJA, Thomsen DB, Shelley WE, et al. Role and mechanismof action of tamoxifen in premenopausal women with metastatic breast cancer. Cancer Res 1986;46: 315273156. 171Ravdin PM, Fritz NF, Tormey DC, Jordan VC. Endocrine status of premenopausal node positive breast cancer patients following adjuvant chemotherapy and long term tamoxifen. Cancer Res 1988;48: 1026-1029. 181Powles TJ, Hardy JR, Ashley SE, Farrington GH, Cosgrove D, et al. A pilot trial to evaluate the acute toxicology and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989;60: 126-131. 191 Barbieri RL, Ferraci AL, Droesch JN, Rochelson BL. Ovarian torsion in a premenopausal woman treated with tamoxifen for breast cancer. Fertil Steril 1993; 59: 459-460.

1101Naylietd SG, Karp JE, Ford LG, Dorr FA, Kramer B.S.

Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 1991;83: 1450-1459. 1111Gherman RB, Parker MF, Macri Cl. Granulosa cell tumor of the ovary associatedwith antecedenttamoxifen use. Obstet Gynecol 1994;84: 717-719. 1121Shoham Z. Epidemiology, etiology and fertility drugs in ovarian epithelial carcinoma: where are we today? Fertil Steril 1994;62: 433-448. iI31 Rossing MA, Daling JR, WeissNS, Moore DE, Self SG. Ovarian tumors in a cohort study of infertile women. N Engl J Med 1994;331: 771-776. iI41 Jordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res 1987;47: 624-630. iI51 Sunderland MC, Osborne CK. Tamoxifen in premenopausal patients with metastatic breast cancer. A review. J Clin Oncol 1991;9: 1283-1297. 1161Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome associatedwith tamoxifen given to the mother during gestation. J Am Med Assoc 1994;271: l905- 1906. 1171 Chyong-Huey L, Hsueh S, Au-Shine C, Yung-Kuei S. Successfulpregnancy after tamoxifen and megestrol acetate therapy for endometrial carcinoma. Br J Obstet Gynaecol 1994; 101: 547-549. ltsl Buvat J, Buvat-Herbaut M, Marcolin G, ArdaensBoulier K. Antiestrogens as treatment of female and male infertilities. Horm Res 1987;28: 219-229.

V.J. Assikis, V.C. Jordan /International

Journal of Gynecology & Obstetrics 49 (1995) 241-257

1191 Ferrazzi E, Cartei G, Mattarazzo R, Fiorentino M. Oestrogenlike effect of tamoxifen on vaginal epithelium. Br Med J 1977; 1: 1351-1352. [20] Boccardo F, Bruzzi P, Rubagotti A, Nicolo GM, Rosso R. Estrogen-like action of tamoxifen on vaginal epitheliurn in breast cancer patients. Oncology 1981; 38: 281-285. [21] De Muylder X, Neven P, De Somer M, Van Belle Y, Vanderick G, et al. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynecol Obstet 1991;36: 127-130. [22] Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder Y. Tamoxifen and the uterus and the endometrium [letter]. Lancet 1989;i: 375. [23] Gal D, Kopel S, Bashevkin M, Lebowicz J, Lev R, et al. Oncogenic potential of tamoxifen on endometria of postmenopausal women with breast cancer - preliminary report. Gynecol Oncol 1991;42: 120-123. [24] Kedar RP, Boume TH, Powles TJ, Collins WP, Ashley SE, et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 1994;343: 1318-1321. [25] Cohen 1, Rosen DJD, Shapira J, Cordoba M, Gilboa S, et al. Endometrial changes with tamoxifen: comparison between tamoxifen-treated and nontreated asymptomatic, postmenopausalbreast cancer patients. Gynecol Oncol 1994; 52: 185-190. [26] Lahti E, Blanc0 G, Kauppila A, Apaja-Sarkinnen M, Taskinen PJ, et al. Endometrial changes in postmenopausalbreast cancer patients receiving tamoxifen. Obstet Gynecol 1993;81: 660-664. 1271 Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder Y. Hysteroscopic follow up during tamoxifen treatment. Em J Obstet Gynecol Reprod Biol 1990; 35: 235-238. [28] Ford MRW, Turner MJ, Wood C, Soutter WP. Endometriosis developing during tamoxifen therapy. Am J Obstet Gynecol 1988; 158: 1119. [29] Morgan MA, Gincherman Y, Mikuta JJ. Endometriosis and tamoxifen. Int J Gynecol Obstet 1994;45: 55-57. [30] Haber GM, Behalek YF. Preliminary report on the use of tamoxifen in the treatment of endometriosis. Am J Obstet Gynecol 1987; 156: 582-586. [31] Cohen I, Altaras MM, Lew S, Tepper R, Beyth Y, et al. Ovarian endometrioid carcinoma and endometriosis developing in a postmenopausal breast cancer patient during tamoxifen therapy: a casereport and review of the literature. Gynecol Oncol 1994; 55: 443-447. [32] Rullo S, Tagliaferri T, Bandierra F, Fiorelli C, Felici A, et al. Uterine changes during tamoxifen therapy. Clin Exp Obstet Gynecol 1993;20: 116-l 19. 1331 Dilts PV, Hopkins MP, Chang AE, Cody RL. Rapid growth of leiomyoma in patients receiving tamoxifen. Am J Obstet Gynecol 1992; 1663: 167-168. (341 Hulka CA, Hall DA. Endometrial abnormalities associated with tamoxifen therapy for breast cancer: sonographic and pathologic correlation. Am J Roentgenol 1993; 160: 809-812.

255

[35] Corley D, Rowe J, Curtis MT, Hogan WM. Noumoff JS, et al. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Ohstet Gynecol 1992;79: 11i-l 16. [36] Nuovo MA, Nuovo GJ, McCaffrey RM, Levine RU. Barron B, et al. Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Pathol 1989; 8: 125-131. [37] Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium [letter]. Lancet 1989; i: 375-376. [38] Fisher B, Costantino JP, Redmond CK, Fisher ER. Wickerham DL, et al. Endometrial cancer in tamoxifentreated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B14. J Nat1 Cancer Inst 1994; 86: 527-537. [39] Seoud MAF, Johnson J, Weed JC. Gynecologic tumors in tamoxifen-treated women with breast cancer. Obstet Gynecol 1993;82: 165-169. [40] Bocklage T, Lee KR, Belinson JL. Uterine miillerian adenosarcoma following adenomyoma in a woman on tamoxifen therapy. Gynecol Oncol 1992;44: 104-109. [41] Silva EG, Tomos CS, Follen-Mitchell M. Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: the effects of tamoxifen. Int J Gynecol Pathol 1994; 13: 248-258. [42] Altaras MM, Aviram R, Cohen I, Cordoba M. Yarkoni S, et al. Role of prolonged stimulation of tamoxifen therapy in the etiology of endometrial sarcomas.Gynecol Oncol 1993;49: 255-258. [43] Fomander T, Hellstrom AC, Moberger B. Descriptive clinicopathologic study of 17 patients with endometrial cancer during or after adjuvant tamoxifen in early breast cancer. J Nat1 Cancer Inst 1993;85: 1850-1855. [44] Mignotte H, Sasco AJ, Lasset C, Saez S, Rivoire M. et al. Traitement adjuvant du cancer du sein par tamoxifene et cancer de I’endomttre. Bull Cancer 1992;79: 969-977. (451 Magriples U, Naftolin F, Schwartz PE, Carcangiu ML. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 1993; I I: 485-490. [46] Barakat RR, Wong G, Curtin JP, Vlamis V, Hoskins WJ. Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associatedwith a higher incidence of adverse histologic features. Gynecol Oncol 1994;55: 164-168. [47] Tosi P, Sfona V, Santopietro R. Estrogen receptor content immunohistochemically determined by monoclonal antibodies in endometrial stromal sarcomas. Obstet Gynecol 1989;73: 75-78. [48] Press MF, Scully RE. Endometrial ‘sarcomas’ complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy. Gynecol Oncol 1985;21: 135- 154. ]49] Altaras MM, Jaffe R, Cohen I, Gruber A. Yamai-Jubar I, Bernheim J. Role of prolonged estrogen stimulation in the pathogenesisof endometrial sarcomas:two casesand a review of the literature. Gynecol Oncol 1990: 38: 273-277. [SO] Ewertz M, Machado SG, Boice JD Jr, JensenOM. Endometrial cancer following treatment for breast cancer: a

256

V.J. Assikis, V.C. Jordan /International

Journal of Gynecology & Obstetrics 49 (1995) 241-257

case-control study in Denmark. Br J Cancer 1984; 50: 687-692. 151) Kelsey JL, Whittemore AS. Epidemiology and primary prevention of cancers of the breast, endometrium and ovary. A brief overview. Ann Epidemiol 1994;4: 89-95. [52] Adami HO, Kruesmo UB, Bergkvist L, Person I, Pettersson B. On the age-dependent association between cancer of the breast and of the endometrium. A nationwide cohort study. Br J Cancer 1987;55: 77-80. [53] Bokhman JB, Maximov SJ. Relative risk of development and active detection of primary multiple endometrial, breast and ovarian cancer. Eur J Gynaecol Oncol 1993; 14: 114-118. [54] Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens.Cancer Treat Rep 1985;69: 237-238. [55] Hakes T, Currie V, Kaufman R, Bosl G, Sordillo P, Rosen P, et al. Low dose continuous vs. high dose intermittent CMF VPT adjuvant therapy for stage II breast cancer [abstract]. Proc Am Sot Clin Oncol 1984;3: 122. [56] Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri [letter]. Lancet 1988;ii: 563. [57] Stewart HJ. The Scottish trial of adjuvant tamoxifen in node-negative breast cancer. Scottish Cancer Trials Breast Group. Monogr Nat1 Cancer Inst 1992; II: 117-120. [58] Dauplat J, Le Bouedec G, Achard JL. Adenocarcinome de I’endomttre chez 2 malades prenant du tamoxifene. PresseMed 1990; 19: 380-381. [59] Malfetano J. Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients. Gynecol Oncol 1990;39: 82-84. [60] Mathew A, Chabon AB, Kabakow B, Drucker M, Hirschman RJ. Endometrial carcinoma in five patients with breast cancer on tamoxifen therapy. NY State J Med 1990;90: 207-208. [6l] Le BouedecG, Dauplat J, Cure H, Achard JL, Feillel V. Endometrial side effectswith tamoxifen for breast cancer [abstract]. Eur J Cancer 199026: 91A. [62] Le BouedecG, Dauplat J. Cancer de I’endomttre du aux anti-estrogens. Rev Fr Gynecol Obstet 1992; 87: 345-348. [63] Atlante G, Pozzi M, Vincenzoni C, Vocaturo G. Four case reports presenting new acquisitions on the association betweenbreast and endometrial carcinoma. Gynecol Oncol 1990;37: 378-380. [64] Rasmussen KL, Nielsen KM. Development of endometrial cancer during tamoxifen therapy. Ugeskr Laeg 1991; 153: 2638. [65] Spinelli G, Bardazzi N, Citernesi A, Fontanarosa M, Curie] P. Endometrial carcinoma in tamoxifen-treated breast cancer patients. J Chemother 1991;3: 267-270. [66] Andersson M, Storm HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Nat] Cancer Inst 1991;83: 1013-1017. [67] Lang-Averous G, Rupp K, Wehner H, Dallenbach-

Hellweg G. Stellenwert der Steroidhormone und biologischverwandter Substanzenin der Aetiologie des Endometriumcarcinoms. Verh Dtsch Ges Pathol 1991; 75: 366-369. [68] Ribeiro G, Swindell R. The Christie Hospital Adjuvant Tamoxifen Trial. Monogr Nat1 Cancer Inst 1992; 11: 121-125. [69] O’Neill, Rodriguez-Mojica W. Asymptomatic carcinoma of the endometrium in a patient on adjunctive tamoxifen therapy for carcinoma of the breast. Bol Asoc Med Puerto Rico 1992;84: 74-77. [70] Deprest J, Neven P, Ide P. An unusual type of endometrial cancer, related to tamoxifen? Eur J Obstet Gynecol Reprod Biol 1992;46: 147-150. [71] Segna RA, Dottino PR, Deligdisch L, Cohen CJ. Tamoxifen and endometrial cancer. Mt Sinai J Med 1992;59: 416-418. [72] Capurro I, Jorquera J, Rojo JA, Wistuba I. Two rare casesof a presentation of endometrial cancer. Rev Chil Obstet Ginecol 1992; 57: 351-355. [73] Uziely B, Lewin A, Brufman G, Dorembus D, MorYosef S. The effect of tamoxifen on the endometrium. Breast Cancer Res Treat 1993;26: 101-105. 1741 Krause A, Gerber B. Postmenopausalbleedings and endometrial carcinoma during tamoxifen therapy. Zentralbl Gynlkol 1994; 116: 44-47. [75] Ciatto S, Cecchini S, Bonardi R, Grazzini G. Ultrasonography surveillance of endometrium in breast cancer patients on adjuvant tamoxifen [letter]. Lancet 1994;343: 60. [76] Hopkins RE, Tasker M. Tamoxifen and the gynaecologist [letter]. Br J Obstet Gynaecol 1994; 101: 645. [77] Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994;47: 827-833. [78] van LeeuwenFE, Benraadt J, Coebergh JWW, Kiemeney LALM, Gimbrere CHF, et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 1994;343: 448-452. [79] Dallenbach-Hellweg G, Hahn U. Mutinous and clear cell adenocarcinomasof the endometrium in patients receiving antiestrogens (tamoxifen) and gestagens. Int J Gynecol Pathol 1995; 14: 7-15. [80] Lahti E, Vuopala S, Kauppila A, Blanc0 G, Ruokonen A, et al. Maturation of vaginal and endometrial epithelium in postmenopausal breast cancer patients receiving long-term tamoxifen. Gynecol Oncol 1994; 55: 410-414. [al] National Cancer Institute. SEER Cancer Statistics Review 1973-1990, Document 93-2789. Bethesda, MD: NCI, 1993. [82] Horowitz RI, Feinstein AR. Estrogens and endometrial cancer. Responseto arguments and current status of an epidemiologic controversy. Am J Med 1986; 81: 503-507. [83] Bonte J, Ide P, Billiet G, Wynants P. Tamoxifen as a possible chemotherapeutic agent in endometrial adenocarcinema. Gynecol Oncol 1981; 11: 140-161.

V.J. Assikis. V. C. Jordan / Internarional Journal of Gynecology & Obstetrics 49 i 199.5) 241-257 [84] Ravn SH, Rosenberg J, Bostofte EP. Postmenopausal hormonal replacement therapy - clinical implications. Eur J Obstet Gynecol Reprod Biol 1994; 53: 81-93. [85] Gibson DF, Johnson DA, Langan-Fahey SM. Lababidi MK, Wolberg WH, Jordan VC. The effects of intermittent progesterone upon tamoxifen inhibition of tumor growth in the 7, I2-dimethylbenzanthracene rat mammary tumor model. Breast Cancer Res Treat 1993; 27. 283-287.

257

[86] Robinson SP, Jordan VC. Reversal of the antitumor effects of tamoxifen by progesterone in the 7,12dimethylbenzanthracene rat mammary carcinoma model. Cancer Res 1987; 47: 5386-5390. [87] Mouridsen HT. Ellemann K, Mattson W, Palshof T. Daehnfeldt JL. et al. Therapeutic effect of tamoxifen versus tamoxifen and medroxyprogesterone acetate in advanced breast cancer in postmenopausal women Cancer Treat Rep 1979; 63: 171-175.