adjuvant chemotherapy for high-risk endometrial cancer

Adjuvant Chemotherapy for High-risk Endometrlal Cancer Terri Pustilnik and Thomas W. Burke

Identification of histopathologic factors that predict the risk of tumor recurrence allows for selection of women with endometrial cancer who might benefit from adjuvant therapy. Most studies of adjuvant treatment have focused on external-beam irradiation or oral progestational agents and have failed to document a survival advantage for treated patients. Although recurrent or metastatic endometrial tumors often respond to salvage treatment with cytotoxic agents, there is relatively

little experience with postoperative systemic chemotherapy used in an adjuvant setting. A few nonrandomized trials--using doxorubicin/platinum-based regimens-- have suggested that adjuvant chemotherapy may be beneficial in some patient subsets. Data from larger- scale, randomized trials do not exist, Additional clinical experience is needed before a definite role for adjuvant chemotherapy can be established. Copyright �9 2000 by W.B. Saunders Company

E ndometrial cancer is most commonly treated surgically by total abdominal hysterectomy and

bilateral salpingo-oophorectomy. Since the adoption of a surgical staging system by the International Federation of Gynecology and Obstetrics in 1988, ~ additional staging procedures--typically some form of lymph node sampling coupled with peritoneal assessment--have been incorporated into the surgical management of this malignancy. Consequently the enumeration of a variety of histopathologic risk factors has allowed the identification of subsets of women at high risk for treatment failure. 2 These high-risk women are good candidates for adjuvant chemotherapy. This article reviews the current experience with this treatment option.

Risk factors for recurrence can be broadly separated into uterine and extrauterine categories. In- cluded in the uterine group are depth of myometrial invasion, histological grade, presence of lymphovascu- lar space invasion, involvement of the cervix or lower uterine segment, and presence of aggressive histological subtypes (papillary serous or clear cell carcinoma). Extrauterine spread to adnexal structures, peritoneal surfaces, omentum, or retroperitoneal lymph nodes greatly increases the potential for treatment failure. In a general population of women with endometrial cancer whose tumors appear to be clini- cally confined to the uterus, about two thirds can be considered low risk and one third high risk on the basis of some combination of these features.

A precise risk assessment of an individual patient

From the Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Thomas W. Burke, MD, Gynecologic Oncology, Box 67, UT M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Copyright �9 2000 by W.B. Saunders Company 1053-4296/00/1001-0004510.00/0

is difficult because so many risk factors have been identified. Consequently, subset analysis of women with homogeneous risk profiles becomes virtually impossible without a population base of thousands of individuals. Morrow et al 2 were able to identify the highest-risk subgroups of patients in their surgical staging study that included nearly 1,000 women. They found that the presence of extrauterine disease--particularly para-aortic node metastases-- was associated with the greatest risk of treatment failure. They also found that patients with multiple risk factors were at greater risk for recurrence than those with a solitary risk factor. Although subject to individual bias, most clinicians would probably con- sider adjuvant therapy for any patient whose esti- mated risk of recurrence exceeds 30%.

Adjuvant Therapy Adjuvant treatment options for women with endometrial cancer can be grouped as irradiation, hormonal therapy, or cytotoxic chemotherapy. Our interest in adjuvant cytotoxic chemotherapy began in the 1980s and developed from a number of observations. First, early attempts to employ progestational agents as postoperative adjuvants failed to demonstrate a survival advantage. 3,4 In fact, women receiving progestational therapy had a higher incidence of cardiovascu- lar complications than those receiving no treatment. 5 When it became evident that most high-risk tumors were not progesterone receptor positive, this provided a rational explanation for the failure of adjuvant hormonal therapy. 6 Second, randomized Scandi- navian trials employing adjuvant whole pelvic external-beam therapy failed to demonstrate a survival advantage for the treatment group] ,8 Many of the treatment failures were at distant sites outside of the pelvic field, suggesting a role for systemic therapy. Third, initial experience with cytotoxic chemother-

Seminars in Radiation Oncology, Vo110, No 1 (JanuaF), 2000: pp 23-28 23

24 Pustilnik and Burke

Table 1. Selected Active Single-Agent Trials in Women With Endometrial Carcinoma

Investigators Agent

Evalu- Response Response able Rate Duration

Patients (%) (too)

Thigpen et al 2~ (1979) DOX 43 37 5.0

Horton et a121 (1978) DOX 21 19 NS Deppe et a122 (1980) CDDP 13 31 4.0 Scski et a123 (1982) CDDP 26 42 5.0 Thigpen et a124

(1989) CDDP 49 20 2.9 Edmonson et a125

(1987) CDDP 14 21 2.0 Long et at 26 (1988) Carbo 26 27 4.3 Green et a127 (1990) Carbo 23 30 4.8 Burkel et a128 (1993) Carbo 27 33 2.7 Ball et a P (1996) TAX 28 36 NS

Abbreviations: DOX, doxorubicin; CDDP, ds-diamminedichloroplatinum (cisplatin); Carbo, carboplatin; TAX, paclitaxel; NS, not stated.

apy in women with recurrent endometrial carcinoma identified agents and regimens with objective response rates high enough to warrant testing them in an adjuvant setting.

Identification of active cytotoxic agents is typically defined by phase II salvage trials in patients with advanced or recurrent disease. A summary of selected positive single-agent trials for women with endometrial carcinoma is presented in Table 1. These studies have tbcused interest on the most active agents--cisplatin/carboplatin, doxorubicin, and paclitaxel for potential use in an adjuvant setting. Further experience with a variety of combination regimens (Table 2) provided evidence that objective

response rates of 40% to 60% were achievable in women with recurrent disease. On the basis of this substantial clinical activity, several trials employing cytotoxic agents as adjuvant therapy in high-risk women were conducted.

Clinical Experience

Stringer et al 9 reported initial experience with six cycles of adjuvant cisplatin (Platinol [Bristol-Myers Squibb, Princeton, NJ]), doxorubicin (Adriamycin [Pharmacia and Upjohn, Kalamazoo, MI]), and cyclophosphamide (PAC) given to a group of 33 women with high-risk clinical stage I endometrial cancer. Eligible patients included those with grade 2 tumors that invaded more than half of the myometrial thickness, grade 3 or variant histological types (papillary serous or clear cell) with any myometrial invasion, and any completely resected extrauterine disease. The overall 2-year survival rate was 83%. Predictably the presence of extrauterine disease-- even when resected significantly reduced the median progression-free survival from >45 to 29 months. An expanded report of this nonrandomized treatment program involving 62 women clearly established the presence of extrauterine disease as the major prognostic factor, l~ Actuarial 3-year survival was 46% in patients with extrauterine disease and 82% in those without. Similarly, median disease-free survival was 26 months when extrauterine disease was detected and >36 months when it was not. This study was conducted before the adoption of the surgical staging system and so includes women with stage I and stage III tumors. The excellent outcomes

Table 2. Experience With Combination Chemotherapy Regimens in Women With Recurrent Endometrial Carcinoma

No. of Response Response Investigators Agent Patients Rate (%) Duration (too)

Seski et aP ~ (1981) CTX/DOX 26 31 4 Horton et a131 ( 1 9 8 2 ) CTX/DOX/Meg 55 27 10 Piver et aP 2 ( 1 9 8 6 ) MEL/5-FU/Provera* 50 48 10 Cohen et a133 ( 1 9 7 7 ) MEL/5-FUAVIeg 77 38 6 Cohen et a134 ( 1 9 8 4 ) CTX/DOX/5-FU/Meg 78 36 5 Deppe et a135 ( 1 9 8 1 ) CTX/DOX/5-FU/Meg 29 45 7 Thig-pen et aP 6 ( 1 9 9 3 ) CDDP/DOX 101 45 NS Trope et aP 7 ( 1 9 8 4 ) CDDP/DOX- 20 60 - 12 Burke et aP 8 ( 1 9 9 1 ) CDDP/DOX/CTX 87 45 6 Alberts et aP 9 ( 1 9 8 7 ) CDDP/DOX/VBL 42 31 8 Long et al 4~ ( 1 9 9 1 ) MqN/VBL/DOX/CDDP 25 60 7

Abbreviations: CTX, cyclophosphamide; DOX, doxorubicin; Meg, megestrol acetate (Megace [Bristol-Myers Squibb, Princeton, NJ]); 5-FU, 5-fluorouracil; MEL, metphalan; CDDP, ds-diamminedichloroplatinum (cisptatin); VBL, vinblastine; MTX, methotrexate; NS, not stated. *Medroxyprogesterone acetate (Provera [Pharmacia and Upjohn, Kalamazoo, MI]).

Adjuvant ChemotherapyJbr High-Risk Endometrial Cancer 25

seen in high-risk surgical stage I cases (who did not receive external-beam pelvic irradiation) seems to establish cytotoxic chemotherapy as a legitimate adjuvant modality.

During the same time interval, the Gynecologic Oncology Group (GOG) conducted a prospective, randomized trial for women that used standard whole pelvic external-beam irradiation with or without adjuvant doxorubicin, 45 to 60 mg/m 2 every 3 weeks to a total dose of 500 mg/m 2 after completion of irradiationJ 1 Eligible clinical stage I patients included those with deep myometrial invasion, exten- sion to the cervix, adnexal metastases, or retroperitoneal nodal spread. No statistically significant differ- ences in overall or progression-free survival were seen among 181 evaluable cases. Five-year survival was 63% in the irradiation-only group and 72% in the irradiation and doxorubicin group.

Jennings et aP 2 treated 18 high-risk women- - including some with papillary serous tumors with postoperative external-beam and intracavitary irradiation followed by six to eight cycles of cisplatin, doxorubicin, and etoposide chemotherapy. In a preliminary analysis, they reported a 2-year survival rate of 67%. In another preliminary report, O'Brien and Killackey 13 treated 26 women with multiple poor prognostic features with four courses of cisplatin and cyclophosphamide chemotherapy followed by external-beam and intracavitary irradiation. Disease-free survival was 58% during a median follow-up interval of 46 months. The authors compared this treatment group with a nonrandomized historical group of 24 women treated with pelvic irradiation alone. Disease- free survival in this historical group was 49%. The authors concluded that adjuvant chemotherapy had only a modest impact on outcome when combined with irradiation.

Smith et a114 conducted a trial of adjuvant PAC chemotherapy followed by tailored external-beam irradiation in 47 women with high-risk endometrial tumors. The 2-year progression-free survival for 31 evaluable women with endometrioid histology was 72.5%. Analysis of data from this trial is incomplete. More detailed data from all of these adjuvant trials are outlined in Fig 1.

The Radiation Therapy Oncology Group has just completed a slightly different phase II trial that treated high-risk unstaged women with concomitant cisplatin and external-beam irradiation followed by four courses of cisplatin and paclitaxel chemotherapy. The GOG also attempted a randomized compari-

son of adjuvant cisplatin and doxorubicin chemotherapy with external-beam irradiation in women with high-risk endometrial cancers confined to the uterus, but the group was unable to meet accrual goals and closed the trial. Accrual was probably hindered by the trial's tight definition of high risk, which was based on actual outcomes data from prior studies, and by investigator bias regarding the absence of irradiation from one treatment arm. Nevertheless, had it been completed, this trial could have provided a valuable comparison of regional versus systemic adjuvant therapy in a well-defined population of high-risk women.

Papillary Serous Tumors

Although it accounts for less than 10% of all epithe- lial endometrial malignancies, uterine papillary serous carcinoma (UPSC) has been identified as a particularly virulent subtype of endometrial cancer characterized by older mean age at diagnosis, fre- quent metastasis to intra-abdominal and lymphatic sites, and more common incidence of higher-stage tumors. 15 Because of the rarity of this tumor and its relatively recent recognition, most of the reported clinical experience for chemotherapeutic treatment is anecdotal. In addition, much of the available information is derived from women receiving chemotherapy for measurable advanced or metastatic le- sions. Specific reports of treatment experience in an adjuvant setting are limited, and many cases are included in larger reports of high-risk women that include all histological subtypes of endometrial le- sions.

Smith et aP 4 documented a particularly poor outcome for the eight women with UPSC tumors treated on their adjuvant therapy trial. This group had a 2-year progression-free survival of only 23%. Levenback et aP 6 reported the outcomes of 20 women with advanced or recurrent UPSC tumors treated with PAC chemotherapy. Six of these women with nonmeasurable extrauterine disease were treated in an adjuvant setting, but their outcomes were not separated from the larger group, which had an actuarial 5-year survival rate of 23%. Seven women with UPSC tumors were treated on the previously cited adjuvant PAC trial from our group/ Their outcomes were also not separated from the larger group experience. Others have reported isolated objective responses of UPSC tumors to platinum-


E L I G I B I L I T Y

Morrow (1990)

> I/2 invasion Cervical invasion Pelvic +/or periaortic nodal metastases Adnexat reels

I [ T R E A T M E N T

Randomized

Po,vic• I J +'a~215 I "1

~[ 89 patients ~1 No further RX

J 92 patients DOX 45-60 rag/m2

~[ q 3 w k x 8

Burke (1994)

Grade 2-3 Variant histology Invasion>l/3 Extrauterine disease

,62 patients [ CDDP 50 mg/m 2

I~" DOX50mg/m z q 4 w k x 6 CTX 500 mg/m 2

O U T C O M E

~[ Median F/U > 36 mos ~[ Survival 75% (2-yr~'

~[ Median F/U > 36 mos ~1 Survival 69% (2-yr)

I Median F/U 37 mos Survival 66% (3-yr) -Uterus only 82% -Extrauterine 46%

O'Brien (I 994)

Invasion >1/2 Bulky tumor Grade 3 or variant histology Lymphvascular invasion Node metastasis Cervix invasion Extrauterine disease

Historical

26 patients CDDP 75mg/m 2 DOX40mg/m z q 4 w k x 4 CTX 750 mglm 2

Pelvic XRT I ~[ Median F/U 46 mos ~l Survival 58% (4-yr)

I Median F/U 46 mos ~1 No further RX ] b.. Survival 49%(7-yr) I 26 patients

~[ Pelvic XRT ~f ~[

Jennings (I 993)

Grade 3 Papillary serous Exlraulerine disease

18 patients CDDP 50 mg/m 2 Median F/U NS

~,,[ PelvicXRT ~ DOX50mg/m 2 q4wkx6 Surviva167%(2-yr) VP-16 150 mg/m 2

Smith (1994)

>2/3 invasion No gross residual disease Papillary serous/clear cell

CDDP 50mg/m 2 Median F/U 27 mos DOX 50 mg/m 2 q 4 wk x 6 Pelvic XRT ~ Survival (2-yr) CTX 500mg/m 2 +/- aortic XRT -72% nonpapillary

-22% papillary

Figure 1. Schematic synopsis of adjuvant chemotherapy experience in endometrial cancer (Abbreviations: XRT, radiation therapy; RX, treatment; F/U, follow-up; DOX, doxorubicin; CDDP, c/s-diamminedi/chloroplatinum [cisplatin]; CTX, cyclophosphamide.)

based therapy, but most of these women were not treated in an adjuvant setting) 7,1a

Although some oncologists believe that UPSC variants behave in a manner similar to the more typical endometrial adenocarcinomas, we believe that this lesion is an aggressive variant with a unique metastatic pattern and a distinctly poor outcome. Women with these tumors are ideal candidates for clinical adjuvant therapy trials and probably should be treated separately from those with the usual types of adenocarcinoma. In contrast to typical endometrial cancers for which potentially useful adjuvant agents have been selected through salvage therapy trials, no significantly active agents have been identified for UPSC. The current focus of adjuvant therapy options seems to be on further testing of new cyto-

toxic drugs for activity and whole abdominal irradiation (see the article by Greven in this issue)) 9

Conclusion

Adjuvant treatment for women with high-risk endometrial carcinoma is a controversial clinical topic that is frequently clouded by strong treatment bias and suboptimal data. The use of cytotoxic agents is especially controversial given the long clinical prac- tice of adjuvant hormonal treatment and radiotherapy. Despite obvious and well-documented responses to these modalities, no prospective randomized study has shown a survival advantage for any adjuvant treatment. The current data to support further examination of cytotoxic adjuvant treatment

Adjuvant Chemotherapy for [tigh-Risk Endometrial Cancer 2 7

a r e l i m i t e d to t h e f e w e x p l o r a t o r y t r i a l s o u t l i n e d

h e r e . T h e s u b s t a n t i a l f r e q u e n c y o f d i s t a n t f a i l u r e a n d

t h e r e l a t i v e l y h i g h r e s p o n s e r a t e s o f e n d o m e t r i a l

t u m o r s g iven sa lvage d r u g t r e a t m e n t m a k e s y s t e m i c

cy to tox ic t h e r a p y a n a t t r a c t i v e a d j u v a n t op t ion . F u r -

t h e r i n v e s t i g a t i o n is i n d i c a t e d .

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adjuvant chemotherapy for high-risk endometrial cancer

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