Tamoxifen and medroxyprogesterone therapy for advanced endometrial carcinoma

Europ. J. Obstet. Gynec. reprod. BioL, 17 (1984) 285-291 Elsevier

285

EJO ooo71

Tamoxifen and medroxyprogesterone therapy for advanced endometrial carcinoma G.M. Rendina, C. Donadio, M. Fabri, P. Mazzoni and P. Nazzicone I Divisione di Osteiricia e Ginecologia, Servizio di Oncologia Ginecologica, Ospedale San Camille de

Lzllis,

Roma, Ita@ Accepted

for publication

11 January

1984

RENDINA, G.M., DONADIO, C., FABRI, M., MAZZONI, P. and NAZZICONE, P. (1984): Tamoxifen and medroxyprogesterone therapy for advanced endometrial cancer. Europ. J. Obstet. Gynec. reprod. Biol., 17/4, 285-291. We have studied the response rates and survival of a group of 93 patients with Stage III or IV endometrial adenocarcinoma after random allocation to therapy with tamoxifen (TAM) 20 mg twice daily (n = 45) or medroxyprogesterone acetate (MPA) 1 g/wk intramuscularly (n = 48). The patients were examined every 4 months. In the non-responders and in those who relapsed, combination therapy with TAM and MPA was given. Twenty-four of 45 (53.4%) responded to TAM alone, 27 of 48 (56.2%) responded to MPA alone. Of the responders 23 later relapsed in the TAM group and 24 in the MPA group and of these 14 (60.8%) and 15 (62.5%), respectively, responded to the combination therapy. Of the original 21 non-responders to MPA alone, 10 responded to the combination (47.6%) and 11 (52.4%) did not; the comparable figures for the TAM alone group were 13 (61.9%) and 8 (38.1%) respectively. Survival rates were much higher in the differentiated than in the undifferentiated carcinomas. In conclusion, we feel that the efficacy, and the few side-effects of these drugs used alone and particularly when used in sequential combination, make them a very attractive treatment for advanced endometrial adenocarcinoma. ‘Nolvadex’;

MPA; antioestrogen;

progesterone;

endometrium;

cancer

Introduction

Between the years 1967 and 1977 we confirmed the efficacy of medroxyprogesterone acetate in the treatment of endometrial adenocarcinoma, observing good therapeutic and long-term benefits for survival and remission (Rendina and Donadio, 1974; Rendina and Iacobelli, 1979). In our experience the optimal dose appears to be 1 g/wk (i.m.). Since then the value of the antioestrogen tamoxifen (‘Nolvadex’-ICI) in both early and advanced breast cancer (Baum, 1983; Mouridsen and Palshof, 1978) Addressfor reprints: Professor G.M. Rendina, 0028-2243/84/$03.00

Via Val Gardena

0 1984 Elsevier Science Publishers

B.V.

35, 00135 Roma,

Italy.

286

stimulated our interest in its possible use in endometrial adenocarcinoma, both organs being markedly hormone-dependent. Therefore, we decided to compare the efficacy of these two drugs, given alone or in combination, in patients with Stage III or IV endometrial carcinoma. Materials and methods

Between 1978 and 1981, 93 patients with advanced endometrial adenocarcinoma (Stage III or IV) seen in the I Division of Obstetrics and Gynaecology, Department of Gynaecological Oncology at the Hospital San Camillo de Lellis in Rome, were examined and then allocated to one of two treatments. Those allocated to Group I received medroxyprogesterone acetate I g/wk intramuscularly (MPA) and those in Group II received tamoxifen 20 mg orally twice daily (TAM) for 4 months. Treatment was allocated without a code, but always ensuring that the two groups were well balanced for age, menopausal status, disease-free interval and both stage and site of tumour. At the end of treatment the responders in each group continued with their therapy unchanged. All patients were examined every 4 months and if progression of the disease occurred using a single therapy then a combination of TAM and MPA treatment was given. Those patients unresponsive after the first 4 months treatment with a single therapy were given a combination of TAM and MPA and again examined every 4 months. The IUCC classification of response was used as shown below: Complete remission (CR), Complete disappearance of all evidence of neoplastic disease. Partial remission (PR), A 50% or more reduction in the diameters of all lesions and/or a 50% reduction in ascites or pleural effusion. No change (NC), No change in the size of lesions. Progressive disease (PD), A 50% or more increase in the diameters of all lesions and/or effusions or the appearance of new lesions. Tumour response was assessed by clinical examination and radiography (Hayward et al., 1977). Results

The entry characteristics for the two groups are shown in Table I. Initially, 45 patients received TAM and 48 patients MPA. The response rates, mean duration of response and survival data are shown in Tables II and III. As may be seen in Tables II and III, 56.2% and 53.4% patients responded to monotherapy with MPA and TAM, respectively. The corresponding average remission rates were 14 months (range 3-26 + months) and 9 months (3-15 months), respectively. Twenty-four of the patients originally responding to MPA alone later relapsed. On receiving combination therapy with MPA plus TAM 15 responded (62.5%) with an average remission of 10.5 months (range 1-18 + months) and average survival of 15 months (range 3-22 + months). In the TAM alone group 23 of the responders

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later relapsed and on combination therapy 14 of these responded (60.8%) with an average remission of 11.5 months (3-19 + months) and average survival of 16 months (2-24 + months). Twenty-one patients in Group I and 21 patients in Group I! did not respond to monotherapy; however, on combination therapy of those in Group I, 10 responded (47.6%) with an average remission of 7.5 months (2-14 + months) and average survival of 10 months (5-15 + months); of those in group II, 13 responded (61.9%) with an average remission of 8.5 months (3-13 + months) and average survival 11 months (5-17 + months). To a limited extent, response to TAM correlated with histological grading; the response rates were 64% and 11% for tamoxifen alone and 66% and 31% when combined with MPA for differentiated and undifferentiated tumours, respectively. In general, the more differentiated the tumour the longer the duration of response. Similar effects were observed with MPA. Lesions responded irrespective of their site, the maximum response being in mobile vaginal tumours (> 70% response) - Table IV. Neither obesity nor hypertension affected the TAM response rates. However, the response rates tended to be higher in the MPA group in the presence of obesity or hypertension. Of the 29 obese patients in this group 62.1% responded to MPA alone and 58.5% responded to the combination; the corresponding figures for the non-obese

TABLE Entry

I characteristics

No. of patients Mean age (yr) Mean menopausal No. postmenopausal No. obese No. hypertensive

of 93 patients

with advanced

age (yr) (%)

Mean disease-free interval in months (range) Symptom duration in months (range) Site of tumour

endometrial

adenocarcinoma

Tamoxifen

MPA

45 60.6 50.4 39 (86.7) 25 (55.5) 19 (42.2)

48 60.4 50.6 43 (89.6) 29 (60.4) 21 (43.7)

28.2 (18-40) 3.9 (l-8)

26.3 (16-36) 4.2 (2-8)

23 20 12 7 5

21 19 11 6 4

(%)

Vagina Lymph node Pelvis (fixed) Lung Bone

(51.1) (44.4) (26.6) (15.5) (11.1)

(43.7) (39.5) (22.9) (12.5) (8.3)

Stage (W) III IV Recurrent Grade

30 (66.6) 4 (8.9) 11 (24.5)

32 (66.7) 5 (10.4) 11 (22.9)

36 (80.0) 9 (20.0)

35 (72.9) 13 (27.1)

(%)

Differentiated Undifferentiated

8 Duration

+ ) month

months)

l/5

4/7

10.5 + month

(rangel-18+

survival at 1 yr

and survival

/3remissionI

of response

+ ) month

of response

TAM/MPA

= 13 + (5-19

213

(62.5%)

of response

duration

= 18 + (9-26

non-responders,

average duration

15 responders

PR 14 Duration

CR

I,.

of responders,

Number

of response

II

TABLE

(range

2-14 + months)

TAM/MPA

214

survival at 1 yr

(43.8%)

with MPA 1 g/week

21 non-responders

treatment

(47.6%)

who received

10 responders

of 48 patients

1 I

I)

0 survived 1 year

to

------I (52.4%)

11 non-responders

i.m. on entry (Group

III

14 responders

(60.8%)

= 10 (6-14)

= 4.5 (3-7)

=

TAM/MPA

of response

NC

8 Duration

of response

of response

6 Duration

non-responders,

PR 10 Duration

Number of responders, (Group II)

TABLE

2.2

l/4

4/8

i

and survival

4 months n = 45

with TAM

(46.6%)

1

20 mg twice daily p.o. on entry

survival

TAM/MPA

] 21 non-responders

treatment

(61.9%)

who received

13 responders

of 45 patients

TAM 20 mg twice daily p.o.

of response

survival at 1 yr

month

duration

290

TABLE Response Secondary

IV of secondary Site

site to treatment

Group No. of Patients

Vaginal (mobile) Lymph node Pelvis (fixed) Lung Bone

21 19 11 6 4

I

Group Responder MPA (I) 16 10 7 3 1

(76.1) (52.6) (63.6) (50.0) (25.0)

to

II

Responder to No. of MPA + TAM (W) Patients

Responder to TAM (W)

Responder to TAM + MPA (S)

17 8 6 4 2

17 9 8 4 1

19 9 9 5 1

(80.9) (42.1) (54.5) (66.6) (50.0)

23 20 12 7 5

(73.9) (45.0) (66.6) (57.1) (20.0)

(82.6) (45.0) (75.0) (71.4) (20.0)

patients were 47.3% and 42.1%, respectively. For the 21 hypertensive patients in the MPA group, 61.9% responded to MPA and 57.1% to MPA plus TAM. The corresponding figures for the 27 normotensive patients were 51.8% and 4&l%,, respectively. The side-effects with MPA were similar to those previously reported in the literature (Ganzina and Robustelli della Cuna, 1982) and included weight gain due to fluid retention (70%), facies lunaris (16%), tremors (14%), gluteal abscess (10%) and vaginal bleeding (10%). These and other reversible side-effects such as sweating, muscular cramps, thrombophlebitis and raised blood pressure were never severe enough to require withdrawal of therapy and the clinical tolerance to MPA treatment was generally good when compared to other agents used in oncology. Treatment was not interrupted in any of the patients on TAM because of side-effects. Those reported were slight nausea (31%) and/or gastralgia (20%), anorexia (38%), urticarial skin reactions (22%), minimal transitory thrombocytopenia (16%) and transitory tumour flare in the first week of therapy in 91% of patients. Discussion

In this study the response and average remission rates observed with TAM alone were very similar to those achieved with MPA alone (response rates of 53.4% and 56.2%; average remission rates of 9 months (range 3-18 + months) and 14 months (range 3-26 + months), respectively). Of particular interest were the beneficial effects of combination therapy in those patients who had failed to respond to or had responded initially to monotherapy and then relapsed. The response and survival rates after the addition of TAM to MPA were apparently greater in those patients who had previously responded to MPA alone and then relapsed. This observation has also been made by Bonte et al. (1978, 1979, 1981) and by Swenerton (1980). A hypothesis has been put forward by Sekiya and Takamizawa (1976) and by Robe1 et al. (1978) that the addition of TAM stimulates the synthesis of progesterone receptors in otherwise progesterone-receptor-poor tissue for occupation by MPA. In this respect, an attractive approach is the use of tamoxifen and medroxyprogresterone as a sequential cyclical therapy. In this and our previous studies, the response and survival rates with these

291

hormone therapies were higher in the differentiated carcinomas compared to the undifferentiated ones. According to Ehrlich and Young (1980) this is because the differentiated ones are progesterone-receptor-rich. We also found that response was partly determined by the location of the secondary sites, maximal responses to both TAM and MPA occurring in mobile vaginal tumours. Unlike MPA, the response to TAM did not appear to be affected by the presence of obesity or hypertension. Finally, we feel that the efficacy and lack of side-effects of these drugs when used alone and particularly when used in combination make them a very attractive treatment for advanced endometrial adenocarcinoma. References Baum, M. (1983): The Lancet i, (1983), 257 Bonte, J., Decoster, J.M., Ide, P. and Billiet, G. (1978): Gynaec. Oncol., 6, 60 Bonte, J. (1979): Rev. Endocr. rel. Cancer, 3, 11 Bonte, J., Ide, P., Billiet, G. and Wynants, P. (1981): Gynaec. Oncol., 11, 140 Ehrlich, G.E. and Young, P.C.M. (1980): Rev. Endocr. Rel. Cancer, 6, 13 Gamma, F. and Robustelli della Cuna, G. (1982): Int. Symp. MPA., Geneva, Switzerland, Feb. 24-25 Hayward, J.L., Carbone, P.P., Henson, J.C., Kumaoka, S., Segaloff, A. and Rubens, R.D. (1977): Europ. J. Cancer, 13, 89 Mouridsen, H. and Palshof, T. (1978): Cancer Treat. Rev., 5, 131 Rendina, G.M. and Donadio, C. (1974): Vol. Atti. 56 Congr. Sot. It., Ost. Gin., 489 Rendina, G.M. and Iacobelli, S. (1979): ‘Ormoni, recettori e cancro’ SEU, Roma, 217 Robe], P., Levy, C., Wolff, J.P., Nicholas, J.C. and Baulieu, E. (1978): Acad. Sci., Paris, 287, D-1353 Sekiya, S. and Takamizawa, H. (1976): Brit. J. Obstet. Gynaec., 83, 183 Swenerton, K.D. (1980): Cancer Treat. Rep., 64, 803