Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions.

REVIEW ARTICLE

Systemic Treatment of Advanced and Recurrent Endometrial Carcinoma: Current Status and Future Directions By Timothy D. Moore, Pamela H. Phillips, Stacy R. Nerenstone, and Bruce D. Cheson Multiple systemic therapies have been used to treat patients with endometrial cancer. Although progestins have been the standard initial treatment for metastatic disease for the past 30 years, they are effective in only 20% of patients, and several large randomized trials have failed to demonstrate any benefit in the adjuvant setting. Alternative agents such as tamoxifen have shown modest activity. Few studies have investigated combinations of hormonally active drugs. Doxorubicin and cisplatin are the most active cytotoxic agents; a

C ANCER

of the endometrium is the fourth most common malignancy in women, accounting for approximately half of the new cases of gynecologic cancers diagnosed in the United States each year. With an estimated 34,000 new cases detected in 1989,' endometrial cancer is more than twice as common as invasive cervical carcinoma. As with cervical cancer, overall 5-year survival figures have improved since 19602 due primarily to recognition of the disease at an earlier stage. Unfortunately, survival rates for advanced or recurrent endometrial cancer are also similar to those for advanced cervical carcinoma; there has been no appreciable improvement in survival in the past 30 years, and almost 70% of the 3,800 women diagnosed with stage III or IV endometrial carcinoma will die of their disease within 5 years. It is clear that significant advances in systemic therapy are needed. This review summarizes the current status of

clinical trials with cytotoxic, hormonal, and combination regimens, which, to date, have met with only modest success. Potential areas for future clinical investigations identified through basic science or preliminary clinical observations are also described. HORMONAL TREATMENT

Historically, steroid hormones and endometrial carcinoma have been interrelated both etiologically and therapeutically. In 1933, Cook and Dodds3 noted that certain carcinogenic anthracene derivatives exerted an estrogenic effect when injected into animals. Conversely, Greene 4 and Meissner et al5 demonstrated that continuous exposure to exogenous estrogens could exert a carcinogenic

current randomized study is comparing the combination of these drugs with single-agent doxorubicin. Maximizing the effectiveness of established drugs, possibly with hematopoietic growth factors, and identifying alternative hormonal and cytotoxic agents with a sound scientific rationale will hopefully increase the effective treatment options for these patients. J Clin Oncol 9:1071-1088, 1991. This is a US government work. There are no restrictionson its use.

effect on endometrial tissue. These early animal studies suggested that the unopposed action of estrogen resulted in a continuum of histologic changes progressing from a proliferative endometrium, to adenomatous hyperplasia, and finally to invasive carcinoma. Similar observations have been made in women with physiologic abnormalities resulting in the noncyclic production of endogenous estrogens (eg, cortical stromal hyperplasia, thecomas, SteinLeventhal syndrome, and Leydig cell hyperplasia6-9). Evaluation of the epidemiology of endometrial cancer suggests an increased incidence in women exposed to exogenous estrogens for symptomatic control of menopausal symptoms."0 This latter association led the Food and Drug Administration to issue a bulletin to physicians in 1976,11 which resulted in a decline in the sale of estrogens, followed shortly thereafter by a decrease in the incidence of endometrial cancer.'2 3 Strong direct and indirect evidence thus exists implicating estrogens in the pathogenesis of endometrial cancer. Endometrial cancer is unusual in women having normal menstrual cycles. This association is thought to be due to the cyclical exposure of the uterine

From the Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda; The EMMES Corporation, Potomac, MD; and Oncology Associates, PC,Hartford, CT. Submitted September 10, 1990; accepted December 10, 1990. Address reprintrequests to Timothy D. Moore, MD, Executive Plaza North, Room 741, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use. 0732-183X/9110906-0017$0.00/0

Journal of Clinical Oncology, Vol 9, No 6 (June), 1991: pp 1071-1088

Downloaded from ascopubs.org by RB DRAUGHTON LIBRARY on April 28, 2019 from 131.204.073.184 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

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MOORE ET AL

lining to progesterone. In 1959, Kistner'4 took advantage of the ability of progesterone to produce a state of "glandular regression" by demonstrating the efficacy of progesterone in the treatment of carcinoma in situ in women who subsequently underwent hysterectomy. Kelley and Baker"1 summarized a decade of experience (1950 to 1960) using progestational agents in the treatment of metastatic disease; in their own series, objective responses were noted in six of 21 patients treated with either progesterone or the synthetic hydroxyprogesterone caproate ([HPCI; Delalutin, Bristol-Myers Squibb Co, Evansville, IN). Kauppila' 6 reviewed 17 subsequent trials of at least 20 women each and a total of 1,068, and calculated an overall response rate of 34%. The average duration of response ranged from 16 to 28 months, with an average survival time of 18 to 33 months. Progestins have played an important role in the treatment of endometrial cancer for over 25 years because of their ease of administration, tolerability, and favorable toxicity profile.17 Studies reported in the last decade, however, suggest that the often quoted overall response rate of 33% may be optimistic. Thigpen et al"8 reported the Gynecologic Oncology Group (GOG) experience with 331 women with measurable disease treated with 150 mg of medroxyprogesterone acetate (MPA) daily. Using standard criteria of response, only 32 (10%) women achieved a complete response (CR) and 26 (8%) a partial response (PR). Both median progression-free interval and overall survival were brief. Podratz et al' 9reported similar findings from the Mayo Clinic experience with a variety of progestational agents over a 12-year period (1968 to 1980). Only 10% of patients had an objective response to therapy, and less than 50% were alive 1 year after initiation of hormonal treatment. In addition, no substantial differences were noted among MPA megesterol, or hydroxyprogesterone. No prospective randomized trials have compared progestational agents. Piver et al20 treated 44 women with hydroxyprogesterone acetate and compared the results with 70 women treated with HPC. The combined overall response rate was only 16%, with no significant difference between the two arms. A number of factors might have contributed to the low observed level of effectiveness, including the large number of patients with grade 3-4 lesions in the series reported by Podratz et al (47%) and the large number of patients with

both estrogen receptor (ER)- and progesterone receptor (PgR)-negative tumors in the GOG study (42%). However, these relatively recent studies indicate that only a limited subset of patients with advanced disease have a reasonable likelihood of responding to conventional progestational therapy. The route of administration of progestins does not appear to influence either the response rate or survival. Sall et a12' randomized 22 patients to either oral MPA (50 mg three times daily) or intramuscular MPA (300 mg weekly). Serum levels were consistently higher in the oral group, demonstrating that adequate blood levels can be achieved with oral MPA. However, response rates were not evaluated in this small trial. In a retrospective analysis, Kauppila'6 found the response rates for 287 patients given intramuscular (IM) MPA (32%) to be similar to those for 223 patients given oral MPA (41%). Based on this evidence, the optimal route of administration of progestational therapy remains to be identified. Few trials have evaluated the possibility of a dose-response effect in endometrial cancer. Geisler22 reported a nonrandomized study of 46 patients treated with three different doses of megesterol acetate. Although higher response rates were observed with the high-dose (160 mg/d) and moderate-dose (80 mg/d) treatments (overall response rates, 48% and 43%, respectively) compared with low-dose (40 mg/d; overall response rate, 14%), this difference was not statistically significant. The GOG recently completed a randomized phase III trial comparing high-dose MPA (1,000 mg/d) with moderate-dose therapy (200 mg/d). Preliminary analysis of the 294 assessable patients indicates no increase in survival or response for patients receiving high-dose MPA (T. Thigpen, personal communication, November 1990). If these results are upheld, there would appear to be no role for high-dose progesterone therapy in this disease. Progestins have also been used as induction therapy for stage I endometrial cancer (Table 1), although this practice is not widely accepted. Decoster et a123 applied MPA regionally via a silastic-releasing device and achieved pathologic CRs in 60% of patients without myometrial invasion. Bokhman et a124 treated 398 women with preoperative oxyprogesterone caproate (OPC). Based on objective responses in 80% of women with anovulatory uterine bleeding or infertility, a


1073

TREATMENT OF ENDOMETRIAL CANCER Table 1. Progestin Induction Therapy in Endometrial Cancer Reference

No. of Patients

Decoster et al"

17

Bokhman et al2

398

Bokhman et al12

Gal'2

19

6

Follow-Up Therapy

Patient Status

Induction Treatment

13 (77%) postmenopausal

MPA 500 mg via silasticreleasing loop in utero

Hysterectomy

NS

OPC 500 mg IM qd (10-16 g total)

Surgery - RT

Premenopausal with an ovulation and hyperestrogenia Postmenopausal with carcinoma in situ

OPC 500 mg IM qd x 3 months

Observation

Megestrol acetate 20 to 40 mg/d

Observation

Patient Results 7 (59%)without residual carcinoma; 0/5 responses with myometrial invasion 34 (8.5%) pathologic CRs; 218 (54.8%) with increased differentiation and secretion 15 cured (3-9 years posttherapy); 2/4 PR at hysterectomy 5/6 CR (nonhyperplastic)

Abbreviations: NS, not stated; RT, radiotherapy; qd, every day.

subsequent study2 5 was conducted in 19 women treated for 3 months with IM HPC followed by a repeat biopsy and surgery for persistent disease. Cures were reported for 15 of 19 patients. Ga126 used a similar approach in six postmenopausal women with carcinoma in situ who were poor surgical risks due to underlying medical conditions. A "nonhyperplastic" histology developed in five, obviating the need for a surgical procedure, and no patient developed endometrial carcinoma at a mean follow-up of more than 5 years. Thornton et al" described a 23-year-old woman with stage I disease cured by hormonal therapy alone. While the results of these descriptive reports are not applicable to the majority of women with endometrial cancer, they indicate a possible role for hormonal therapy alone in the conservative management of women for whom preservation of the uterus and fertility is a major consideration. Several randomized clinical trials have investigated the use of progestins as adjuvant therapy following definitive surgery and/or radiation therapy (Table 2). Lewis et al28 randomized patients to either adjuvant MPA therapy or placebo; patients were stratified according to whether or not they received preoperative intracavitary radium. The 4-year survival rate (87%) for 285 women given MPA was not significantly different from that reported for 287 women given placebo (92%); however, there was a substantial ineligibility rate due, in large part, to patients found at the time of surgery to have disease beyond the uterus. More recently, two large randomized adjuvant trials have failed to demonstrate a benefit for adjuvant hormonal therapy. De Palo et a129 randomized 747 women with pathologic stage I endometrial cancer to either MPA or observation. Patients were

stratified by histologic grade, lymph node involvement, and extent of myometrial invasion; those women whose tumor penetrated more than one third of the myometrium received radiation therapy in addition to progestins. With a median follow-up of 22 months, recurrence and survival rates for patients receiving MPA were not significantly different than for women who did not receive hormonal therapy. In a recently reported British trial, 30 429 patients with stages I to III endometrial cancer were randomized to receive preoperative IM HPC (100 mg/d) followed by postoperative oral MPA or observation. Although all patients underwent a hysterectomy, the use of radiation varied according to grade and extent of disease. With the majority of patients at least 5 years following surgery, there is no apparent survival benefit for adjuvant hormonal therapy. In a nonrandomized study of 123 women, Bonte31 reported a 5-year survival of 87% for women treated with MPA versus 72% for untreated controls. Subsequently, a number of small or singlearm studies32-34 have been reported with conflicting

results. The inability of large randomized trials to demonstrate a survival advantage for adjuvant hormonal therapy may reflect the fact that hormonal therapy is most likely to benefit patients with well-differentiated, hormone receptor-positive tumors; however, these tumors are less likely to recur following primary therapy. Unfortunately, it is the poorly differentiated, hormone receptornegative stage I tumors that are more likely to recur, and these tumors are usually unresponsive to progestin therapy.'" Thus, there appears to be no indication for postoperative adjuvant hormonal therapy. The modest response rates achieved with pro-


1074

MOORE ET AL Table 2. Progestin Adjuvant Therapy in Endometrial Cancer No. of Patients

Reference Randomized Lewis et al"

Stage of Disease

Treatment

574

I

747

I

429

I-I11

123

I

799

I and II

Malkasian and Decker"4

35

I

Piver"'

25

I with malignant peritoneal cytology

2

De Palo et a1 9

30

Macdonald et a1 Nonrandomized 3 Bonte" 32

Kauppila et a1

Patient Results

MPA + RT v MPA alone v Placebo + RT v Placebo alone MPA (100 mg/d x 12 months) + RT v control (. RT)

-

168/195 (86%) alive at 4 years 78/90 (87%) alive at 4 years 164/183 (90%) alive at 4 years 100/104 (96%) alive at 4 years Median follow-up 22 months Recurrences: 1.5% MPA group, 2.6% control group; distant metastases: 2.4% MPA group, .5% control group; deaths from disease: 6 MPA group, 6 control group 154/214 (72%) alive at 5 years 159/215 (74%) alive at 5 years

MPAv Control MPA

--

Methyl-HPA v Placebo Progesterone

--

26/30 (87%) alive at 5 years 67/93 (72%) alive at 5 years Stage 1: 609/677 (90%) alive at 5 years, stage 2: 98/122 (80%) alive at 5 years 14/18 (78%) alive at 5 years 15/17 (88%) alive at 5 years 25/25 (100%) disease-free (median follow-up, 33 months)

HPC then MPA v Control

gestational agents in advanced endometrial cancer have stimulated studies of other drugs that exert

alone38 -445 or in combination with other hor6 mones. -50

their effect via alternative hormonally mediated mechanisms. Tamoxifen (TAM) has been the most extensively studied of these agents. Jordan

Results of clinical trials for single-agent TAM are summarized in Table 3. The pooled response rate is approximately 22%; however, response

and Hoerner" reported that TAM could inhibit

rates vary greatly among studies. Possible explana-

the binding of estradiol to the ER in endometrial carcinoma, potentially blocking the proliferative stimulus of circulating estrogens. Several investiga-

tions for this discrepancy include the variability in pathologic grade, degree of prior treatment, and whether patients were truly progesterone-refrac-

tors36 37 ' have also shown that TAM can increase

tory (compared with those who responded initially

the number of PgRs in human endometrial carcinoma in vivo. Subsequently, multiple clinical trials have evaluated the efficacy of this agent, either

and later failed progestational therapy). In addition, the dose of TAM varied from 20 to 40 mg/d. Taken as a whole, these studies suggest that

Table 3. Results With Single-Agent TAM Therapy in Endometrial Cancer CR Reference Quinn and Campbell 4 Edmonson et a1 '

38

Slavik et al4 39 Swenerton et al Rendina et al" Hald et al" 3 La Vecchia et al Bonte et a144 Total

PR

Dosage

Assessable Patients

No.

%

No.

%

Overall %

20 mg bid 10 mg bid

49 24 no prior treatment 22 progesterone-refractory 24 35 45 26 15 17 257

6 1 0 0 2 6 4 0 2 21

12 5 0 0 6 13 15 0 12 8

4 4 0 0 6 10 4 0 7 35

8 16 0 0 17 22 15 0 41 14

20 21 0 0 23 36 31 0 53 22

10 mg 10 mg 20 mg 10 mg 20 mg 20 mg

bid bid bid bid qd bid

Abbreviation: bid, twice a day.


1075

TREATMENT OF ENDOMETRIAL CANCER

women with well-differentiated tumors, or those who previously responded to progestational therapy, are most likely to benefit from TAM. Of concern are recent reports suggesting that TAM therapy may induce endometrial cancer in both an animal model"5 and in women receiving adjuvant TAM for early breast cancer.5 2 In an analysis of 1,846 postmenopausal women with breast cancer randomized to adjuvant TAM (40 mg/d) or observation, a significantly increased risk of endometrial cancer was observed in the TAM group, particularly in women receiving TAM for more than 2 years." Recently, an additional seven cases, from a 413 patient cohort, were described, bringing to 43 the total number of women reported in the literature who have developed endometrial cancer while taking TAM for breast cancer.5 4 Although a causal relationship has not been proven, TAM's estrogen-like activity has been implicated in the development of endometrial hyperplasia in previously oophorectomized women."5 However, in vitro evidence indicates that TAM does not stimulate the proliferation of established endometrial carcinoma cell lines 56; in fact, some investigators have found that it has an inhibitory effect."57 Taken as a whole, these discrepant preclinical and clinical observations suggest caution in the use of TAM in advanced endometrial cancer. Progestins and TAM have been combined in the treatment of endometrial cancer (Table 4). Both preclinical and clinical data suggest that TAM,

when bound to the cytoplasmic ER, can stimulate the production of PgRs and therefore, in theory, potentiate the activity of progestin therapy"'"9 by reversing down-regulation. Carlson et a146 exam-

ined tumors from 25 untreated women for ER and PgR levels before and after 5 days of TAM treatment. An increase was noted in the number of specimens exhibiting detectable levels of PgR after therapy (21 of 25, 84%) compared with the number before therapy (13 of 25, 52%); most of the stimulation occurred in grade 1 and 2 tumors. The mean increase in PgR content for tumors that were initially PgR-negative was 132 fmol/mg cytosol protein. However, five specimens demonstrated a decrease in PgR content, and PgR content remained undetectable in three women with grade 3 disease. The investigators subsequently evaluated concurrent TAM and MPA in 12 previously untreated patients with advanced or recurrent disease and observed a 33% overall response rate (Table 4). Another trial of the same combination demonstrated minimal activity in 42 patients,48 while the combination of the active estrogen ethinyl estradiol and MPA showed no activity in 12 assessable patients." However, it should be noted that the former study was conducted in women with grade 3 disease previously treated only with hormones, while the latter was in a cohort consisting predominantly of patients previously exposed to cytotoxic therapy. Similar response rates were achieved in a study recently

Table 4. Combination Hormonal Therapy for Endometrial Cancer

Reference

Dose/Schedule

Pandya et al"

Megesterol 80 mg po bid, TAM 10 mg po bid Ethinyl estradiol 50 mg po days 1-7, MPA 500 mg po days 8-25, repeat cycle on day 31 TAM 10 mg bid x 5, MPA 50 mg bid x 20 (sequential) TAM 10mgpobid x 5, MPA 250 mg IM weekly (concurrent) TAM 20 mg bid, MPA 250 mg IM q week

Tatman et also

Kline et al"

Carlson etal 6

8

Rendina et al1

CR

PR

Prior Treatment

Assessable/Entered

No.

%

No.

%

Response Duration

NS

42/45

1

2

7

17

NS

CT 11

12/15

0

0

0

0

NS

RT 17, CT 2, no HT

20

1

5

0

0

41 months

No HT

12

1

8

3

25

CR 7 months, PR 7, 10, 24 months

TAM or MPA

42/42 (nonresponders to single hormone) 51/51 (responders to single hormone)

2

5

11

26

8 months (mean)

5

10

15

29

11 months (mean)

Abbreviations: CT, chemotherapy; HT, hormonal therapy; po, orally.


1076

MOORE ET AL

completed by Pandya et al.49 Finally, thrombotic5s or reversible hepatocellular" toxicities have been noted with combination hormonal regimens. Limited data exist for other hormonal ap6 proaches to endometrial cancer. Hubbard" reported a single case of endometrial carcinoma that responded to surgical adrenalectomy. Quinn et al62 treated 11 women unresponsive to MPA with aminoglutethimide, TAM, or both agents. One of five patients initially treated with aminoglutethimide had a CR, and one had a PR to the combination of both hormonal agents. Wall et a163 treated nine women with clomiphene citrate and noted two definite "histologic" responses. Finally, Perl et al" have recently reported a case of endometrial cancer that responded to a luteinizing hormonereleasing hormone (LHRH) analog. The low response rate with progestins emphasizes the need to identify the subset of women most likely to respond to hormonal therapy. Analyses of several large clinical trials using progestational agents have identified multiple factors that predict response and survival of women with endometrial cancer. A consistent relationship between tumor grade and progestin sensitivity has been found.6 5 In a subset analysis of the GOG study of 47 women with measurable disease in whom both the histologic grade and hormone receptor status were known, a response rate of 20% (two of 10) was observed in patients with grade 1 lesions and 24% (six of 25) in women with grade 2 tumors; no responses were seen in 12 patients with grade 3 disease.' 8 Podratz et al"'9 reported a 40% response rate for patients with grade 1 tumors and a 1.4% response rate for patients with grade 3 lesions. There also appears to be a direct correlation between the interval from primary treatment to the initiation of hormonal therapy (> 3 years v < 3 years) and subsequent response rate.19 Other factors such as age, number of metastatic lesions, site or extent of metastatic disease, or prior radiation therapy have not consistently been found to be prognostic. Hormonal responsiveness correlates with ER and PgR expression. Pooling data from five studies, Kauppila' 6 noted responses in 89% of PgRpositive tumors, but in only 17% of the PgRnegative tumors. A similar association was found between ER and response. In the GOG subset analysis'" of 51 women with both measurable disease and hormone-receptor data available, 40%

(four of 10) of those with ER-positive, PgRpositive tumors responded to progestins, while only 12% (five of 41) of PgR-negative patients responded. Not surprisingly, ER and PgR expression is highest in grades 1 and 2 tumors. Most studies indicate that PgR and ER expression is more predictive than tumor grade of hormonal response." In addition, a retrospective analysis, using a relatively high threshold for PgR positivity (> 100 fmol/mg cytosol protein), showed this parameter to be the single most important prognostic variable with respect to survival for stage I 6 disease." Several major problems limit the overall ability to interpret hormone receptor correlations such as lack of consensus as to what constitutes a "positive" receptor level and the absence of an accepted standardized assay to limit interlaboratory variability.' 65 Immunolocalization studies have also identified heterogeneity in PgR distribution as a potential source of error, particularly the contamination of PgR-negative tumors with adjacent normal endometrium, resulting in falsepositive results.66'67 Despite these cautions, most current data support the correlation between PgR and ER expression with subsequent response to hormonal therapy. CYTOTOXIC THERAPY Cytotoxic therapy is most often used to treat advanced tumors when hormonal therapy fails. However, patient characteristics such as advanced age, poor performance status, and coexisting illness have precluded the use of chemotherapy in many women with advanced tumors. In view of the limited number of patients appropriate for clinical investigations using nonhormonal chemotherapy, previous reviews have stressed the necessity to develop effective systemic therapy in a logical and methodic way.,'768-70 A large variety of chemotherapeutic agents have been tested in endometrial cancer since the early 1960s. Most of the earlier studies screened single agents in broad, multidisease phase II trials. Two reviews68,69 summarized the treatment of recurrent and advanced endometrial cancer in the mid-1970s. At that point, only meager data were available from fewer than 200 patients with endometrial cancer. When the data were pooled, only three active drugs were tested in a sufficient number of patients to estimate their efficacy:


1077


doxorubicin (DOX), cyclophosphamide (CTX), and fluorouracil (5-FU). Of all the cytotoxic agents studied to date, DOX has proven to be the most consistently effective. Three disease-specific trials71 73 have evaluated single-agent DOX (Table 5) with the pooled results of 161 patients demonstrating a 12% CR rate and a 26% overall response rate. In addition, a recent phase II study74 indicates that the DOX analog, epirubicin, is also active in this disease. Another anthracycline, idarubicin,7 5 and a related anthracendione, mitoxantrone,76'77 appear to be inactive, although the latter study was conducted in a predominately pretreated patient population. Early clinical studies suggested that CTX was active in endometrial cancer; however, more recent reports have failed to support its efficacy. DeVita et a169 identified seven responses out of 33 patients treated in five broad-based phase II studies. However, Eastern Cooperative Oncology Group investigators were unable to confirm this level of activity in a subsequent site-specific randomized phase II trial72 (Table 6). High response rates have been reported for CTX when combined with either DOX or DOX and cisplatin (CDDP).78"8 However, a phase III trial73 failed to demonstrate a statistically significant improvement in response rate, progression-free interval, or survival for the combination of CTX and DOX compared with DOX alone. Thus, a role for CTX in the treatment of endometrial cancer is unproven at this time. Ifosfamide, a structural analog of CTX, has recently been reported as having some activity (two responses in 16 patients) in a small phase II

study reported by Barton et al.86 However, toxicity was severe and responses were brief. Additional evidence must be obtained before concluding that this agent is effective in endometrial cancer. 5-FU was tested in seven studies completed before 1975; 10 responses were observed among 43 patients for an overall response rate of 23%.69 5-FU has also been included in several combination regimens evaluated in the early 1980s.87-91 One postulated mechanism of action for 5-FU when combined with 5,10 methyltetrahydrofolate (leucovorin) is the inhibition of thymidylate synthetase (TS), resulting in the depletion of intracellular thymidine stores. 92 Recent clinical trials in colon adenocarcinoma have indicated that a precursor of 5,10 methyltetrahydrofolate leucovorin can potentiate the activity of 5-FU. 93 In view of these

data, there has been renewed interest in the use of 5-FU in endometrial cancer, either as a single agent or in combination with leucovorin. In the 1980s, CDDP 94 98 and carboplatin, an

analog with a different toxicity profile, 99 ' 1 emerged as another group of cytotoxic agents with modest but reproducible activity in endometrial cancer (Table 5). One of the initial trials of CDDP in endometrial cancer demonstrated activity in patients previously exposed to cytotoxic therapy. 94 However, severe dose-related toxicity resulted in the discontinuation of treatment of 31% of the women on study. The GOG was unable to confirm this level of activity with only one response observed in 25 patients." Subsequently, the GOG evaluated CDDP in cytotoxic-naive patients and demonstrated a 20% overall response rate.98 The dose and schedule in this study (50 mg/m2 every 3

Table 5. Single-Agent Activity in Endometrial Cancer Responses/ Assessable Reference Anthracyclines Thigpen et al" Thigpen at aol7 Horton et al" 4 Calero et al' CDDP or carboplatin Thigpen et al" Thigpen et al" Seski et a19' Trop6 et al"9 Deppe et al"9 1 Green et al " Long et al"1

Drug/Dosage DOX 60 mg/m2 DOX 60 mg/m2 2 DOX 50 mg/m Epirubicin 80-90 mg/m

2

CDDP 50 mg/m2 2 CDDP 50 mg/m (previously treated patients) CDDP 50, 70, 100 mg/m2 CDDP 50 mg/rn' CDDP 3 mg/kg Carboplatin 400 mg/mrn Carboplatin 300-400 mg/m'

CR

No.

%

No.

%

22/97 16/43 4/21 6/24

22 37 19 25

7 11 1 2

7 25 5 8

10/49 1/25 11/26 4/11 4/13 7/23 7/25

20 4 42 36 31 30 28

2 0 1 1 2 2 0

4 0 4 9 15 9 0


1078

MOORE ET AL Table 6. Results With CTX in Endometrial Cancer CR Reference

Tx Dose/Schedule

Single-agent 2 Horton et al

6

Barton et a18 CTX and DOX Seski et al79

Muggia et a178

3

Thigpen et a17

CAP De Oliveira et als'

8

Hancock et a1o

8

Turbow et a1 '

Edmonson et a183

Lovecchio et al17

Prior Treatment

Assessable/ Entered

No.

Overall %

No.

%

Response/Survival Duration

5 0

4 0

19 0

Median surv, PS 0-1, 280 days; PS 2-3, 92 days

DOX 50 mg/m' IVq 3 weeks or CTX 666 mg/m' IV q 3 weeks Ifosfamide 5 g/m' q 3 weeks

No prior CT

Prior progestins 12, CT 1

16/16

1

6

2

12

Responses, 12 and 19.7 weeks

DOX 40-50 mg/m', CTX 400-500

Prior progestins 12

26/26

0

0

8

31

Median, 4 months

No prior CT

8/11

3

38

5

63

Median, 10 months

No prior CT

202/NS DOX, 97

7

5

29

22

DOX + CTX, 105

15

14

43

30

DFS 3.4 months, surv 6.8 months DFS4.0 months, surv 7.6 months

HT 13 No CT

59/91

12

20

30

51

RT 16 HT 15 No CT RT 17, HT 8

18/18

5

28

10

56

NS

19/21

2

11

9

47

NS

RT 11, HT 16, No CT

16/16

0

0

5

31

Median surv, 202 days

RT 11, CT 2

15/15

5

33

9

60

MeanDFS, 8 months; mean surv, 12 months

mg/m' q 4 weeks (some patients received CTX po 2 200 mg/m /d x 4) DOX 37.5 mg/m' CTX 500 mg/m' q 3 weeks DOX 60 mg/m2 v 2 DOX 60 mg/m + CTX 500 mg/m'

CTX 600 mg/m', DOX 45 mg/m', CDDP 50 mg/m2 q 4 weeks 2

CTX 500 mg/m , 2 DOX 50 mg/m , 2 CDDP 50 mg/m CTX 600 mg/m', DOX 50 mg/m 2 , 2 CDDP 60 mg/m q 4 weeks CTX 400 mg/m', DOX 40 mg/m 2 , 2 CDDP 40 mg/m q 4 weeks CTX 300 mg/m' q 4 weeks, DOX 30 2 mg/m q 4 weeks, CDDP 50 mg/m q 4 weeks, megestrol acetate 40 mg tid

40/47 DOX, 21 CTX, 19

1 0

Median response, 37 weeks

Abbreviations: Tx, treatment; DFS, disease-free survival; surv, survival; IV, intravenous; tid, 3 times a day; PS, performance status; CAP, CTX, Adriamycin (DOX; Adria Laboratories, Columbus, OH), and CDDP.

weeks) appeared tolerable, with only two patients experiencing life-threatening toxicity (one renal failure and one septic shock). Although CDDP has reproducible activity in endometrial cancer, the renal and neurologic toxicities prevent prolonged high-dose administra-

tion. The North Central Cancer Treatment Group (NCCTG) and the Southwest Oncology Group (SWOG) have both evaluated carboplatin9 9w1 in advanced or recurrent endometrial cancer, with similar response rates of about 30%. Myelosuppression was the most prominent toxicity encountered


1079


in each trial, with fatal neutropenic sepsis in one patient in the NCCTG study (in a patient who had received prior pelvic irradiation) and platelet counts of less than 75,000/p.L in 17 of 27 patients in the SWOG trial, although no hemorrhagic complications were noted. Hexamethymelamine (HMM) was originally thought to be active in endometrial cancer on the basis of a trial in 20 women'01 ; however, no CRs were noted. The response duration was brief (median, 3.5 months), and attempts to increase response duration by prolonged administration of the drug were limited by toxicity (neurotoxicity, nausea/vomiting). A later phase II trial by the GOG found that toxicity was tolerable with the schedule used, but only three responses were documented out of 34 assessable patients. 10 2 A number of other drugs demonstrated sporadic activity (primarily in chemotherapy-naive patients), but none of these was promising enough to warrant further development in this disease 0 3 "114 (Table 7). COMBINATION CHEMOTHERAPY

Multiple combination chemotherapy regimens have been evaluated in endometrial cancer73,78-85,87-91,

"115-122 (Table

8), but few randomized trials have

been completed. Because of a dearth of both appropriate patients and drugs with documented

Responses/ Assessable Patients Reference

Thigpen et al' Seski et al"o' Hilgers ef al•" Thigpen et al1" Kavanagh et al.. 12 Thigpen et al' Homesley et al"•" 6 Slayton et al"° 7 Hilgers et al' 7 Muss et a1 6 Hakes et a175 03 Slayton et al' 0 Stehman et al' ' Slayton et al'" 0 Muss et alo' 09 Asbury et all

NONHORMONAL ADJUVANT STUDIES

Few clinical studies have evaluated the role of nonhormonal systemic therapy in the adjuvant setting (Table 9).123-127 The only phase III study

Table 7. Single Agents With Limited Activity in Endometrial Cancer

0 2

single-agent activity, early phase III studies compared two multidrug regimens without including a control arm.87'" 8 ECOG compared megesterol, CTX, and DOX (MCA) to megesterol, CTX, DOX, and 5-FU (MCAF). The GOG compared melphalan, 5-FU, and Megace (megestrol acetate; Bristol Myers Squibb Co, Evansville, IN) with DOX, CTX, 5-FU, and Megace. In neither study was one regimen proven to be superior to the other. Moreover, the response rates appeared to be comparable to published data for DOX alone. Therefore, the GOG next compared DOX, the drug with the most clearly established single-agent activity, with the combination of DOX and CTX.73 As previously described, this study failed to demonstrate a meaningful increase in survival for combination therapy. The GOG is currently comparing DOX to a combination of DOX and CDDP. Although many combination regimens appear to have substantial activity in a nonrandomized setting (Table 8), there are no data from controlled trials supporting the superiority of combination therapy to single-agent DOX. Current phase III strategies should be aimed at building on the established activity of DOX in an orderly, sequential manner.

Drug

No.

%

%CR Rate

HMM HMM m-AMSA Vinblastine Vinblastine Piperazinedione ICRF - 159 Diaziquone Mitoxantrone Mitoxantrone Idarubicin MGBG Dianhydrogalactitol Etoposide Methotrexate Aminothiadiazole

3/34 6/20 1/19 4/34 0/14 1/20 0/24 2/26 0/15 1/19 2/21 3/21 1/17 1/29 2/33 0/21

9 30 5 12 0 5 0 8 0 5 10 14 6 3 6 0

6 0 5 3 0 0 0 4 0 5 0 5 0 0 3 0

Abbreviations: m-AMSA, amsacrine; MGBG, methyl-glyoxalbisguanylhydrazone.

reported to date' 23 failed to demonstrate benefit from adjuvant DOX plus pelvic radiation therapy compared with radiation therapy alone in a group of patients at high risk of recurrence. However, the statistical power of this trial was compromised by a higher than expected recurrence-free survival rate in the control arm and a high rate of patient refusal to take chemotherapy following randomization. Since patients suitable for adjuvant high-risk endometrial cancer protocols are uncommon, accrual to these trials is slow. However, the lack of established alternatives for these women at highrisk for recurrence justifies future randomized studies, even in the face of an anticipated long trial duration. Such considerations should be taken into account for cytotoxic adjuvant studies in the future. In three small nonrandomized trials, intraperitoneal chromic phosphate 32P appeared to be effective in patients with a positive peritoneal


1080

MOORE ET AL Table 8. Combination Cytotoxic Regimens in Endometrial Cancer CR

Reference

PR

Dose/Schedule

Phase

Thigpen 7 et al

DOX 60 mg/m2, t CTX 500 mg/m2 q 3 weeks

III

97 DOX alone 105 DOX + CTX Total 202

7 15

7 14

15 19

15 18

Cohen et .als

Melphalan 7 mg/m'/d x 4 days q 4 2 weeks, 5-FU 525 mg/m /d x 4 days q 4 weeks, Megace 180 mg/d x 8 weeks

III

126/146 (77 assessable for response)

12

16

17

22

NS

131/149 (78 assessable for response), (+54/63 patients assigned to regimen without DOX)

13

17

15

19

NS

56/64

4

7

11

20

NS

MCAF megestrol 80 mg, tid x q 4 2 weeks, CTX 250 mg/m q 4 weeks, 2 DOX 30 mg/m q 4 weeks, 5-FU 300 mg/m2 days 1-3 q 4 weeks

58/67

3

5

6

11

NS

MLF megestrol 80 mg tid, 1-phenylalamine mustard, 6 mg/m' days 1-3 q 4 weeks 5-FU 350 mg/m2 days 1-3 q 4 weeks (nonrandomized)

12/18

1

8.5

1

Assessable/Entered

No.

%

No.

%

Response Duration Median, 3.4 months Median, 4.0 months

or 2

DOX 40 mg/m /q 3 weeks, 5-FU 400 2 mg/m /q 3 weeks, CTX 400 mg/ 2 m /q 3 weeks

Total 311/358 Horton et al.s

MCA megestrol 80 mg tid x q 4 2 weeks, CTX 400 mg/m q 4 weeks, 2 DOX 40 mg/m q 4 weeks or

2

Hoffman etal116

CDDP 50 mg/m', DOX 30 mg/m , CTX 250-500 mg/m2, Megace 40160 mg bid

Ayoub et aol

CTX 400 mg/m2, DOX 30 mg/m , 2 5-FU 400 mg/m' - TAM 20 mg po/d x 21 (sequential) and MPA 200 mg/d x 21

Lovecchio 7 et a1l

CTX 300 mg/m q 4 weeks, DOX 30 mg/m2 q 4 weeks, CDDP 50 mg/m2 q 4 weeks, megestrol acetate, 40 mg po 3 x 1 day

Nishida etal1'

CDDP 50 mg/m2, IFOS 1 gm/m /d x 2 5, mesna I gm/m /d x 5

2

2

III

2

NS

Total 126

8

6

18

14

II

15/15

4

27

1

7

11

43/46 CT CT + HT

1 6

5 26

2 4

10 17

Median surv 11 months Median surv 14 months

15/15

5

33

4

27

Mean DFS 8 months, mean surv 12 months

4/7

3

75

1

25

NS

II

2

2

8.5

Responders: median surv 60 weeks, median DFS 32 weeks

Alberts et a11"

DOX 30 mg/mr, CDDP 50 mg/m , 2 VBL5 mg/m q 3-4 weeks

II

42/64

3

7

10

24

Median 8 months

Piver 9 et al o

Melphalan 0.2 mg/kg/d x 4 days, 5-FU 10-15 mg/kg/d x 4 days q 4 weeks, MPA I g IM 18 patients: randomized to above _ TAM (40 mg/d)

II

50/50

10

20

14

28

Median DFS 5 months, median DFS (responders) 10 months

Pasmantier 12 0 et a1

DOX 60 mg/m2, CDDP 60 mg/m2

II

16/16

6

38

7

44

II

20/20

2

10

10

50

II

20/20

5

25

Trope et 01121 Kauppila 1 15 etal

2

DOX 50 mg/m , CDDP 50 mg/m

2

2

DOX 40 mg/m2, CTX 500 mg/m , 2 5-FU 500 mg/m , VCN 1.5 mg q 3 weeks

Mean 14.7 months

Abbreviations: VBL,vinblastine; VCN, vincristine; bid, 2 times a day.

cytology,125 -127although it was associated with considerable toxicity, particularly in women receiving pelvic irradiation. Interpretation of these data is difficult because none of the studies included a control arm. DISCUSSION The results of treatment for disseminated or recurrent endometrial cancer with either hor-

monal or cytotoxic therapy have been disappointing to date. However, recent laboratory and preliminary clinical observations have provided new insights into the biology of this disease. Creative exploitation of these discoveries could result not only in new therapeutic approaches, but also in the potentiation of modalities that already exist. Current efforts aimed at altering the hormonal milieu, while relatively nontoxic, appear to be of


1081

TREATMENT OF ENDOMETRIAL CANCER Table 9. Nonhormonal Adjuvant Trials in Endometrial Cancer Reference Soper et al"26

65 with positive peritoneal cytology: 53 stage I, 9 stage II, 3 stage Ill

Creasman et a112"

23/175 clinical stage I with positive peritoneal cytology 39/243 with positive peritoneal cytology: 25/190 stage 1,7/40 stage II, 3/8 stage III,4/5 stage IV

Heath et 01125

Morrow et a123

Stringer et a112"

224 entered, 181 assessable stage I or II (occult) with one or more risk factors: at least 50% myometrium invasion; documented pelvic or paraaortic nodes; occult stage II; adnexal metastases 30/33 assessable: 31 stage 1,2 stage II (occult)

Results

Treatment

Patients 32

32

P 15 mCi IP x 1

P 15 mCi IP

32

P 15 mCi IP

RT (pelvic ± paraaortic) or RT + DOX (45-60 mg/m')

CTX 500 mg/m', DOX 50 mg/m2, CDDP 50 mg/m2

11 recurrences (1 intraperitoneal, 4 intra- and extraperitoneal, 6 extraperitoneal) 4 recurrences in clinical stage I patients (89%2-year DFS) 3/23 recurred (9-36 month F/U; all extraperitoneal) Clinical stage I, positive cytology patients: 3/14 (21%) treated with 32 P recurred, 3-year DFS 76%; 7/11 not treated recurred (64%), 3-year DFS 27%; only 2 stage II patients were treated with 32p, both recurred; no stage IIIor IV patients were treated 16/39 with positive cytology treated 59/89 alive 56/92 alive

9 recurrences (8/9 with extrauterine disease); median progressionfree interval: 29 months (extrauterine disease), 45+ months (no extrauterine disease)

Abbreviations: IP, intraperitoneal; F/U, follow-up.

use in only a limited subset of patients. Recent evidence indicates that the 33% response rate commonly quoted in the literature is excessive and more likely approximates 20%.'7-19 Research is

needed to better define the role of hormones in this disease. Efforts should be made to identify with some precision women most likely to benefit from hormonal manipulations. Toward this end, studies with standardized receptor determinations are required. In discussing the GOG experience, Thigpen et al1' noted three difficulties in assessing PgR/ER data. First, receptor levels are usually not collected in a prospective manner; second, the data are pooled from multiple institutions using different assay systems and lacking adequate interlaboratory controls; and finally, the threshold for a positive receptor assay, particularly PgR, varies widely. Although most investigators currently believe that to be considered positive the PgR concentration should be higher than the 10 fmol/mg cytosol protein threshold used in breast cancer studies,6 5 there is no clear consensus on this issue. This variability limits the ability to compare published studies. By prospectively controlling these

variables, it will be possible to more accurately define the prognostic role of PgR and ERs in this disease. Combinations of hormonally active agents are of interest primarily based on laboratory evidence indicating a synergistic interaction between TAM and progestins. However, response rates in the small numbers of trials reported to date do not confirm the superiority of this approach, and serious toxicities are encountered when these agents are used concurrently. It is not clear what the optimal dose and schedule is for combination hormonal therapy, and ways to efficiently evaluate the various possibilities must be established. The recent descriptions of a nude mouse model,128130 in which PgR dynamics in response to progestin treatment were monitored, might serve as a useful paradigm in this regard. The development of alternative classes of active hormonal agents in other malignancies has raised the possibility that these agents might be effective in endometrial cancer as well. For instance, a LHRH analog has been described as active in a recent case report of endometrial cancer.' 31 Con-


1082

MOORE ET AL

ceptually, such an analog might affect the tumor through several mechanisms; the primary site of action is at the pituitary where, by down-regulating the receptor number, a decrease in gonadotropin levels is effected, with a subsequent decrease in estrogen levels. Endometrial cancer specimens have also been found to express large numbers of high-affinity receptors for LHRH, indicating that LHRH analogs might have a direct effect on endometrial carcinomas. However, it is possible that this effect might take the form of tumor stimulation, which must be considered before larger clinical trials are conducted. A number of clinical research questions exist regarding the use of cytotoxic agents in endometrial cancer, which should be addressed in an orderly, sequential manner. One issue is whether current combination cytotoxic regimens are superior to DOX alone. The only currently active phase III study in advanced endometrial cancer addresses this concern by comparing DOX to DOX and CDDP. This trial is also designed to provide prospective information regarding the importance of dose intensity in endometrial cancer. A retrospective analysis of 209 endometrial cancer patients in 10 trials1 3 2 indicates that a dose-response relationship exists for DOX and CDDP. Using an admittedly arbitrary and nonvalidated methodology, the average relative dose intensity for the combination arm (1.35) appears to be substantially higher than that for the DOXalone arm (0.8) in the current GOG study. Thus, this important study addresses two essential questions regarding the optimal delivery of cytotoxic therapy in women with advanced endometrial cancer. The availability of recombinant hematopoietic colony-stimulating factors (eg, granulocyte-CSF [G-CSF], granulocyte-macrophage-CSF [GMCSF], interleukin-3 [IL-3]) has stimulated interest in dose-intensity trials. Bronchud et al'33 have demonstrated that high doses of DOX (125 to 150 mg/m2) can be safely given to women with breast and ovarian cancer every 2 weeks for up to three cycles by using G-CSF. In addition, the emergence of carboplatin as an active drug provides a basis for developing high-dose regimens. The doselimiting toxicity of carboplatin is myelosuppression, and recent studies indicate that substantial increases in the dose, which can normally be delivered, can be achieved in the presence of

GM-CSF in women with ovarian cancer, 134 although thrombocytopenia remains a substantial problem. These observations provide a rationale for developing a combined carboplatin plus DOX plus G-CSF or GM-CSF regimen in endometrial cancer. Concurrent medical problems in many of these women often make them poor candidates for aggressive cytotoxic regimens. Hematopoietic growth factors that potentially influence platelet production (eg, IL-3 and/or IL-1) may increase the widespread applicability of this approach. Development of new agents for endometrial cancer continues to be a high priority. The inability of currently available drugs to prolong survival makes it ethical to explore investigational agents as initial treatment for this disease. At present, the GOG and SWOG are investigating new drugs in this manner. However, relative to other disease sites, drugs cannot be evaluated as rapidly due to fewer available patients eligible for clinical protocols. These restricted resources necessitate the prioritization of new drugs, focusing on those with activity in related malignancies, or those for which preclinical data suggest a rationale for use in endometrial cancer. One such drug is taxol, an agent with substantial activity in epithelial ovarian cancer refractory to CDDP-based therapy. 135' 136 Although supplies of this promising drug are currently limited, it is hoped that increased availability for phase II testing will be forthcoming. The role of adjuvant cytotoxic therapy has not yet been adequately explored. As evident in the GOG study, it is imperative to identify a group of patients at high risk of recurrence. Previous studies have identified extent of disease, tumor grade, and depth of myometrial invasion as being predictive of tumor virulence. 137 -139In addition, women with either positive peritoneal cytology' 25 -127,140 or certain histologic subtypes,141',142 such as adenosquamous, papillary serous, or clear-cell carcinomas, recur at a high rate. Recent laboratory studies have also indicated that hormone receptor,143,1 " flow cytometry,1415,"6 and fms-oncogene analyses 147 may complement standard histopathology in identifying high-risk groups. Since the number of eligible patients will be limited, any trial in this setting will require a collaborative effort. Biologic response modifiers are early in their development for endometrial cancer. In vitro data suggest that endometrial carcinoma is sensitive to


1083

TREATMENT OF ENDOMETRIAL CANCER tumor necrosis factor148 ; the GOG and SWOG are all currently evaluating this agent in phase II trials. IL-2-induced lymphokine-activated killer (LAK) cells have demonstrated cytotoxicity against human endometrial carcinoma preclinically both in an in vitro and a nude mouse model1 49; however, clinical studies containing IL-2 + LAK have not been done. Recently, IL-2, in combination with alpha-interferon, has shown activity in an endometrial cancer patient treated as part of a broad 15 A phase II study combining alphaphase I trial." interferon and 5-FU has also been shown to have promising activity against colon adenocarcinoma.'51 This latter regimen, in particular, and combination biologic-cytotoxic regimens in general, should be considered for phase II evaluation in endometrial cancer. Several preclinical observations may prove to have clinical relevance. P-glycoprotein, one of a class of membrane-bound proteins associated with multidrug resistance (mdr),'5 2 has been found to be expressed in pregnant rat endometrial tissue.' 3 In addition, progesterone was found to inhibit the ability of the cell to extrude a xenobiotic, the mechanism purportedly operational in conferring the mdr phenotype. There are no reports of endometrial cancer specimens expressing the P-glycoprotein de novo or during the course of cytotoxic therapy. This putative mechanism of acquired resistance to DOX provides a rationale for further investigations; however, it will be important to include correlative laboratory studies in the design of future interventional therapeutic trials in this area. Growth factor receptors on endometrial cancer cells have also been studied. Insulin-like growth factor I (IGF-I) receptors have been found in endometrial carcinomas in concentrations signifi-

cantly higher than normal endometrium; these concentrations increase in proportion to tumor grade, indicating that IGF-I may have an important growth-supporting role in the pathogenesis of this malignancy.'54 Likewise, the fms-oncogene product, which is the M-CSF receptor, is expressed in large concentrations in clinically aggressive tumors.1 47 Conversely, the epidermal growthfactor receptor (EGFR), while found on endometrial cancer specimens,"' is not expressed as strongly or as frequently as on surrounding normal endometrial tissue,'5 6 and its concentration is negatively correlated with increasing tumor grade.' 57 The etiology of these observations is not clear. Epidermal growth factor has been shown to have an inhibitory effect on an endometrial cell lines' and it is possible that the decrease in receptor number represents a circumvention of this growthfactor pathway. Other investigators, however, have implicated down-regulation as being operational.' 75' 51 9 Understanding the biology of these growth factors as they relate to the pathogenesis of endometrial cancer may lead to novel therapeutic approaches in the future. Finally, in vitro testing of endometrial tumor sensitivity to cytotoxic agents has been evaluated.',1" 1' Currently, these assays are more sensitive for predicting drug resistance than for identifying active drugs. Improvement in the systemic approach to disseminated endometrial carcinoma requires the development of new agents as well as maximizing currently available therapy. Achieving more effective systemic treatment will only be possible if priorities are established so that the limited patient resources available for clinical trials are used as efficiently and as expeditiously as possible.

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