Combination Chemotherapy for Advanced Endometrial Cancer

An Evaluation of Three Regimens

JOHN HORTON, ME, CHB.' PAUL ELSON, MS,t PHILLIP GORDON, MD,+ RICHARD HAHN, MD,§ AND RICHARD CREECH, MD"

In patients with advanced uterine corpus carcinoma treated with the combination chemotherapy of megestrol, cyclophosphamide, and doxorubicin (MCA) or with this combination and 5-fluorouracil (MCAF), the overall response rate was 22%. There was no significant difference in response rates between the two regimens. There is some indication that survival was longer in ambulatory patients who were treated with MCA, but this combination produced more hematologic toxicity than MCAF. Patients unsuitable for treatment with doxorubicin received megestrol, 1-phenylalanine mustard, and 5-fluoro- uracil (MLF), which produced objective responses in 2 of 12 patients.

Cancer 492441-2445. 1982.

TERINE CORPUS CARCINOMA is a significant health U problem in the United States and other countries.' Patients with localized stages of disease are often cured with surgery and/or radiation, but many patients have or develop metastases that require systemic treatment. Hormones, particularly progestins, have antitumor ac- tivity.',' The Eastern Cooperative Oncology Group has reported objective remission rates of 19% and 0% for the cytotoxic agents doxorubicin and cyclophospha- mide, respectively. Other workers, however, have re- ported that cyclophosphamide is effective and that 5- fluorouracil (5-FU) is also an active agent.5 Combi- nations of these agents effectively treat other tumor types such as breast cancer. This justified studying them

From the Eastern Cooperative Oncology Group (Paul P. Carbone, MD, Chairman, CA-21115).

Supported by Public Health Service grants from the NCI, National Institutes of Health, and the Department of Health, Education and Welfare.

Albany Medical College, Albany, New York (CA-06594). t Sidney Farber Cancer Institute, Boston, Massachusetts (CA-

$ Brigham Women's Hospital, Boston, Massachusetts. Mayo Clinic, Rochester, Minnesota (C.4-I 3650).

!American Oncologic Hospital, Philadelphia, Pennsylvania (CA- 18281).

Other participating institutions include: Albert Einstein College of Medicine. Bronx, New York (CA- 14958); Baystate Medical Center, Springfield, Massachusetts (CA-20182); Brookdale Hospital Cancer, Brooklyn, New York; Brown University, Providence, Rhode Island (CA- 15947); Case Western Reserve University, Cleveland, Ohio (CA- 14548); Chicago Medical School, Chicago, Illinois (CA-14144); Hah- nemann Medical College, Phiadelphia. Pennsylvania (CA-I 361 I ); Harbor General Hospital, Torrance, California (CA-2109 I ); Jeffer-

233 18).

in advanced endometrial cancer. This study compares the effectiveness of two combination chemotherapy reg- imens that include two or three cytotoxic agents com- bined with the progestin megestrol. Since both of these regimens contained doxorubicin, another regimen that contained 5-FU, 1 -phenylalanine mustard, and meges- trol was tested in patients who were not candidates for doxorubicin treatment because of their cardiac prob- lems.

The objectives of the study were to determine which of the two randomized treatments had superior fre- quency and duration of objective tumor response and length of survival. These measurements were also used to evaluate the nonrandomized treatment.

son Medical College, Philadelphia, Pennsylvania (CA- 1421 5 ) ; Johns Hopkins Oncology Center. Baltimore, Maryland (CA-161 16); Med- ical College of Ohio, Toledo, Ohio; University of Minnesota, Min- neapolis, Minnesota (CA-20365); Mount Sinai Medical Center, New York. New York (CA-17152); New York University Medical Center, New York, New York (CA- 16395); Northwestern University Medical Center, Chicago, Illinois (CA-I 7145); University of Ottawa, Ottawa, Ontario; University of Montreal Affiliated Hospitals, Quebec, Canada (CA-21653); University of Rochester Cancer Center, Rochester. New York (CA-I IOR3); Roswell Park Memorial Institute, Buffalo, New York (CA- 12296); Rush-Presbyterian& Luke's Medical Center, Chicago, Illinois (CA- 10948); University of Pretoria, Pretoria. South Africa (CA-2 1692); Tufts University, Walpoole. Massachusetts, (CA- 07 190); Natalie Warren Bryant Cancer Center, Tulsa, Oklahoma; Medical College of Virginia, Richmond, Virginia (CA-I 0572); Wis- consin Clinical Cancer Center, Madison, Wisconsin (CA-21076).

Address for reprints: John Horton, MB, ChB, Head, Division of Oncology, Albany Medical College, Albany NY 12208.

Accepted for publication April 3, 1981.

0008-543X/82/06l5/2441 $0.75 0 American Cancer Society

244 1

2442 CANCER June I5 1982 V O l . 49

Materials and Methods

Patients with histologically confirmed Stage 111 or IV recurrent or metastatic adenocarcinoma of the uter- ine corpus were eligible for study provided they were no longer candidates for standard surgical or radio- therapeutic treatment. Adequate hepatic, renal, and bone marrow function and no prior treatment with cy- totoxic chemotherapy were required. Prior treatment with progestational agents was permissible. The pa- tients had components of their disease that could be either measured-termed “measurable” disease; that could be palpated or evaluated but not measured- termed “evaluable, nonmeasurable disease”; or disease components that were documented to be present but were not palpable or measurable-termed “nonevalu- able, nonmeasurable” disease. Patients were ineligible if they were bedridden, had acute infection, or had an- other active cancer. All patients gave informed written consent for study.

Patients with congestive heart failure or other heart disease such as arrhythmias or recent myocardial in- farction were not eligible to receive the randomized treatments MCA or MCAF but were eligible for the nonrandomized therapy MLF.

The following treatment schedules were used: MCA: megestrol-80 mg, three times daily by mouth;

cyclophospharnide-400 mg/m2, i.v. bolus over a 5- minute period on day 1; and doxorubicin-40 mg/m2, i.v. bolus on day 1.

MCAF: megestrol-80 mg three times daily by mouth; cyclophosphamide-250 mg/m2, i.v. bolus over a 5-minute period on day 1; and doxorubicin-30 mg/ m2, i.v. bolus on day 1 and 5-fluorouracil 300 mg/m2, i.v. bolus on days 1-3.

Each course of intravenous injections was repeated every four weeks. The maximum dose of doxorubicin was limited to 450 mg/m2.

MLF: Megestrol-80 mg, three times daily by mouth; 1 -phenylalanine mustard-6.0 mg/m2, by mouth on days 1-3; and 5-FU-350 mg/m2, i.v. bolus on days 1-3.

The cytotoxic agents were repeated every four weeks. A parenteral progestin was substituted for megestrol if nausea and vomiting developed. The initial doses of cytotoxic drugs were reduced by one third in patients who had previously received pelvic irradiation. If no hematologic toxicity was encountered, subsequent courses were administered at full doses. Leukocyte and platelet counts were obtained weekly. Treatments were delayed for up to two weeks if these counts were low. If the counts did not recover by the end of the two-week period, doses of the cytotoxic drugs were reduced to produce acceptable nadirs. Doxorubicin was discontin-

ued if the patient experienced cardiac arrhythmias or electrocardiographic changes. Doses of doxorubicin and 5-FU were reduced by 50% for severe stomatitis, and the dose of doxorubicin was reduced by 50% if jaundice developed. For patients experiencing cyclophospha- mide-related cystitis, drug therapy was stopped until the cystitis disappeared. It was then restarted at half the full dose for one course of treatment and increased to the full dose in subsequent courses if no further cys- titis was noted. Phenothiazines were recommended for nausea and vomiting. Patients were taken off the study if disease progression was demonstrated. Those with stable disease continued treatment until objective evi- dence of response or progression was noted. Those who responded continued treatment until disease progres- sion. I n the event that the maximum dose of doxorubicin was reached, this drug treatment was discontinued, but the doses of the other cytotoxic drugs were increased by 33% if the hematologic status of the patients per- mi t ted.

Assignment to treatment was made by using ran- domly permuted blocks within the strata defined by the following factors: Performance status (PS): ( 1 ) Ambulatory: ECOG 0, 1, (2) Nonambulatory: ECOG 2, 3; Prior progestin therapy: ( 1 ) No, (2) Yes; Disease measurability: ( 1 ) Measurable, (2) Evaluable, nonmea- surable, (3) Nonevaluable, nonmeasurable; Medical contraindication to doxorubicin: ( 1 ) No, (2) Yes (as- signed to MLF). In addition, treatments were balanced within institutions by forcing the maximum difference between the number of patients randomized to MCA and MCAF to be less than three at all times.

Complete response (CR) signified disappearance of all clinically detectable malignant disease for at least four weeks. Partial response (PR) signified a 50% de- crease in the sum of all the areas of tumor lasting for at least four weeks. For patients with evaluable but nonmeasurable disease, two investigators had to agree independently that there had been >50% improvement. Disease progression signified that patients with mea- surable disease experienced at least a 25% increase in lesion size or developed new lesions. Survival was mea- sured from the time of randomization into the study.

Results

One hundred forty-nine patients were studied. Twenty-three were excluded for reasons including in- adequate renal or bone marrow function,” inadequate records,’ major protocol violations,’ and the wrong pri- mary tumor site.2 The distribution of excluded cases is shown in Table 1. The distribution of prognostic factors among the randomized treatments, shown in Table 2, was even. Table 3 summarizes the incidence of objective

No I 2 TREATMENT OF ENDOMETRIAL CA * Horton el al. 2443

responses for each of the three treatments. There was no statistically significant difference in response rates between MCA and MCAF. When data for these treat- ments were pooled, the incidence of CR plus PR was 24% for ambulatory vs. 17% for nonambulatory pa- tients. Those who had had prior progestational agent therapy had a 17% response rate compared with 24% for those who had not had such treatment. Of the 41 patients previously treated with progestins, 34 were an- alyzed to determine how success or failure with that therapy affected response to the current treatments. Fourteen of the 34 (41%) had experienced either an objective (7) or subjective (7) response from proges- tational agents. Four of these 14 patients (29%) sub- sequently achieved a second remission. Three of 20 ( 1 5%) of the patients who did not respond to the pro- gestin therapy responded to the test treatments. The difference between these response rates is not statisti- cally significant.

Of the analyzed cases, 81% had their pathology re- viewed by the ECOG Pathology Committee. The dis- tribution of patients with adenocarcinoma, adenocar- cinoma with squamous metaplasia, adenosquamous carcinoma, and undifferentiated carcinoma is shown in Table 4 and was similar between the two randomized treatments; so was the degree of histologic differentia- tion. There were no significant differences in response rates for either histologic type or differentiation of tumor.

Treatment, performance status, prior progestational therapy, disease measurability, histopathology, and grading were compared individually by using the log rank test to determine which factors affected time to treatment failure. The overall median time to failure was 12 weeks. Performance status was identified as the only important prognostic indicator of failure time: 14.2 weeks for ambulatory patients and 8.2 weeks for those with worse performance status (P < 0.01).

When patients who received progestational agents before entering the study were analyzed separately, it became evident that those patients who did not achieve an initial tumor remission with progestins failed the current treatments earlier than those patients who had responded (P = 0.01, log rank).

Survival from the two randomized treatments was similar; the overall median survival time was 27 weeks. Those patients who were ambulatory (PS 0-I), how- ever, had a median survival of 37 weeks compared with 14 weeks for those (PS 2-3) who were not. There was also an indication that histopathologic type of tumor had an effect on survival. The median survival for pa- tients with adenocarcinoma with squamous metaplasia was 38 weeks compared with 20 weeks for patients with adenosquamous carcinoma and 22 weeks for patients

TABLE I . Case Accession

MCA MCAF MLF Total

Cases registered 64 67 18 I49 8 9 6 23 Excluded

Cases analyzed 56 58 I2 I26

TABLE 2. Distribution of Stratification Factors by Randomized Treatments

MCA MCAF Level (7@) ( YO )

Performance status ambulatory 70 69 nonambulatory 30 3 1

Prior progestational no therapy Yes

63 62 37 38

Disease measurability measurable 61 5 2

measurable 21 3 3

nonmeasurable 18 16

evaluable, non-

nonevaluable,

with adenocarcinoma (P = 0.03). This conclusion is ten- tative, however, since only 1 1 patients had adenocar- cinoma with squamous metaplasia. The degree of dif- ferentiation, while significant by itself ( P = 0.03, log rank), was not significant when included in the Cox model with the other factors. The median survival for patients with Grade I and I 1 tumors was 32 weeks, and for those with Grade I11 tumors, 19 weeks. The survival for ambulatory patients who were treated with MCA

TABLE 3. Incidence of Objective Response

CK I’ K CR t PR N o response

MCA 4 (7%) 1 1 (20%) 15/55 (27%) 40 (73%) MCAF 3 ( 5 % ) 6 ( 1 1 % ) 9 / 5 6 (16%)) 47 (84%) MLF I ( 8 . 5 % ) I (8.5%) 2/12 (17%) 10 (83%)

There is no statistically significant difference between MCA and MCAF response.

T A B L . ~ . 4. Distribution of llistopathology and Tumor Grade by Randomired Treatment

Treatment

Cell type Adenocarcinoma Adenocarcinoma with Squamous Metaplasia

Adenosquamous Undifferentiated

Differentiation Grade I Grade I1 Grade 1 1 1 Unknown

71 10

19 -

14 52 29

5

80 14

4 2

16 45 39 -

2444 CANCER June 15 1982 Vol. 49

0

E D

> I *

x U .- .- I

I z 8

(median 40 weeks) was somewhat better than for MCAF (median 35 weeks) (P = 0.06, log rank). The median survival for the patients treated with MLF was 23 weeks.

The incidence and severity of toxicity from the treat- ments were reported by using the standard ECOG 5 point severity scale that ranges from 0 (no toxicity) through 5 (lethal toxicity). One hundred twenty-four of the 126 eligible patients were analyzed for toxicity. Patients treated with MCA received an average of five cycles of therapy, and those treated with either MCAF or MLF received an average of four cycles. Table 5 presents the distribution and severity of the toxicities for the three treatments. Hematologic toxicity and nau- sea and vomiting were the most common side effects. Two patients who received MCA and one who received MCAF had lethal toxicity. There were five instances of life-threatening hematologic toxicity for MCA and one for MCAF. Of the patients treated with MCA, 32% reported Grade 3 or worse hematologic toxicity, whereas only 18% of the MCAF patients reported similar grades of toxicity. In addition, of the nine patients reporting extreme grade reactions, only two received MCAF, and both had an initial performance status of 3. Of the 124 cases analyzed for toxicity, 92 had previously received radiotherapy. Prior radiotherapy did not increase the incidence of toxic reactions, but all three instances of lethal toxicity occurred in patients who had received prior radiation.

Discussion

The overall response rate for the patients in the ran- domized part of this study was 22%. This is similar to the 19% response rate for doxorubicin reported from our previous comparative study of the single agents doxorubicin and cyclopho~phamide.~ Others have re- ported encouraging response rates for similar combi- nation regimes6-* The responses in this study were ob- tained often at a cost of considerable toxicity. The three- drug regimen MCA produced more hematologic tox- icity than MCAF but seemed to produce greater sur- vival benefit than MCAF in ambulatory patients. The overall toxicity was such that severe and lethal toxicities were obtained frequently, and it is unlikely that higher doses of these agents can be used safely. The demon- stration that responses to chemotherapy are obtained in patients who had previously responded to progesta- tional therapy is encouraging, but it is still debatable as to whether aggressive combination chemotherapy should be tested in patients at an earlier time in their disease. The minor effect of the histologic type of uter- ine corpus adenocarcinoma on response rates was not surprising. Cellular differentiation in patients with ad- vanced disease is usually poor (Grade and is in-

No. 12 TREATMENT OF ENDOMETRIAL CA - Horton et al. 2445

dependent of response and subsequent survival. This study shows that significant numbers of patients with advanced or metastatic disease had Grade I or Grade I1 tumors. However, those patients with poorly differ- entiated tumors had a shorter survival than those with moderately or well-differentiated tumors.

Since the incidence of antitumor responses to these three cytotoxic-hormone combinations is low, studies are needed to define drugs that have greater activity used either alone or in combination with others.

REFERENCES

I . Horton J, Caputo T. Gynecologic neoplasms. In: Horton J, Hill GJ, eds. Clinical Oncology. Philadelphia: WB Saunders Co.. 1977; 403-409.

2. Reifenstein EC Jr. Hydroxyprogesterone caproate therapy in advanced endometrial cancer. Cancer 197 I ; 27:485-582.

3. Wait R. Megesterol acetate in the management of advanced endometrial cancer. Obsiei Gynecol 1973; 41:129-136.

4. Horton J. Begg CB. Arseneault J e f a/. Comparison of adria- mycin with cyclophosphamide in patients with advanced endometrial cancer. Cancer Trear Rep 1978; 62: 159- 161.

5. Donovan JF. Non hormonal chemotherapy of endometrial ad- enocarcinoma: a review. Cancer 1974; 34: 1587-1 592.

6. Muggia FM, Chia G, Reed LJ ef a/. Doxorubicin-cyclophos- phamide: effective chemotherapy for advanced endometrial carci- noma. Am J Obsier Gynecol 1977; 128:314-319.

7. Bruckner HW, Deppe G. Combination chemotherapy of ad- vanced endometrial adenocarcinoma with adriamycin, cyclophospha- mide. 5-FU and medroxyprogesterone acetate. Obsier Gynecol 1977;

8. Cohen C, Deppe G, Bruckner HW. Treatment of advanced ad- enocarcinoma of the endometrium with melphalan, 5-FU and me- droxyprogesterone acetate. Obsfei Gynecol 1977; 50:415-417.

9. Malkasian GD Jr. Carcinoma of the endometrium: eRect of stage and grade on survival. Cancer 1978; 41:996-1001.

50: 105- 125.

David A. Karnofsky Fellowship

The David A. Karnofsky Fellowship is available annually to a physician or basic scientist who desires specialized training beyond the postdoctoral level in cancer research at St. Jude Children’s Research Hospital. Possible areas of interest include biochemistry, hematology-oncology, immunology, nutrition and metabolism, pa- thology, pharmacology, radiology or virology. Stipend $ 1 5.000-$30,000. Open to national and international competition. Deadline for 1983 applications is September I , 1982. Decision will be made October 15, 1982. Beginning date is July 1, 1983. For further information contact: Director, St. Jude Children’s Research Hospital, P. 0. Box 318, Memphis, Tennessee 38101.