Efficacy of sequential cyclical hormonal therapy in endometrial cancer and its correlation with steroid hormone receptor status

GYNECOLOGIC ONCOLOGY 31, 327--337 (1988)

Efficacy of Sequential Cyclical Hormonal Therapy in Endometrial Cancer and Its Correlation with Steroid Hormone Receptor Status 1 J. AYOUB, 2 P. AUDET-LAPOINTE, Y. METHOT, J. HANLEY, R. BEAULIEU, R. CHEMALY, A, CORMIER, J. P. DIARY,P. DROUIN,P. GAUTHIER, J. P. GUAY, D . H u s s o N , F . LABRIE, B . LAMBERT, J. LATREILLE, R . MANDEVILLE, B . MICHON, R . PICHET, S. SIDRAC, A . S1MARD, P. SIMARD, G . STANIMIR, R . VAUCLAIR, AND J. VIGEANT Le R(seau Interhospitalier de Canc(rologie, Universit~ de Montreal (RICUM) and the McGill Cancer Center, Montreal, Quebec, Canada H2L 41(8 Received December 29, 1987 Forty-six eligible women with metastatic endometrial cancer were randomly allocated to receive monthly cycles of either CAF (cyclophosphamide, adriamycin, 5-fluorouracil) or CAF plus Provera 200 nag daily for 3 weeks followed cyclically by Tamoxifen 20 mg daily for 3 weeks. Overall response rates of 15 and 43% were seen with CAF and CAF plus hormonal therapy. Using a multivariate analysis of the results, this difference is significant (P value 0.05). In 8 patients with operable endometrial cancer, negative estrogen receptor concentration (ER < 15 fmole/mg protein) and Grade 3 disease, the clinical course was aggressive in 4 patients with systemic and local relapse. In 10 other similar patients (negative ER and Grade 3) who received adjuvant cyclical hormonal therapy only 1 relapsed and the other 9 are disease-free for an average of more than 31 months. Sequential cyclical hormonal therapy with ER and progesterone receptor analysis has a place in the management of endometrial carcinoma. © 1988AcademicPress, Inc.

INTRODUCTION In industrialized countries, endometrial cancer is the most common invasive malignant tumor of the female reproductive tract [1]. The classical curative treatment in localized disease is hysterectomy with bilateral salpingo-ovariectomy with or without pelvic radiotherapy [2]. A significant number of patients, however, will develop metastases that require systemic treatment with either hormonal or cytotoxic chemotherapy [3]. Doxorubicin, alone or in combination with other J This research was supported by a grant from the National Cancer Institute of Canada, ICI Americas, Inc., and Upjohn of Canada. 2 To whom reprint requests and correspondence should be addressed at Division of Clinical Research, Institut du Cancer de Montr6al, 1560, Sherbrooke Street Est, Montr6al, Qu6bec H2L 4K8. 327 0090-8258/88 $1.50 Copyright © 1988by AcademicPress, Inc. All rightsof reproductionin any form reserved.

328

AYOUB ET AL.

antineoplastic agents, has been used by several investigators for the treatment of advanced disease. Although the percentage of responders is around 30%, the majority of patients have only a partial response with a median duration ranging from 4 to 10 months [4,5]. As for progestin therapy, a collaborative study has confirmed its value in the management of advanced endometrial cancer. It produces a response rate in one-third of the patients with a 31% 5-year survival [6]. This response is most probably related to the presence of progesterone receptors (PR) within the tumor [7]. Unfortunately, progestin treatment leads to depletion of PR within the target tissue and accordingly, a short duration of response. On the other hand, the antiestrogen Tamoxifen, has been shown to increase PR concentration in rat uteri [8] and recently in endometrial carcinoma transplanted into nude mice [9]. Its clinical effectiveness was first tested by Swenerton [10] and showed a 30% response rate. A hypothesis has thus been put forward by Mortel, et al. that Tamoxifen might enhance the degree and duration of response of endometrial cancer to medroxyprogesterone therapy [11]. The present report accordingly details the results of a randomized prospective clinical trial to determine the therapeutic value of adding sequential cyclical hormonal therapy (Provera-Tamoxifen) to combination chemotherapy (cyclophosphamide-adriamycin and 5-fluorouracil) in the management of metastatic or recurrent endometrial cancer. It also points to the therapeutic implications of steroid hormone receptor analysis based on the results of estrogen and PR concentrations in patients with localized endometrial cancer receiving postoperative adjuvant cyclical hormonal therapy. MATERIALS AND METHODS

This multi-institutional trial was initiated in September 1981. Eligibility criteria included a histologic diagnosis of adenocarcinoma of the endometrium in patients less than 75 years of age, with a performance score of 2 or better (ECOG) and who had no history of a second primary (except cured basal cell or squamous cell skin cancer). They had to show evidence of adequate cardiac, renal, hepatic, and hematopoietic functions. All eligible patients signed an informed consent. Clinical staging was done using the FIGO criteria as adopted by the American Joint Committee [12]. Prerandomization treatments. All patients had as local treatment a total abdominal hysterectomy with bilateral salpingo-ovariectomy and lymph node sampling. This was followed, 4 to 6 weeks later, by locoregional radiotherapy. It consisted of an external midpelvic irradiation at a dose of 4500 cGy plus an intravaginal irradiation for the superior one-third of the vagina in a dose of 1500 cGy at 5 mm depth under the vaginal mucosa. Randomized systemic treatment. From September 1981 through February 1987, 262 eligible women with endometrial cancer were classified into one of the following three groups according to their clinical stage and their subsequent systemic treatments. Group I patients. Group I included 163 patients with Stage I operable adenocarcinoma of the endometrium. Patients with Grade 1 or 2 cellular differentiation

CYCLICAL H O R M O N A L THERAPY IN ENDOMETRIAL CANCER

329

were only eligible if they had more than a two-third myometrial invasion. All patients with Grade 3 undifferentiated cells were eligible. After local treatment, patients were prospectively randomized either into a control arm or into an adjuvant sequential cyclical hormonal treatment which consisted of medroxyprogesterone acetate (Provera) 200 mg/dag given orally for 3 weeks followed by Tamoxifen 20 mg/day orally for 3 weeks. This was given for 1 year. Group H patients. Group II consisted of 53 patients with high-risk localized operable disease, namely patients with one or more of the following: positive lymph nodes, cervical involvement, and ovarian involvement. Patients were prospectively randomized after local treatment to receive either adjuvant chemotherapy or adjuvant chemohormonal therapy for 1 year. The combination chemotherapy consisted of 4-week cycles: cyclophosphamide (400 mg/m 2 intravenously (iv) on Days 1 and 8), adriamycin (30 mg/m 2 iv on Day 1), and 5-fluorouracil (400 mg/m 2 iv on Days 1 and 8) (CAF). Conventional dose reductions were to be used when toxicity was encountered. When a patient had more than one toxicity, the lowest appreciable dose was given. Treatment was delayed due to severe anorexia, nausea, vomiting, diarrhea, intercurrent infection, or hematopoietic toxicity. The sequential cyclical hormonal treatment was the same as the one given to Group I patients. Group III patients. Group III included 46 patients, with advanced de novo Stage IV disease or recurrent and metastatic disease, who were no longer suitable for curative surgical or radiotherapy treatment. Patients with recurrent disease had already been locally treated in the above manner, i.e., hysterectomy plus locoregional irradiation. Patients admitted into this group were not eligible if they had received previous systemic hormonal or chemotherapy. Measurable or evaluable disease had to be present. Eligible patients were prospectively randomized to chemotherapy or chemohormonal therapy after stratification on the basis of advanced pelviabdominal disease versus distant metastatic disease. Treatment was stopped in the presence of progressive disease or severe toxicity. In patients who achieved a complete remission (CR) chemotherapy was continued for three further cycles. Sequential cyclical hormonal treatment was however continued indefinitely. Some patients in this group were allowed to receive palliative radiotherapy to relieve local distressing symptoms. Evaluation. Clinical, hematologic, biochemical, roentgenologic, and radionucleide assessments were made to determine initial staging and response to therapy. In their follow-up, patients in Groups I and II had, besides a clinical examination and a biochemical profile, a chest X-ray, an abdominopelvic ultrasound, and a vaginal cytology every 6 months. The following response criteria were used: disease-free interval, evidence of relapse, and survival. In Group III patients, tumor measurements, hemogram, and liver/renal function tests were repeated before each cycle of treatment and a chest X-ray, abdominopelvic ultrasound, and any initially positive examination were obtained every 3 months. Response criteria were based on those suggested by the International Union against Cancer (UICC) [13]. Standard ECOG criteria were used to assess toxicity [14]. Steroid receptor analysis. Following hysterectomy, a sample of neoplastic endometrial tissue was removed by the pathologist, rinsed in buffer, and immediately

330

AYOUB ET AL.

frozen in liquid nitrogen for short-term storage. Every 2 weeks, all preserved samples were sent in dry-ice containers to an independent laboratory (F.L.). Estrogen (ER) and PR concentrations in the endometrial tumor samples were determined by dextran-coated charcoal assay [15]. Specific binding was calculated by Scatchard analysis [16] using a computer program [17]. For the purposes of this study and as reported in the literature [7] bindings of > 15 fmole/mg protein for both ER and PR were considered to be positive. Statistical methods. Analysis of treatment differences in response percentages (complete and partial) was done using a multivariate linear logistic regression model [18]. Survival function was estimated by the product limit method of Kaplan and Meier [19]. The word "significant" is used with P values <0.05. All tests use two-sided alternatives. RESULTS

Analysis of the Addition of Cyclical Hormonal Therapy to Chemotherapy for Advanced Endometrial Cancer (i.e., Group III Patients) Forty-six patients were randomized to receive chemotherapy or chemohormonal therapy. Three patients refused to begin chemotherapy, so that 43 patients were evaluable. Of these, 20 were assigned to chemotherapy and 23 to chemohormonal therapy. The age at entry in the study ranged from 40 to 74 years, with a median of 63 years. The patient characteristics by treatment are shown in Table 1. Randomization was stratified by the site of advanced disease (pelviabdominal vs distant metastases). It can be seen that the treatment groups are well balanced with respect to whether the disease is newly diagnosed (i.e., de novo Stage IV disease) or recurrent, and with respect to whether patients had received palliative radiation therapy or not, prior to commencing chemo- or chemohormonal therapy. Objective tumor responses (complete plus partial remission) were reported for 13 patients, as is described in Table 2. There is a difference in response rates (RR) between the two treatment groups, with a 15% RR for patients treated with TABLE 1 PATIENT CHARACTERISTICSIN ADVANCED ENDOMETRIAL CANCER (GRouP I!I) Pelviabdominal disease

Number of patients Newly diagnosed Stage IV (%) Palliative radiotherapy (%) Vaginal relapse (%)

Distant metastasis

Total

Rx E"

Rx F b

Rx E

Rx F

Rx E

Rx F

11 5 (45%) 5 (45%) 4 (36%)

14 6 (43%) 8 (57%) 4 (29%)

9 2 (22%) 5 (56%)

9 3 (33%) 3 (33%)

20 7 (35%) 10 (50%)

23 9 (39%) 11 (48%)

" Rx E, combination chemotherapy. b Rx F, chemotherapy + cyclical hormonal therapy.

331

CYCLICAL HORMONAL THERAPY IN ENDOMETRIAL CANCER TABLE 2 OBJECTIVE TUMOR RESPONSE 1N ADVANCED ENDOMETRIAL CANCER (GROUP III PATIENTS)

Response

Rx Ea

Rx F h

Complete Partial

12}15%

~}43%

17 20

Stable/progression Total

14 23

a Rx E, combination chemotherapy. b Rx F, chemotherapy + cyclical hormonal treatment.

chemotherapy and a 43% RR for patients receiving chemohormonal therapy. Using a multivariate linear logistic regression model, which takes prior radiotherapy into account, this difference is statistically significant with a P value of 0.05. As can be seen from Table 3, patients who received palliative radiotherapy (in each treatment group) are more likely to respond (10/22) than those who did not (2/21) while the response rate does not seem to depend on whether the disease was newly diagnosed or recurrent. Likewise, there is no evidence that the response rate is higher in those with local (7/25) rather than distant metastases

(5/18). The duration of remission, defined as the time from response to relapse, did not differ so far significantly between chemotherapy and chemohormonal therapy patients (averages, 10 and 25 + months, respectively). It is still continuing, however, beyond 40 months in four patients in CR who were on chemohormonal therapy. The survival curves for Group III patients, estimated by the method of Kaplan and Meier, for the two treatment groups are depicted in Fig. 1. They show a TABLE 3 OBJECTIVE TUMOR RESPONSE IN ADVANCEDENDOMETRIALCANCER (GRouP IIl PATIENTS) IN RELATION TO VARIOUS PATIENT CHARACTERISTICS

Extent of disease Local

Rx E" Disease Newly diagnosed Recurrent Radiation therapy

Rx F b

Distant

Tot.

Rx E

Rx F

Tot.

Total Nos. in Rx E Rx F

Total No. of patients

0/5" 1/6

3/6 3/8

3/11 4/14

0/2 2/7

2/3 1/6

2/5 3/13

0/7 3/13

5/9 4/14

No

0/6

0/6

0/12

0/4

2/5

2/9

0/10

2/11

2/21

Yes Overall

1/5 1/11

6/8 6/14

7/13 7/25

2/5 2/9

1/4 3/9

3/9 5/18

3/10 3/20

7/12 9/23

10/22 12/43

Rx E, chemotherapy. b Rx F, chemohormonal therapy. c Entries represent number responding/number treated.

5/16 7/27

332

AYOUB ET AL.

too~ >~ 80

[ [

~

~

~

chemo-hormonal therapy ..... chemotherapy

-,

6°t

1;

....

20[

~----* 3

6

9

12

15

18

21

24

MONTHS

FIG. 1.

Survival curves in metastatic endometrial cancer (Method of Kaplan and Meier [19]).

median survival of 11 months for patients on chemotherapy (13/20 are dead) and 14 months for patients on chemohormonal therapy (12/23 are dead). This difference is not statistically significant (P > 0.5). Toxicity to chemotherapy was analyzed according to the ECOG toxicity criteria. As shown in Table 4, 14% of the patients developed a moderately severe myelotoxicity (essentially a granulocytopenia) while 12% had moderately severe nausea and vomiting and 7% developed a chemical cystitis. Nevertheless, 75% of the patients were able to receive their optimal dose of chemotherapy. Hormonal therapy-related toxicity revealed a high incidence of phlebitis (5/23).

Relationship between Steroid Hormone Receptor Status, Clinical Evolution of the Disease, and Cyclical Hormonal Therapy in Patients with Localized Operable Endometrial Cancer (i.e., Group I and H Patients) Of the 216 women with localized operable endometrial cancer admitted into Group I and II patients (163 and 53, respectively) ER and PR analysis of a sample of neoplastic endometrial tissue was only done in 35 cases. Hormonal receptor analysis was also available in 70 other patients with localized operable disease that were ineligible to the study mostly because of refusal of randomization. They were however treated locally in the same way and regularly followed-up. This brings the total number of patients with localized operable disease and receptor analysis to 105. Table 5 shows ER and PR concentrations in the two TABLE 4

TOXICITYTOCHEMOTHERAPYIN PATIENTSWITHADVANCEDENDOMETRIALCANCER(GROUPIII) Toxicity Hematologic Nausea/vomiting Cystitis

Mild (2)

Moderate (3) a

Severe (4) a

Mod.-Severe % total

4 6 0

1 1 0

5 4 3

14 12 7

a ECOG toxicity criteria--Grade 3: neutrophils 2.0-3.0 x 103/mm 3, controlled nausea and vomiting; Grade 4: neutrophils 1.0-2.0 x 103/mm 3, uncontrolled vomiting.

CYCLICAL HORMONAL THERAPY IN ENDOMETRIAL CANCER

333

TABLE 5 RELATION BETWEEN RECEPTOR CONCENTRATION RATE OF RELAPSE AND CYCLICAL HORMONAL THERAPY IN PATENTIS WITH LOCALIZED OPERABLE ENDOMETRIAL CANCER

Treatment Without hormonal Rx With hormonal Rx Total

Number of Patients

ER*

PR*

Relapses

74 (20)6 31 (15) 105 (35)

121 86

282 374

5 (4) 1 (1) 6 (5)

a The number in parentheses represents the number of patients with receptor analysis within the randomized study (Group I and II patients). * Mean values in fmole/mg protein.

therapeutic groups (without and with adjuvant cyclical hormonal therapy). Six patients relapsed and 5 of them are in the group of patients who did not receive cyclical hormonal therapy. Their characteristics are presented in Table 6. Five out of the 6 relapses have a negative ER concentration (15 fmole/mg protein) and a Grade 3 disease. Moreover, an analysis of all patients with negative ER (36 patients) reveals that only 1 of the 16 patients who received a sequential cyclical hormonal therapy relapsed. On the other hand, as seen in Table 7, out of the 20 patients who did not receive adjuvant hormonal therapy, 4 relapsed (20%) with an aggressive clinical course. In the present receptor analysis, 26 women had Grade 3 disease. Table 8 reveals the characteristics of these patients. Eight patients who had positive ER concentration are without evidence of disease after an average disease-free interval (DFI) of more than 3½ years. In patients with negative ER concentration and no adjuvant treatment, the clinical course is aggressive with 4/8 relapses and a short DFI (not related to the degree of myometrial invasion). If, on the other hand, they receive an adjuvant sequential cyclical hormonal therapy, the clinical course is good, with only one relapse (1/10 patients) after an average DFI of 31 months. One notes however that this single patient who relapsed with malignant ascites TABLE 6 CHARACTERISTICS OF THE SIX RELAPSESIN PATIENTS WITH LOCALIZEDOPERABLEENDOMETRIALCANCER Patient's initials

Stage/grade

ER*

PR*

DFI"

L.E.

IA/3

10

30

3

E.M. B.S.

IIIA/3 IB/3

14 5

315 0

24 20

11/2 111/3 IA/3

42 7 0

305 1 527

21 12 6

B.L. B.R. P.M. +

Site of relapses Lung Abdominal carcinomatosis Lung Vagina and small intestine Paraaortic nodes Malignant ascites

a DFI, disease-free interval in months. b This is the only relapsing patient who received cyclical hormonal therapy (had only one cycle). * Mean values in fmole/mg protein.

334

AYOUB ET AL. TABLE 7 ANALYSIS OF PATIENTS WITH LOCALIZED OPERABLE ENDOMETRIAL CANCER AND NEGATIVE ER CONCENTRATION (<15 fmole/mg PROTEIN)

Number of patients

Treatment Without hormonal Rx With hormonal Rx Total

ER*

PR*

Relapses

9 9

125 211

4 (3) 1 (t) 5 (4)

20 (9)4 16 (10) 36 (19)

° The number in parentheses represents the number of patients with receptor analysis within the randomized study (Group I and II patients). * Mean values in fmold/mg protein.

had not received treatment as optimally described, i.e., pelvic radiotherapy was started 2 months after hysterectomy and only one cycle of sequential cyclical hormonal treatment was given 2 months after the end of radiotherapy. The difference between the two groups as calculated by a two-sided Fisher exact test is not yet statistically significant. (P value 0.03 if this patient is excluded and 0.12 if she is included). DISCUSSION This randomized prospective multi-institutional study shows that there is a potential advantage for CAF therapy combined with cyclical Provera-Tamoxifen over CAF therapy alone in the treatment of metastatic or recurrent adenocarcinoma of the endometrium. The beneficial effect of cyclical hormonal therapy can be explained by our concomitant ER and PR concentration results in localized operable disease. They reveal that patients with negative ER have more undifferentiated neoplasms and a higher tendency to relapse which can be significantly diminished by adjuvant cyclical hormonal therapy. The prognostic value of ER TABLE 8 RELATION BETWEEN E R CONCENTRATION CLINICAL COURSE OF THE DISEASE AND CYCLICAL HORMONAL THERAPY IN PATIENTS WITH LOCALIZED OPERABLE GRADE 3 ENDOMETR1AL CANCER

ER

Positive

Negative

Adjuvant hormonal Rx None Cyclical hormonal Rx None Cyclical hormonal Rx Total

Number of patients

Number of relapses

ER*

PR*

DFI"

6 (3) b

164

277

44 +

0

2 (0) 8 (4)

91 6

142 50

45 + 16 +

0 4 (3)

10 (9) 26 (16)

7

303

31 +

1 (1) 5 (4)

DFI, disease-flee interval in months. b The number in parentheses represents the number of patients with receptor analysis within the randomized study (Group I and II patients). * Mean values in fmole/mg protein.

C Y C L I C A L H O R M O N A L T H E R A P Y IN E N D O M E T R I A L C A N C E R

335

and PR measurements and the role of hormonal therapy is now better appreciated. Negative PR levels in anaplastic carcinomas were reported by many investigators [7,11]. However, only 15% of such tumors respond to progestins [5]. Recently, it was shown that ER status is also an important prognostic factor in patients with endometrial cancer. In a series of 62 patients, Martin et al. reported that those with a negative ER level had a significantly shorter median survival (62.4 months) than those with a positive ER concentration (169 months) [20]. On the basis of the success of the antiestrogen Tamoxifen (TAM) in breast cancer, Swenerton and Bonte et al. used it in a small group of metastatic patients with response rates similar to those achieved with Provera alone [10,21]. This was followed subsequently by the use of combinations of TAM and Provera in a small number of patients with benefits not significantly different from either alone [22,23]. As for the value of combined chemotherapy and progestins, it was reported by many cooperative groups with results that look slightly superior to either alone [24,25]. The independent contribution of the cytotoxic agents and the hormone cannot unfortunately be assessed in these single-arm studies. In our randomized study on metastatic disease, the results of the combination chemotherapy arm are similar to those reported by the Eastern Cooperative Oncology Group [26]. Chemohormonal therapy, on the other hand, shows a significantly better response rate with a 26% complete remission rate for a period of more than 38 months. This period of remission in complete responders exceeds any one published so far in patients with metastatic disease receiving chemohormonal therapy [24,25]. One of the factors that probably helped in obtaining the above results is the administration of palliative radiotherapy. Fifty percent of the patients in our metastatic study received this local therapeutic modality. This was equally distributed between the two therapeutic regimens and was taken in consideration in the statistical multivariate analysis of the results. However, as shown in Table 3, most of the responders were among the patients who received chemohormonal therapy and palliative radiation. Our utilization of a sequential cyclical schedule of Provera followed by TAM stems from Mortel's hypothesis which postulates that TAM may increase the degree and duration of response of endometrial carcinoma to progestin therapy [9]. It is well known that Provera alone rapidly depletes PR [26]. On the other hand, TAM alone increases PR concentration [27,28]. We felt accordingly that a cyclical use of these two agents in therapeutic doses will ensure a continuous tumor inhibition. This prediction has been partly confirmed recently in the experimental model of human endometrial carcinoma grown in athymic nude mice. In this model, TAM followed by Provera is superior to the latter alone for the treatment of receptor-positive endometrial adenocarcinoma. In receptor-negative tumors, however, neoplastic growth was very rapid and several animals were dead before or during progestin treatment [9]. Our clinical study in localized operable disease confirms the aggressive course in patients with undifferentiated tumors and negative ER levels. However, contrary to what has been published [22], it is this particular group of patients with a bad prognosis that benefits the most from cyclical hormonal treatment. Our explanation is that Provera blocks whatever PR is present in the tumor, thus initiating tumor

336

avouB ET aL.

inhibition. The subsequent administration of TAM produces an increase in PR concentration which at its turn will be blocked by cyclical Provera. This schedule ensures a continuous tumor inhibition. In our study, it led to a prolonged diseasefree interval (more than 31 months) and only 1 relapse in l0 patients with negative ER level and Grade 3 operable disease as compared to an aggressive clinical course and 4/8 relapses in patients who did not receive such a treatment. These results have not yet reached statistical significance and need to be confirmed by further receptor analysis and accrual of patients in the ongoing part of our randomized multiinstitutional clinical trial in operable endometrial cancer (i.e., Group I and Group II patients). In conclusion, ER and PR analysis with consequent cyclical hormonal therapy is indicated in the management of endometrial carcinoma.

ACKNOWLEDGMENTS The following institutions and investigators participating in the R6seau Interhospitalier de Canc6rologie de l'Universit6 de Montr6al (RICUM) and the McGill Cancer Center contributed to this study. Institutions

Investigators

D6partement d'Epid6miologie, McGill Hanley, James, M.D. HOpital G6n6ral de Montr6al Boileau, Guy, M.D.; Freedman, Carolyn, M.D.; Seymour, Robert, M.D.; Thirlwell, Michael, M.D. H6pital Notre-Dame Audet-Lapointe, Pierre, M.D.; Ayoub, Joseph, M.D.; Cormier, Andr6, M.D.; Drouin, Pierre, M.D.; Gauthier, Philippe, M.D.; Guay, Jean-Pierre, M.D.; M6thot, Yvan, M.D.; Vauclair, Ren6, M.D. Gelfand, Morrie, M.D.; de St-Victor, Jean, M.D. H6pital Sir Mortimer Davis Beaulieu, Raymond, M.D.; Boivin, Yvan, M.D.; Chebeir, HOtel-Dieu de Montrdal Samir, M.D.; D6ry, Jean-Paul, M.D.; Lambert, Bernard, M.D.; Latreille, Jean, M.D., Mont6 Marc, M.D.; Pretty, Harry, M.D.; Simard, Paul, M.D.; Neemeh, Jean, M.D. Ayoub, Joseph, M.D.; Husson, Danielle, R.N.; Simard, Institut du Cancer de Montr6al Antoine, Ph.D. Hazel, Bernard, M.D.; Lamoureux, Christian, M.D.; Maisonneuve-Rosemont Pichet, Robert, M.D.; Tun Nugyen, Huu, M.D. Roman, Ted, M.D.; Stanimir, G6rald W., M.D. Royal-Victoria Ch6maly, Ren6, M.D. Sacr6-Coeur Gari6py, Gilles, M.D.; Michon, Bertrand, M.D.; Thuot, Saint-Luc Claude, M.D.; Vigeant, Jacques, M.D. Arjane, Georges, M.D. Verdun

REFERENCES 1. Weiss, N. S., Szekeby, D. R., and Austin, D. F. Increasing incidence of endometrial cancer in the United States, N. Engl. J. Med. 294, 1259-1262 (1976). 2. Jones, H. W., III. Treatment of adenocarcinoma of the endometrium, Obstet. Gynecol. Surv. 30, 147-169 (1975). 3. Boronow, R. C. Endometrial cancer: Not a benign disease, Obstet. Gynecol. 47, 630-634 (1976). 4. Muggia, F. M., Chia, G., Reed, J. L., and Romney, S. L. Doxorubicin-cyclophosphamide: Effective chemotherapy for advanced endometrial adenocarcinoma, Amer. J. Obstet. Gynecol. 128, 314-319 (1977). 5. Deppe, G. Chemotherapy of endometrial carcinoma, in Chemotherapy of gynecologic cancer (D. Deppe, Ed.), A. R. Liss, Inc., New York, p. 139-150 (1984). 6. Reifenstein, E. C. The treatment of advanced endometrial cancer with hydroxyprogesterone caproate, Gynecol. Oncol. 2, 377-414 (1974).

CYCLICAL HORMONAL THERAPY IN ENDOMETRIAL CANCER

337

7. Creasman, W. T., Soper, J. T., McCarty, K. S., Jr., McCarty, K. S., Sr., and Clarke-Pearson, D. L. Influence of cytoplasmic steroid receptor content on prognosis of endometrial cancer, Amer. J. Obst. Gynecol. 151, 922-932 (1985). 8. Davies, P., Syne, J. S., and Nicholson, R. I. Effects of estradiol and Tamoxifen on Steroid hormone receptor concentration in rat uteri, Endocrinology 105, 1336-1342 (1979). 9. Zaino, R. J., Satyaswaroop, P. G., and Mortel, R. Hormonal therapy of human endometrial adenocarcinoma in a nude mouse model, Cancer Res. 45, 539-541 (1985). 10. Swenerton, K. D. Treatment of advanced endometrial adenocarcinoma with Tamoxifen, Cancer Treat. Rep. 64, 805-811 (1980). 11. Mortel, R., Levy, C., Wolff, J. P., Nicholas, J. C., Robel, P., and Baulieu, E. E. Female sex steroid receptors in post menopausal endometrial carcinoma and biochemical response to an antiestrogen, Cancer Res. 41, 1140-1147 (1981). 12. American Joint Committee on Cancer Staging and End--Results Reporting. Manual for staging o f cancer. AJC, Chicago (1978). 13. International Union against Cancer. Assessment of response to therapy in advanced cancer, Brit. J. Cancer 35, 292-295 (1977). 14. Oken, M. M., Creech, R. H., Tormey, D. C., et al. Toxicity criteria of the Eastern Cooperative Oncology Group. Amer. J. Clin. Oncol. 5, 649-655 (1982). 15. Allegra, J. C., Lippman, M. E., Thompson, E. B., et al. Distribution, frequency and qualitative analysis of estrogen, progesterone and glucocorticoid receptors in human breast cancer, Cancer Res. 39, 1447-1454 (1979). 16. Scatchard, G. The attraction of proteins for small molecules and ions, Ann. N.Y. Acad. Sci. 51, 660-665 (1949). 17. Aitken, S., and Lippman, M. E. A simple computer program for quantitation and Scatchard analysis of steroid receptor proteins, J. Steroid Biochem. 8, 77-80 (1977). 18. Cox, D. R. The analysis o f Binary Data, London, Methuen, pp. 14-26 (1970). 19. Kaplan, E. L., and Meier, P. Non parametric estimation from incomplete observations, J. Amer. Stat. Assoc. 53, 457-481 (1958). 20. Martin, J. D., Hahnel, R., McCartney, A. J., et al: The effect of ER status on survival in patients with endometrial cancer, Amer. J. Obstet. Gynecol. 147, 322-324 (1983). 21. Bonte, J., Ide, P., Billiet, G., and Wynants, P. Tamoxifen as a possible chemotherapeutic agent in endometrial adenocarcinoma, Gynecol. Oncol. 11, 140-161 (1981). 22. Carlson, J. A., Allegra, J. O., Day, T. G., and Wittliff, J. L. Tamoxifen and endometrial carcinoma: Alteration in ER and PR in untreated patients and combination hormonal therapy in advanced neoplasia, Amer. J. Obstet. Gynecol. 149, 149-153 (1984). 23. Rendina, G. M., Donadio, C., Fabri, M., et al. Tamoxifen and Provera for advanced endometrial carcinoma, Eur. J. Obstet. Gynecol. Reprod. Biol. 17, 285-291 (1984). 24. Lovecchio, J. L., Averette, H. E., Lichtinger, M., et al. Treatment of advanced endometrial carcinoma with cyclophosphamide, Doxorubicin, Cis-Platinum and Megestrol acetate, Obstet. Gynecol. 63, 557-560 (1984). 25. Cohen, C. J., Bruchner, H. W., Deppe, G., Blessing, J. A., Homesley, H., Lee, J. H., and Watring, W. Multidrug treatment of advanced and recurrent endometrial carcinoma: A G O G study, Obstet. Gynecol. 63, 719-726 (1984). 26. Horton, J., Begg, C. B., Arseneault, J., Bruckner, H. W., Creech, R., and Hahn, R. G. Comparison of Adriarnycin with Cyclophosphamide in pateints with endometrial cancer, Cancer Treat. Rep. 62, 159-161 (1978). 27. Janne, O., Kauppila, A., Kontula, K., et al. Female sex steroid receptors in endometrial carcinoma. in Steroid receptors and hormone dependent neoplasia (J. L. Wittliff and I. Dapunt, Eds), Masson Publishing, Inc., New York, p. 37-44 (1980). 28. Satyaswaroop, P. G., Zaino, R. J., and Mortel, R. Estrogen like effects of Tamoxifen on human endometrial carcinoma into nude mice, Cancer Res. 44, 4006-4010 (1984).