Progestatinal drugs in the management of endometrial cancer

Progestational Drugs in the Management of Endometrial Cancer By HENRY CLAY FRICK, II The progestational agents have a definite place in the management of disseminated adenocarcinoma of the endometrium. Twenty-two patients have been treated at the Delafield and Presbyterian Hospitals with 5 objective remissions. The patients with chest

metastases appeared to show a better response than those with generalized abdominal spread. In our opinion progestational agents should not be used instead of radiation and surgery in the operable cases.

T

HE FACTOR OF -4 HORMONAL RELATIONSHIP in endometrial cancer has been suspected for many years but only recognized recently. This discovery was about 10 years behind the discovery that alterations of the host’s endocrine pattern could produce regressions in carcinoma of the breast and prostate. Kelly and Baker? published the first series of cases of disseminated endometrial cancer treated by 17-alpha-hydroxy-progesterone-17-N-caproate in 1961. There were 21 cases in their original series; 6 showed objective regression lasting from 9 months to 4% years. Most of their improvements were the disappearance of shadows on chest x-ray films that were interpreted as metastatic disease. Since that time, there have been a few additional reports (table 1). According ‘to the 12th Annual Report on the Results of Treatment in Carcinoma of the Uterus1 in 16,665 cases from 36 clinics, the S-year over-all cure rate was 58.1 per cent. The cure rate was 73.1 per cent when the tumor was confined to the uterus but only 21.8 per cent for those in whom the growth had spread outside of the uterus. At the Presbyterian and Delafield Hospitals 40 to 46 cases of carcinoma of the corpus are seen per year. From 1961 to 1964 there were 22 cases of disseminated endometrial carcinoma which recurred after radiation, surgery, or a combination of both, treated at these institutions with massive dosages of 17-alpha-hydroxy-progesterone-17-N-caproate ( Delalutin) . The dosage levels ranged from 1.5 to 2 Cm. per week, There were 4 definite objective remissions among these patients. The case material is given in table 2, with the location of the metastases. As can be seen, the patients with chest metastases seemed to respond the most frequently. Patients with disease in the abdomen and especially those with ascites appeared to give the worst results. No patients with ascites showed a response. All 3 patients presently living that showed a response had an elapse of between 1 and 2 years between their primary therapy and recur-From the Department of Obstetrics and Gynecology, Skm.w ad Deb&&i Hospitals, New York, New York.

METABOLISM,

Columbia

University

and

the

VOL. 14, No. 3, PART 2 ( MARCH), 1965

PROGESTATIONAL

DRUGS IN ENDOMETRIAL

Table L-Patients

349

CANCER

with Disseminated

with Progestationul

Endometrial Agents

No. of Patients

Cancer Treated Length of Remissions

Remissions

Authors

Type

Kelly and Bakers

Recurrent

28

7

9-54 mo.

Kennedy” Sykes” Varga and Henriksen”

Recurrent Recurrent Recurrent

27 6 6

8 3 3

3-34 mo. 4-5-6 mo. Not given

Untreated

13

13

Not given

Patients with Mettlstatic Adenocarcinomu of the Corpus Treated with Hydroxyprogesterone Caproate

Table B.-Twenty-Two No. of Patients

7

12 2 1 ~~~__-.

_

Remissions

Length of Remission

Chest

Site of Metastases

3

2mo. + 6 mo. (died) 24 mo. +

Generalized Vulva-vagina

0 0

Chest-periwethral

1

36 mo. +

___-.-

rence. On the other hand, the patients that did not respond, had their remissions following primary therapy anywhere from 3 months to 2 years. It appears that the patients that show regression of their disease with progestational agents usually have biologically slow growing ‘tumors, but all patients that have biologically slow growing tumors do not necessarily respond to this type of therapy. _ TOXICITY Progestatiunal agents are exceptionally free from toxic ‘reactions when compared to other anticancer compounds such as the alkylating and antimetabolic agents. The majority of workers in the cancer chemotherapy field are convinced that a good level of an anticancer drug has not been administered unless the host shows a marked toxic response such as leukopenia, stomatitis, etc. What such responses do to the host’s resistance mechanisms to the cancer is not known. The majority of anticancer agents today are poisons that in many instances make the patient dieing of disseminated disease miserable without affecting the cancer and in some instances, hastening their death. The progestational agents, on the other hand, have very few toxic responses. In our series of patients treated with Delalutin, we have had 3 patients with gluteal abscesses resulting from intramuscular injection necessitating incision and drainage. One patient acquired a fairly severe cough on several occasions immediately following the injections of Delalutin after about 6 months of therapy. Skin test results showed no reaction to the drug and there were no other manifestations of an allergic response. One of the coughing attacks was witnessed while the patient was in the hospital. The drug was discontinued after this episode.

350

Fig. L-A representative field of well-differentiated evidence of degeneration. H & E x 960.

HENRY

adenocarcinoma

CLAY

FRICK

with no

We had some experience in treating patients with other forms of metastatic gynecologic cancer with this compound without any success. Two patients with adenocarcinomas of the cervix, 1 with endocervical carcinoma, 1 with epidermoid carcinoma of the vagina, 2 with adenocarcinomas of the ovary, 1 with leiomyosarcoma of the uterus, and 2 with endometrial stromal sarcomas

PROGESTATIONAL

DRUGS IN ENDOMJWRIAL

CANCER

351

Fig. 2.-Chest x-ray showing pulmonary metastases for first time, occurring 16 months after primary therapy.

treated with Delalutin with no evidence of objective change. These patients had all been treated previously by surgery or radiation or a combination of both and their disease was not controlled. Provera (medroxyprogesterone acetate) has not been used extensively by our group. Two of our patients that have shown objective response have been maintained on this compound after the regressions had been produced by Delahrtin for periods of 6 months and 1 year. These changes in therapy were made because the patients objected to repeated intramuscular injections but agreed to take an oral preparation. We had no experience with using progestational agents in conjunction with surgery and radiation therapy, nor have any operable or radiatable patients been treated with the compound. It is believed that surgery and radiation still offer the best chances of cure in adenocarcinoma of the corpus, We are of the opinion that a cancer is a cancer and when the diagnosis has been established histologically by a competent pathologist, the clinician should treat the patient with the disease by established therapy. Realizing that the reported cure rate by surgery for adenocarcinoma of the corpus that is limited to the normal size corpus runs about 80-90 per cent in some series, we feel that trying to reverse these lesions with steroids is not in the best interests of the patient.

352

Fig.

HENRY CLAY FRICIi

S.-Chest

x-ray following

1 month of Del&tin

therap!,

showing

cavitation

of lesion in the left side of the chest. To illustrate the efficacy of the Delalutin to produce remissions in some patients with metastatic adenocarcinoma of the corpus, the following patient is presented. CASE

REPORTS

L. G., a 61 year old white para 1, gravida 1 housewife, had her last normal menstrual period in August, 1938. On September 25, 1958, she underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer at an outside hospital. At operation metastases were found in both ovaries and there was evidence of pelvic peritoneal spread with ascites. The postoperative course was complicated by severe paralytic ileus and a large retroperitoneal abscess which necessitated drainage through a right lower quadrant, retroperitoneal incision on the 18th postoperative day. The abscess was thought to have been caused by leakage from a damaged right ureter at the time of the original surgery. Postoperatively, there was urinary leakage from the incision-and-drainage wound which subsided spontaneously. The ileus subsided but a decubitus ulcer with necrosis of much of the skin and subcutaneous tissue overlying the sacrum developed. The patient was transferred to the P’rancis Delafield Hospital for further treatment. On admission November 15, 1958, the physical examination revealed the following positive findings: ( 1) Cataract of left eye. ( 2) Abdomen: welI-healed mid-line scar with pinpoint draining sinus in lower angle. Right lower quadrant stab wound almost completely healed. (3) Large decubitus ulcers of skin of sacral region extending full thickness through skin and subcutaneous tissues. (4) Pelvic examination: atrophic external genitalia; well supported vault. No masses felt. 5) Rectal examination confirmatory. The chest x-ray, blood count, urine analysis, barium enema and electrocardiogram were all within normal

PROGESTATIONAL

DRUGS IN ENDOMETRIAL

CANCER

Fig. 4.-A representative field of markedly well-differentiated tures. Note the ciliated margin of the epithelium. This epithelium the anaplastic features illustrated in figure 1. H & E x 960.

353

glandular struchas lost most of

limits. Intravenous pyelogram, dye studies, and cystoscopy failed to reveal any evidence of ureterocutaneous or ureterovaginal fistulas. The upper urinary tracts were within normal limits. Biopsy of the presacral ulcer showed granulation tissue. Review of slides taken from operative specimen at other hospital showed papillary adenocarcinoma of the endometrium. On November 19th the decubitus ulcer over the sacral area was removed and the defect

354

HENRY

Fig. 5.-Chest Provera therapy.

x-ray following 5 months of Delalutin therapy The metastatic lesions have largely resolved.

closed by rotating

a full-thickness

skin flap over the left buttock.

tient did well and the graft took without

difficulty.

The

patient

CLAY FRICK

and 1 year of

Postoperatively was discharged

the pahome

on

January 22, 1959. It was planned to give this patient external x-ray therapy to the pelvis as an outpatient. On January 29, 1959, a lesion was noted in the periurethral region which on biopsy proved to be metastatic adenocarcinoma (see fig. 1). The lesion was treated with 1350 I tumor dose through a 2 cm. vaginal cone on a 250 K.V. machine given over a period of 4 elapsed days February 3 to 6, 1959. This was followed by 4400 r tumor dose to the pelvis February 9th to March 20th, 1959, through 15 x 17 cm. opposing fields on a 2 M E V machine. The patient tolerated the treatments well and there was almost complete healing of the periurethral lesion. She had no complaints other than slight urgency and some stress incontinence for the next 9 months. In January, 1960, a recurrence was noted in the periurethral region which showed metastatic adenocarcinoma on biopsy. Chest x-ray on January 11, 1960, showed me&static carcinoma in both chest fields for the first time (see fig. 2 ). Urologic work-up, including intmvenous pyelogram and cystoscopy, was negative except for the periurethral recurrence. Cytoxan, 1 Gm., was administered intravenously in 4, 500 mg. doses January 24th to 27th, 1960. The patient was maintained on oral Cytoxan between 50 to 100 mg. a day from February, 1960 to J~rly 5, 1960. Repeat chest x-ray showed suggestive cavitation of one, the largest metastases, during the first 3 months of therapy, but then the lesion continued to increase in size. There was no marked depression of the white blood cell count. The periurethral recurrence increased in size. A positive biopsy specimen for metastatic periurethral cancer was obtained from this lesion on June 28, 1960 and September 8, 1960. Cytoxan was discontinued in early July, 1960, and Thio-TEPA, 75 mg. was administered intravenously in five 15 mg. daily doses beginning in early August, 1960. There was gradual further increase in size of both the chest metastases and the periurethral lesion from

PROGESTATIONAL August,

1960

DRUGS IN ENDOMETRIAL

to February

21,

1961.

355

CANCER from

the

vaginal lesion at this time. The patient appeared increasingly weak and tired. Delalutin, 500 mg. intramuscularly thrice weekly was started on February 21, 1961.

A positive

biopsy

specimen

was obtained

On

March 13, 1961, there appeared to be some diminution in size of the pulmonary metastases and cavitation (see fig. 3). The periurethral lesion was present on April 6, 1961, and metastatic adenocarcinoma was found on biopsy. The chest x-ray findings continued to improve during the ensuing months. A positive biopsy specimen from the periurethral lesion was last obtained on June 8, 1961. There appeared to be histologic changes in the lesion with differentiation of the tumor cells (see fig. 4). When the patient was seen in July, 1961, the vaginal lesion had completely healed. Delalutin was discontinued and the patient has been maintained ever since on oral Provera, 100 mg. daily and 100 mg. intramuscularly every week. On x-ray there continues to be some decrease in the size of the pulmonary metastases as can be seen from figure 5 taken on June 5, 1962. The patient feels exceedingly well and maintains herself on full activity, 38 months since the start of progestin

therapy

and 67 months

from the onset of her disease.

REFERENCES 1. Annual

Report

on the Results

of Treat-

ment in Carcinoma of the Uterus, vol. 12. Stockholm, Editorial O&e, Radiumhemmet, 1960. 2. Frick, H. C., II, Southam, A. L., and Azar, H. A.: Favorable response of metastatic adenocarcinoma of the corpus to massive progestational therapy: report of a case. Bull. Sloane Hosp. Women 9:10, 1963. 3. Kelley, R. M., and Baker, W. H.: Progestational agents in the treatment of carcinoma Engl.

of the

J. Med.

endometrium.

264:216,

1961.

New

4. Kennedy, B. J.: A progestogen for treatment of advanced endometrial cancer. J.A.M.A. 184:758, 1963. 5. Sykes, M. P.: Treatment of metastatic endometrial cancer with progestational agents. Read before II Simposio lnternazionale di Chemioterapia, Napoli, September 14-17, 1961, Napoli:Idelson, 1961. 6. Varga, A., and Henriksen, E.: and histopathologic evaluation

Clinical of the

effect of 17-alpha-hydroxyprogesterone17-n-caproate on endometrial carcinoma. Obst. & Gynec.

18:658,

1961.