GYNECOLOGIC

ONCOLOGY

47, 373-316 (1992)

A Prospective Trial of Progesterone Therapy for Malignant Peritoneal Cytology in Patients with Endometrial Carcinoma M.

STEVEN

PIVER,

M.D.,’ Department

FERNANDO

0.

of Gynecologic

RECIO, Oncology,

M.D., Roswell

TRUDY Park

R.

M.D.,

BAKER,

Cancer

Institute,

Buffalo,

AND

RONALD

New

York

E.

HEMPLING,

M.D.

14263

Received April 24, 1992

From February 1982 to February 1991, 45 patients with endometrial carcinomaconfinedto the uterus except for malignant peritonealcytology weretreated with 1 year of progesteronetherapy. Thirty-six patientshave undergoneplannedsecond-looklaparoscopywith repeat peritoneal washingsand the remaining 9 patientseither refusedsecond-looklaparoscopyor the procedure wasmedically contraindicated.Of the 36 who underwentsecondlook laparoscopy,34 (94.5%)were NED (no evidenceof disease) and had negative repeat peritoneal cytology and 2 (5.5%) had persistentmalignant cytology. The latter two patients, after an additional year of progesteronetherapy, were found to be NED and had negative peritonealcytology at third-look laparoscopy. Of the 45 women enrolled in this protocol, no patient has developed recurrent endometrial cancer, and the expected S-year disease-freeSUrViVal was 88.6%. 0 1992 Academic PRSS, IIIC.

group), a prospective trial was initiated in February 1982 to treat patients with adjuvant progesterone therapy who had endometrial carcinoma confined to the uterus except for malignant peritoneal cytology [5,6]. The purpose of this study is to report on 45 evaluable patients who have completed 1 year of progesterone therapy for malignant peritoneal cytology. The use of progesterone therapy was based upon (1) the effectiveness of progestational (medroxyprogesterone acetate or hydroxyprogesterone caproate) therapy in 114 patients with metastatic endometrial adenocarcinoma [7], (2) its known antimitotic and antiproliferative properties, and (3) the lack of significant toxicity. MATERIALS

AND METHODS

INTRODUCTION

From February 1982 through February 1992, 45 evaluable patients with endometrial carcinoma confined to the Several studies have suggested that recurrence and uterus except for malignant peritoneal cytology were endeath are more common in patients with early stage enrolled into the protocol. Patients were not evaluable if dometrial carcinoma when peritoneal washings contain they had (1) evidence of metastasis at surgery, (2) occult malignant cells at the time of primary surgery [l-3]. In cervical or ovarian involvement on histologic review, or contrast, our initial report of 93 patients with peritoneal (3) histologic evidence of paraaortic lymph node metascytology obtained at the time of hysterectomy for clinical tasis in those patients who underwent paraaortic stage I endometrial cancer showed no significant differlymphadenectomy. ence in recurrence rate or survival between patients with All patients were to be treated according to the folmalignant peritoneal cytology and those with negative lowing protocol: (1) patients with grade 1 or 2 tumors peritoneal cytology [4]. Significantly, all patients in the and less than 50% myometrial invasion would be treated latter study had been followed for a minimum of 10 years by total abdominal hysterectomy, bilateral salpingo-oopor until death from cancer or intercurrent disease and 110 horectomy, and postoperative vaginal radium/cesium depatient received treatment for their malignant peritoneal livering 3000 cGy at 0.5 cm but without staging paraaortic cytology. However, since there was a 10% recurrence or postoperative pelvic radiation berate in the group with malignant peritoneal cytology (7% lymphadenectomy cause of the low incidence of pelvic or paraaortic lymph recurrence rate in the negative peritoneal cytology node metastasis in such instances [8]; (2) patients with invasion greater than 50% ’ To whom reprint requests should be addressed at Department of grade 3 tumors or myometrial would undergo staging paraaortic lymphadenectomy; Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Fax: (716) 845-3545. those patients without histological evidence of paraaortic 373 All

0090-825X/92 $4.00 Copyright 0 19Y2 by Academic Press, Inc. rights of reproduction in any form reserved.

374

PIVER ET AL. TABLE

1

STAGEI* ENDOMETRIALCARCINOMA

Exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal cytology

Malignan C5.._.. Peritoneal Cytology

Myometrizk

12 month Progesterone Therapy

Invasion

MyometiJial Invasion

Postoperative vaginal radium/cesium

Staging Paraaortic Lymphadenectomy

Histologically Negative Aortic Nodes 1 Negative Peritoneal Cytology

Discontinue Progesterone Therapy

I Whole pelvis radiation therapy 5040 cGy

Malibnant Peritoneal Cytology

ConI inue Progesterone Therapy

Third Look Laparoscopy G = grade * 1976 International

Federation

of Gynecologists

lymph node involvement would receive postoperative whole pelvis radiation therapy of 5040 cGy over a period of 5% weeks because of the high incidence of pelvic lymph node metastasis in such instances [8]. Patients with histologic evidence of paraaortic lymph node metastasis were not evaluable. Patients with malignant peritoneal cytology were to receive 1 year of adjuvant progesterone therapy and to then undergo second-look laparoscopy and repeat peritoneal washings. If repeat cytologic washings were negative for malignant cells, treatment would be discontinued. If cytologic washings were still positive for ma-

and Obstetricians

(FIGO)

lignant cells and no macroscopic disease was present at second-look laparoscopy, an additional 12 months of progesterone therapy was given and a third-look laparoscopy was performed at the end of therapy (Table 1). Treatment would be also discontinued at the end of 1 year of progesterone therapy in patients who refused second-look laparoscopy. Peritoneal washings for cytology were obtained immediately upon entering the abdomen by instilling and aspirating 100 cc of normal saline solution from the pelvis and right and left paracolic gutters. The solution was sent directly to the cytology laboratory,

PROGESTERONE

IN ENDOMETRIAL

where volume was recorded before the sample was divided into two centrifuge tubes and spun down. The precipitate was smeared directly onto slides and fixed in 95% ethyl alcohol before being stained by the Papanicolaou method. All cytologic specimens were reviewed by our cytopathologist. The criteria for establishing the presence of malignant cells were those described by Koss [9]. Commencing in 1986, estrogen and progesterone receptor status was evaluated on all endometrial adenocarcinoma specimens (N = 20). Progesterone therapy initially consisted of medroxyprogesterone acetate (Depo-Provera) in 24 patients and hydroxyprogesterone caproate (Delalutin) in 1 patient at a dose of 1 g intramuscularly weekly gratis from the hospital to these 25 patients. When the Depo-Provera was no longer free to the patients, the subsequent 20 patients received 160 mg megesterol acetate, orally daily for 1 year, obviating the need for intramuscular injections. The 5-year progression-free survival was defined as the time from surgery to recurrence (if recurrence occurred) or last follow-up if no recurrence occurred. Patients who died with no evidence of disease (NED) were treated as censored. Survival curves were calculated by the method of Kaplan and Meier [lo]. The median follow-up is 5 years as of February 1992. RESULTS A total of 45 patients with endometrial adenocarcinoma confined to the uterus except for malignant peritoneal cytology were entered into the prospective trial. Patient characteristics are seen in Table 2. The median age was 67 years (40 to 88). Seventy-one percent had grade 2 tumors. 66% had less than 50% myometrial invasion or tumor confined to the endometrium, and 89% had adenocarcinoma. Of the 15 women with grade 3 tumors or greater than 50% myometrial invasion, 3 did not undergo paraaortic lymphadenectomy; two because of age (greater than 85) and one because of obesity (350 pounds). All 45 patients completed at least 1 year of progesterone therapy. There were no complications attributable to progesterone therapy. Thirty-six patients underwent secondlook laparoscopy, 5 refused second-look laparoscopy, and in 4 patients the procedure was medically contraindicated. Of the 36 patients who underwent second-look laparoscopy, 34 (94.5%) had no laparoscopic evidence of macroscopic disease and their repeat peritoneal cytologies were negative for malignant cells. Two (5.5%) patients had peristent malignant peritoneal cytology at secondlook laparoscopy and were treated with an additional year of progesterone therapy. Both patients underwent thirdlook laparoscopy and were found to have negative peritoneal cytology and no evidence of malignancy. Two of the 36 patients who underwent second-look

CANCER

375

TABLE 2 Patient Characteristics Characteristics

Results

Median age Grade 1 2 3 Myometrial invasion Endometrium only 40% 250% Histology Adenocarcinoma Adenosquamous Papillary serous Estrogen receptors Positive’” Negative Not done Progesterone receptors PositiveZb Negative Not done Progesterone therapy

67 (range 40-88) 18% ( 8) 71% (32) 11% ( 5) 4% ( 2) 62% (28) 34% (15) 89% (40) 9% ( 4) 2% ( 1) 80% (16) 20% ( 4) (25) 90% (18) 10% ( 2) (25) 100% (45)

Note, TAH/BSO, Total abdominal hysterectomy and bilateral salpingo-oophorectomy. ” Greater than 10 fentomol of protein. ’ Greater than 20 fentomol of protein.

laparoscopy died of intercurrent disease NED at 31 and 94 months, and 34 are alive NED (14-112 months). Of the 9 women who did not undergo second-look laparoscopy, 3 died of intercurrent disease and were without evidence of recurrent cancer (24-74 months) and 6 are alive NED (24-94 months) off therapy. With a median follow-up of 5 years, of the 45 patients, none has developed recurrent carcinoma; 5 died of intercurrent disease without evidence of recurrent cancer from 24-94 months; 40 are alive NED at a median of 63 months (14-112) since the time of initiation of therapy. The 5-year estimated survival and disease-free survival is 88.6%. DISCUSSION The prognostic significance of malignant peritoneal cytology in endometrial carcinoma without clinically apparent extrauterine spread remains controversial and the origin of these cells remains unknown. Several authors have suggested that patients with endometrial cancer who demonstrate malignant peritoneal cytology are at increased risk of recurrence and have significantly lower survival rates [l-3,11,12], while an equal number of reports fail to corroborate these results [4,13-171. Some authors have suggested the use of intraperitoneal radioactive chromic phosphate (P”) as treatment for patients

376

PIVER ET AL.

with malignant peritoneal cytology associated with endometrial carcinoma [3]. Because of the known activity of progesterone in patients with metastatic endometrial adenocarcinoma, we initiated a prospective trial of progesterone therapy for patients with endometrial carcinoma confined to the uterus except for malignant peritoneal cytology. In addition, patients were treated by a defined protocol of postoperative vaginal cesium/radium or pelvic radiation depending on grade of the tumor and depth of myometrial invasion. To date, 45 patients have completed a minimum of 1 year of progesterone therapy. To evaluate the effectiveness of such therapy, a second-look laparoscopy with repeat peritoneal washings was to be carried out at the completion of 1 year of therapy. Thirty-six women underwent second-look laparoscopy and 9 refused second-look laparoscopy or the procedure was medically contraindicated. Of the 36 women who underwent second-look laparoscopy, 94.5% (34) had no evidence of macroscopic disease and repeat peritoneal cytology was negative for malignant cells. Two (5.5%) women with persistent malignant peritoneal cytology at second-look laparoscopy were treated with an additional year of progesterone therapy. Both then underwent third-look laparoscopy and repeat peritoneal washings. Both were negative for malignant cells. Of the 45 women enrolled in this protocol, no patient has developed recurrent endometrial carcinoma and the expected 5-year disease-free survival is

3.

4.

5.

6.

7.

8. 9. 10. 11.

12.

88.6%. Since all patients did not have positive steroid receptors, it is difficult to postulate about these results. However, of interest, the 20 patients who did have receptor status evaluated, 80% had positive estrogen receptors and 90% positive progesterone receptors, which is a possible explanation for the results. We believe caution should be exercised in interpreting these results, since patients were treated by a defined surgical staging and postoperative radiation protocol relative to known adverse prognostic factors [18]. However, progesterone therapy is easily administered and possibly effective therapy based on findings at follow-up, laparoscopy, and prolonged diseasefree survival.

13.

14

15.

16.

17.

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18.

with peritoneal cytology in the management of gynecological malignancies, Am. J. Obstet. Gynecol. 120, 174 (1974). Creasman, W. T., DiSaia, P. J., Blessing, J., Wilkinson, R. H., Jr., Johnston, W., and Weed, J. C., Jr. Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals, Am. J. Obstet. Gynecol. 141, 921 (1981). Yazigi, R., Piver, M S., and Blumenson, L. Malignant peritoneal cytology as prognostic indicator in Stage I endometrial cancer, Obsret. Gynecol. 62, 359-362 (1983). Piver, M. S., Lele, S. B., and Gamarra, M. Malignant peritoneal cytology in Stage I endometrial adenocarcinoma: The effect of progesterone therapy (A preliminary report), Eur. J. Gynecol. Oncol. 9, 187-190 (1988). Piver, M. S. Progesterone therapy for malignant peritoneal cytology: Surgical Stage I endometrial adenocarcinoma, Semin. Oncol. 1.5, 50-52 (1988). Piver, M. S., Barlow, J. J., Lurain, J. R., and Blumenson, L. E. Medroxyprogesterone acetate (depo provera) versus hydroxyprogesterone caproate (delalutin) in women with metastatic endometrial adenocarcinoma, Cancer 45, 268-272 (1980). Creasman, W. T., Morrow, C. P., Bundy, B. N., Homesley, H. D., Graham, J. E., and Heller, P.B. Surgical pathologic spread patterns of endometrial cancer, Cancer 60, 2035 (1987). Koss, L. G. Diagnostic cytology and its Histopathologic basis, Lippincott, Philadelphia, PA (1979). Kaplan, E. L., and Meier, P. Non-parametric estimation from incomplete observations, J. Am. Stat. Assoc. 53, 457-481 (1958). Mazurka, J. L., Krepart, G. V., and Lotocki, R. J. Prognostic significance of positive peritoneal cytology in endometrial carcinoma, Am. J. Obstet. Gynecol. 158, 303-306 (1988). Harouny, V. R., Sutton, G. P., Clark, S. A., Geisler, H. E., Stehman, F. B., and Ehrlich, C. E. The importance of peritoneal cytology in endometrial carcinoma, Obstet. Gynecol. 72, 394-398 (1988). Kennedy, A. W., Peterson, G. L., Becker, S. N., Runez, C., and Webster, K. D. Experience with pelvic washings in Stage I and II endometrial carcinoma, Gynecol. Oncol. 28, 50-60 (1987). Morrow, C. P., Creasman, W. T., Homesley, H., Yordan, E., Park, R., and Bundy, B. Recurrence in endometrial carcinoma as a function of extended surgical staging data. A Gynecologic Oncology Group study, in Morrow CP, Smart GE (eds.) Gynaecological Oncology (C. P. Morrow and G. F. Smart, Eds.), SpringerVerlag, New York, pp. 147-153 (1986). Imachi, M., Tsukamoto, N., Matsuyama, T., and Hitoo, N. Peritoneal cytology in patients with endometrial carcinoma, Gynecol. Oncol. 30, 76-86 (1988). Lurain, J. R., Rumsey, N. K., Schink, J. C., Wallemark, C. B., and Chmiel, J. S. Prognostic significance of positive peritoneal cytology in clinical Stage I adenocarcinoma of the endometrium, Obstet. Gynecol. 74, 175-179 (1989). Grimshaw, R. N., Tupper, W. C., Fraser, R. C., Tompkins, M. G., and Jeffrey, J. F. Prognostic value of peritoneal cytology in endometrial carcinoma, Gynecol. Oncol. 36, 97-100 (1990). Piver, M. S., and Hempling, R. E. A prospective trial of postoperative vaginal radium/cesium for Grade l-2 less than 50% myometrial invasion and pelvic radiation for Grade 3 or deep myometrial invasion in surgical Stage I endometrial adenocarcinoma, Cancer 66, 1133-1138 (1991).

A prospective trial of progesterone therapy for malignant peritoneal cytology in patients with endometrial carcinoma.

From February 1982 to February 1991, 45 patients with endometrial carcinoma confined to the uterus except for malignant peritoneal cytology were treat...
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