www.elsevier.com/locate/ygyno

Gynecologic Oncology

High-risk endometrial cancer subgroups: candidates for

target-based adjuvant therapy$

Andrea Mariania, Sean C. Dowdya, Gary L. Keeneyb, Harry J. Longc,

Timothy G. Lesnickd, Karl C. Podratza,*

aSection of Gynecologic Surgery, Mayo Clinic, Rochester, MN 55905, USAbDivision of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USAcDivision of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA

dDivision of Biostatistics, Mayo Clinic, Rochester, MN 55905, USA

Received 10 December 2003

Abstract

Objective. To identify patients with endometrial cancer at risk for hematogenous, lymphatic, or peritoneal recurrence (or combinations of

them) who might potentially benefit from target-based therapies.

Methods. During a 13-year period, 915 patients had endometrial cancer managed with hysterectomy and standard adjuvant therapy. On

the basis of our previous regression analyses, depth of myometrial invasion predicted the risk for hematogenous recurrence; positive lymph

nodes and cervical stromal invasion predicted lymphatic recurrence; stage IV disease or combination of nonendometrioid histology, cervical

stromal invasion, positive lymph nodes, and positive peritoneal cytology was predictive of peritoneal recurrence. Median follow-up was 66

months.

Results. Applying the above criteria to the population of 915 patients, 24% were considered at risk for hematogenous recurrence, 18% for

lymphatic recurrence, and 16% for peritoneal recurrence. The respective relapse rates at 5 years were 28% for patients who were at risk for

hematogenous recurrence, 31% for lymphatic recurrence, and 42% for peritoneal recurrence. This contrasted with less than a 5% recurrence

rate in the corresponding subgroups not at risk for relapse (P b 0.001). Collectively, of the 915 patients, 324 (35%) were considered at risk for

recurrence in one or more of the above three sites. Overall, 89% of all recurrences were identified in this at-risk group. Importantly, 46% of

the patients considered at risk subsequently had recurrence in one or more of the three sites, compared with only 2% of patients not at risk for

relapse (P b 0.001).

Conclusion. Patients at risk for relapse had a 46% probability of experiencing recurrence within 5 years despite management with

standard therapy. New target-based algorithms for the 35% of endometrial cancer patients deemed at risk should be incorporated in the

development of future prospective multimodality clinical trials predicated on site(s) of recurrence.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Endometrial cancer; Hematogenous; Lymphatic; Peritoneal; Recurrence; Therapy

0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.ygyno.2004.06.042

$

Presented at the 13th International Meeting of the European Society

of Gynaecological Oncology (ESGO), Brussels, Belgium, April 6–10,

2003.

No conflicts of interest exist for this manuscript.

* Corresponding author. Division of Gynecologic Surgery, Mayo

Clinic, 200 First Street SW, Rochester, MN 55905.

Introduction

In the United States, endometrial cancer is the most

common malignancy of the female reproductive tract and is

exceeded annually in overall frequency only by breast,

colon, and lung cancers. It is estimated that during calendar

year 2004, 40,320 new cases of endometrial cancer will be

diagnosed and 7090 women will die of this disease [1]. This

neoplasm generally becomes manifest early in its natural

95 (2004) 120–126

A. Mariani et al. / Gynecologic Oncology 95 (2004) 120–126 121

history, resulting in approximately 80% of patients present-

ing with stage I disease. Nevertheless, nearly one of every

three women who die of endometrial cancer presents with

presumed localized disease.

The majority of treatment failures and the accompanying

compromised longevity are the result of the failure to

recognize sites of occult extrauterine dissemination at the

time of primary treatment. Furthermore, adjuvant therapy has

generally been dictated by traditional preferences (modality-

based) rather than target-based algorithms as determined by

patterns of recurrence.

The natural history of epithelial corpus cancer includes

four potential routes of metastasis: contiguous extension,

hematogenous dissemination, lymphatic embolization, and

exfoliation with intraperitoneal spread. The associated

recurrences for each of these diverse routes of spread would

presuppose different adjuvant treatment strategies. In

addition, such target-based therapies are predicated on the

cataloging of specific pathologic or molecular factors that

identify patients at high risk for harboring occult disease

disseminated via one or more of these routes.

In a preliminary analysis, we reported independent risk

factors for recurrence based on hematogenous [2,3],

lymphatic [4], and intraperitoneal [5] routes of dissem-

ination in endometrial cancer (Table 1).

The objective of the present study was to identify

subgroups of patients with predictable regional or distant

patterns of recurrence who might potentially benefit from

target-based adjuvant therapies.

Materials and methods

From 1984 to 1996, 1109 patients with endometrial

cancer were managed surgically at Mayo Clinic (Rochester,

MN). Based on data from their medical records, 915

patients with epithelial endometrial cancer met the follow-

ing inclusion criteria: (1) treatment included hysterectomy

and removal of existing adnexal structures and (2) no other

Table 1

Risk factors for hematogenous, lymphatic, and peritoneal recurrences [2–5]

Route of recurrence Risk factors

Hematogenous

All stages of disease Myometrial invasion N50%

Stage I disease, negative LNs Myometrial invasion z66%

Lymphatic

Pelvic/paraaortic LNs CSI, LN metastases

Peritoneal spread Stage IV disease

Stages II–III disease, z2 CSI,

PPC, LN metastases, or type II histo

CSI indicates cervical stromal invasion; LN, lymph node; PPC, positive

peritoneal cytology; type II histo, nonendometrioid subtypes.

malignancy was diagnosed within 5 years before or after

the diagnosis of endometrial cancer (except for carcinoma

in situ or skin cancer other than melanoma).

Staging was defined according to the International

Federation of Obstetricians and Gynecologists (FIGO)

surgical staging system [6]. For patients treated before

1988, stage was determined retrospectively on the basis of

the surgical and pathologic assessments. The histologic

classification was according to the World Health Organ-

ization classification [7]. Architectural grading was based on

the degree of glandular differentiation in accordance with

the FIGO guidelines [6]. Lymphovascular invasion was

considered present when tumor cells were within or attached

to the wall of a capillary-like space.

All hematoxylin- and eosin-stained slides of the tumor

were reviewed retrospectively by one of us (G.L.K.) to

confirm the original diagnosis of adenocarcinoma and to

determine FIGO grade, histologic subtype, and lymphovas-

cular invasion.

All surgical procedures were the responsibility of a

gynecologic oncologist. Lymphadenectomy usually was

performed in patients considered by the surgeon to be at

risk for lymph node metastasis, according to the histologic

grade of the tumor and the depth of myometrial invasion as

determined by an intraoperative analysis of frozen tissue

sections. Postoperative adjuvant radiotherapy consisted of

external pelvic, paraaortic, or abdominal irradiation or

vaginal brachytherapy or a combination of these. Occasion-

ally, oral megestrol acetate was prescribed or adjuvant

chemotherapy was administered.

When sufficient follow-up information about survival

and recurrence was not available in the clinical records,

death certificates were obtained and letters were sent or

telephone calls were made to patients and family physicians

to obtain the information.

For the definition of the different sites of recurrence, we

focused on the primary areas of dissemination as follows:

bperitoneal recurrenceQ was defined as disease recurring in

the upper abdomen or involving the pelvic peritoneum (or

both). Frequently, these recurrences were manifested by

ascites or intestinal obstruction. Recurrences in the

abdominal cavity that involved exclusively the pelvic

sidewall or the paraaortic area were not included in

bperitoneal recurrence.Q Peritoneal relapse usually indicates

disease that has the potential to spread throughout the entire

abdominal cavity. In the present study, the term bperitonealrecurrenceQ was used synonymously with babdominal

recurrence.Q bHematogenous disseminationQ was defined

as the presence of the first site of recurrence detected in the

lung or the liver or other sites, that is, adrenals, breast,

brain, bone, or skin, presumed accessed via the vascular

system. bLymphatic recurrenceQ was defined as primary

relapses occurring along the pelvic sidewall, within the

paraaortic/vena cava area, or in other node-bearing areas

(i.e., groin, axilla, supraclavicular, mediastinal) as the

primary site of recurrence.

Table 2

Characteristics of the 915 study patients

Characteristic Patients

No. %a

Stage of disease

I 632 69

II 45 5

III 155 17

IV 83 9

Cervical stromal invasion

No 809 88

Yes 106 12

Myometrial invasion

V50% 684 75

N50% 223 25

Not verifiableb 8 –

Peritoneal cytology

Negative 715 85

Positive 131 15

Not recordedb 69 –

Lymph nodesc

Negative 421 82

Positive 93 18

Not harvestedb 401 –

Lymphovascular invasion

No 701 86

Yes 110 14

Not verifiableb 104 –

Histologic subtype

Endometrioid 812 89

A. Mariani et al. / Gynecologic Oncology 95 (2004) 120–126122

On the basis of our previous regression analyses [2–5],

the following characteristics were used to define subgroups

at risk: (1) patients with stage I disease (negative nodes)

with myometrial invasion of z66% and those with stage I

(nodal status unknown) or stages II to IV disease with

myometrial invasion of N50% were considered at risk for

hematogenous recurrence; (2) positive lymph nodes (pelvic

and/or paraaortic) or cervical stromal invasion (or both) was

predictive of lymphatic recurrence; (3) stage IVor stages II–

III disease with at least two risk factors (i.e., positive lymph

nodes, nonendometrioid histologic subtype, positive peri-

toneal cytology, cervical stromal invasion) was predictive of

peritoneal recurrence (Table 1).

For statistical purposes, endometrioid, endometrioid with

squamous differentiation, and adenosquamous tumors were

considered together. Grades 1 and 2 lesions were combined

and compared with grade 3 lesions. If the information about

one or more risk factors was not available (e.g., no

information about lymph node status), the patient was

considered bnegativeQ for that risk factor (i.e., negative

lymph nodes).

Statistical analysis was performed with the Fisher exact

test and v2 analysis to test for relationships between pairs of

categorical variables. The Kaplan-Meier method and log-

rank test were used for time-to-event analyses, with

recurrence as the end point. Censoring was considered at

date of last contact or death in case of no recurrence.

Differences were considered statistically significant at P b

0.05. SAS System 6.10 statistical software and JMP

statistical program (Version 4.0.4; SAS Institute Inc.) were

used for the analysis.

Nonendometrioid 103 11

Histologic grade

1 410 45

2 291 32

3 213 23

Not verifiableb 1 –

a Percentages exclude missing cases.b For statistical purposes, patients with information missing about a risk

factor were considered bnegativeQ for that risk factor.c Pelvic or paraaortic or both.

Results

The mean age F SD of the 915 patients was 64.5 F 11.0

years (range, 22–95 years). The clinical and pathologic

characteristics of the patients are summarized in Table 2.

Overall, lymph node dissection was performed in 514

patients (56%), specifically, pelvic lymphadenectomy in

497 (54%) and paraaortic lymphadenectomy in 152 (17%)

(paraaortic lymphadenectomy only in 12 and concomitant

pelvic and paraaortic lymphadenectomy in 140); the site

from which the nodes were harvested was not identified in

five patients. Lymph node dissection was performed in

50% of patients with stage I disease, 60% with stage II,

85% with stage III, and 48% with stage IV. Adjuvant

radiotherapy was administered to 296 patients (32%),

adjuvant chemotherapy to 36 (4%), and adjuvant hormone

therapy to 45 (5%). Of the 296 patients who received

adjuvant radiotherapy, 186 (63%) received external beam

radiotherapy only (all patients received pelvic radiotherapy,

with the paraaortic area included in 40 patients and the

whole abdomen in 90), 20 (7%) had intraperitoneal

injection of phosphorus 32, 19 (6%) had vaginal brachy-

therapy only, and 71 (24%) received combined vaginal

brachytherapy and external beam radiotherapy (all were

managed with pelvic radiotherapy, nine with extended field

to the paraaortic area, and 12 with whole abdominal

radiotherapy).

The median follow-up was 66 months (range, 0–213

months). As previously suggested, deep myometrial inva-

sion was the strongest predictor of hematogenous recur-

rence [2]. Considering all stages of disease, hematogenous

recurrences at 5 years were detected in 28% of patients with

myometrial invasion of N50%, compared with only 4%

with myometrial invasion of V50% (P b 0.01). However, in

surgical stage I (node-negative) patients, the discriminating

depth of myometrial invasion was the outer third [3]; 2% of

patients at 5 years had recurrence via hematogenous

Table 3

Rates of recurrence at 5 years according to the different risk categories

(n = 915)

Risk category % Recurrences

at 5 years

Hematogenous

All stages

Myometrial invasion V50% 4

Myometrial invasion N50% 28

Stage I (negative lymph nodes)

Myometrial invasion b66% 2

Myometrial invasion z66% 34

Lymphatic

No risk factors 2

CSI and/or positive lymph nodes 31

Peritoneal

Stage IV disease 63

Stages II–III disease z2 risk factorsa 21

Stages I–III disease V1 risk factora 1

Overallb

Not at riskc 2

At riskc 46

CSI indicates cervical stromal invasion.a Cervical stromal invasion, nonendometrioid histologic subtype, positive

lymph nodes, positive peritoneal cytology.b Excluding vaginal recurrences.c For at least one of the three categories of recurrence (i.e. hematogenous,

lymphatic, or peritoneal).

Fig. 1. Recurrence-free survival (RFS) according to risk classification.

Patients at risk for any site of recurrence (35% of population) had a 54%

5-year RFS (excluding isolated vaginal recurrences) versus 98% for

patients not at risk (P b 0.001).

Fig. 2. Percentage of patients with different sites of recurrence. Overall, 190

(21%) patients had recurrence: 9% hematogenous recurrences, 6%

lymphatic recurrences, 6% peritoneal recurrences, and 5% vaginal

recurrences. Approximately half of the patients in each category had

multiple sites of relapse.

A. Mariani et al. / Gynecologic Oncology 95 (2004) 120–126 123

dissemination with myometrial invasion of b66%, com-

pared with 34% of patients with myometrial invasion of

z66% (P b .01) (Table 3).

Cervical stromal invasion and positive lymph nodes were

the strongest risk factors for lymphatic recurrence in the

pelvic and paraaortic areas [4]. Among patients with at least

one of the above two characteristics, 31% experienced

lymphatic recurrence at 5 years, compared with 2% of those

without either of these risk factors (P b 0.01) (Table 3).

Stage IV disease or stage II or III disease in the presence

of two or more of the following factors, cervical invasion,

positive peritoneal cytology, positive lymph nodes, or

nonendometrioid subtype, strongly predicted peritoneal

recurrence [5]. Overall, 42% of the patients in the at-risk

group had disease recurrence by 5 years, compared with

only 1% of those not at risk (P b 0.01). According to

stratification by stage, 63% of patients with stage IV disease

had peritoneal recurrence by 5 years. If only patients with

stages I to III disease are considered, 1% experienced

peritoneal recurrence at 5 years when one or no risk factor

was detected, compared with 21% of those with two or more

of the above risk factors (P b 0.01) (Table 3).

Consistent with our previous studies [2–5], the predicted

sites of recurrence were stratified according to pathologic

risk factors (Table 1). According to the above criteria (Table

1), 223 patients (24%) were identified to be at risk for

hematogenous recurrence, 168 (18%) for lymphatic recur-

rence, and 145 (16%) for peritoneal recurrence. Because of

the presence of multiple risk factors, some patients were

considered at risk for recurrence in more than one site.

Collectively, 324 patients (35% of the overall population)

were considered at risk for recurrence in one or more of the

three sites (i.e., hematogenous, lymphatic, peritoneal).

However, these at-risk patients accounted for 141 (89%)

of the 158 observed relapses (excluding 32 isolated vaginal

relapses). Moreover, 46% of the patients at risk for any site

of recurrence experienced a relapse in one or more of these

three sites by 5 years (notwithstanding having received

traditional modality-based therapy), compared with only 2%

of patients not included in the at-risk group (P b 0.001)

(Fig. 1, Table 3). The negative predictive value for

recurrence of the identified risk factors was 97%, and the

positive predictive value was 44%.

Considering the overall population of 915 patients, 190

(21%) had identifiable relapse of disease. The site of

recurrence was unknown in 14 patients. Excluding these 14

patients, we observed 84 (9%) hematogenous recurrences,

57 (6%) lymphatic recurrences, 57 (6%) peritoneal recur-

rences, and 41 (5%) vaginal recurrences (Fig. 2). More

Fig. 3. Of all recurrences, 48% had hematogenous component (21%,

isolated hematogenous recurrences), 32% had lymphatic component (16%,

isolated lymphatic recurrences), 32% had peritoneal component (18%,

isolated peritoneal recurrences), and 18% had isolated vaginal recurrences.

Approximately 27% of recurrences had multiple components of recurrence.

A. Mariani et al. / Gynecologic Oncology 95 (2004) 120–126124

precisely, 32 of the 176 (18%) patients whose site of

recurrence was known had isolated recurrence in the

vagina, 37 (21%) had an isolated hematogenous relapse,

28 (16%) had an isolated lymphatic relapse, and 31 (18%)

had an isolated peritoneal relapse. However, 22 patients

(12.5%) had concomitant hematogenous and lymphatic

recurrence, 19 (11%) had concomitant hematogenous and

peritoneal recurrence, one (0.5%) had concomitant lym-

phatic and peritoneal recurrence, and six (3%) had

concomitant recurrence in all three sites. Of all the

recurrences, 48 (27%) had multiple sites of primary relapse

(Fig. 3).

Discussion

Approximately 70% to 80% of patients with endometrial

cancer present with localized disease that potentially can be

cured with surgery alone. However, approximately one of

every three women dying of endometrial cancer was

considered to have early-stage locoregional disease [1].

The main reason for treatment failure after traditional

modality-based therapy is the presence of documented or

occult extrauterine systemic disease and our inability to

recognize and treat it successfully.

Traditional treatment strategies for endometrial cancer

have been based mainly on uterine histologic risk factors.

Patients identified to be at risk for recurrence have usually

been managed with adjuvant pelvic radiotherapy. However,

it is reasonable to suggest that, for postoperative therapy to

significantly affect disease-free survival, treatment must be

directed appropriately according to the predicted site or sites

of recurrence. Different patterns of recurrence presuppose

potentially independent or unique pathologic [2–5] or

molecular predictive characteristics [8].

In the present study, we used the same risk factors that

we previously identified as predictive of the different sites

of recurrence [2–5] but, compared with the previous series,

analyzed an expanded population of patients. The larger

population of patients (n = 915) included in the present

report and, consequently, the larger number of recurrences

(n = 190) permitted analysis of stratified subgroups

according to the different and simultaneous sites of the

primary recurrence.

Because of the unique characteristics of vaginal recur-

rence, essentially minimized with adjuvant vaginal brachy-

therapy [9], and with a salvage rate exceeding 60% at 5

years [10,11], we did not include predictors of vaginal

recurrence in the present analysis.

Invasion beyond the inner half of the myometrium was

a strong predictor of distant hematogenous recurrences

(mainly in the lung), as previously reported (Tables 1 and

3) [2]. Moreover, on the basis of our previous analysis

[3], we chose the cutoff of 66% for defining the depth of

myometrial invasion that was predictive of hematogenous

recurrence in patients with documented surgical stage I

disease. Of interest, we observed an extremely high rate

of hematogenous recurrence in patients with surgical stage

I disease with invasion of the outer third of the

myometrium (34% at 5 years). This rate of recurrence

is higher than the 10% to 16% distant recurrence rate that

has been reported for patients with similar characteristics

[12–15]. However, documented early localized disease

associated with deep (z66%) myometrial invasion is

relatively infrequent in patients whose disease has been

adequately staged [3]. Moreover, in accord with the

FIGO staging system [6], the threshold for identifying

tumors with deep myometrial invasion is usually 50%

[16–18]. Hence, the information available in the literature

about the patterns and rates of recurrence in early

(adequately staged) endometrial cancer with invasion of

the outer third of the myometrium is limited, and our

findings urge further verification in prospective or

retrospective studies.

We previously identified cervical stromal invasion and

metastatically involved lymph nodes as the strongest

predictors of lymphatic recurrence along the pelvic sidewall

and in the paraaortic area (Tables 1 and 3) [4]. Furthermore,

stage IV disease and stages II and III disease with at least

two risk factors (i.e., cervical stromal invasion, positive

peritoneal cytology, positive lymph nodes, nonendometrioid

histologic subtype) were the strongest predictors of abdomi-

nal recurrence (Tables 1 and 3) [5].

With the use of the above-identified risk factors (Table

1), patients are readily stratified according to their risks for

different patterns of recurrence. This stratification based on

histopathologic risk factors would appear to facilitate more

appropriate adjuvant treatment strategies predicated on

anticipated routes of dissemination and subsequent relapse.

Therefore, recognition of the potential for hematogenous

recurrence would presuppose the use of systemic cytotoxic

therapy [19]. Furthermore, the risk of pelvic or paraaortic

(or both) lymphatic recurrence might be minimized with

adequate lymphadenectomy [20,21] and adjuvant radio-

therapy (pelvic or paraaortic or both) [22,23]. In addition,

Table 4

Algorithm for the surgical treatment of endometrial cancer at Mayo Clinic

Treatment—hysterectomy, bilateral salpingo-oophorectomy, peritoneal

cytology, bilateral pelvic/paraaortic lymphadenectomy

(up to renal vessels)

1. Can omit lymphadenectomy if

(A) All the following: no myometrial invasion, endometrioid,

no evidence of tumor outside the corpus (independently of grade or

tumor diameter)

(B) All the following: endometrioid, grades 1–2, 0bmyometrial

invasion b50%, tumor diameter of V2 cm, no evidence of tumor

outside the corpus

2. If nonendometrioid (serous, clear cells), add complete omentectomy,

appendectomy, peritoneal biopsies (11 pairs: cul-de-sac, bladder

peritoneum, R diaphragm, R/L colic gutters, R/L pelvic sidewall,

small-/large-bowel serosa and mesentary, any suspicious area)

A. Mariani et al. / Gynecologic Oncology 95 (2004) 120–126 125

the risk factors for peritoneal recurrence appear to identify

patients who potentially would benefit from therapy

directed at the entire abdomen. However, because the

present study and a previous report [5] have demonstrated

an extraabdominal recurrence rate exceeding 40% in the

presence of intraperitoneal recurrence, the traditional

modalities of intraperitoneal phosphorus 32 [24] and

whole abdominal radiotherapy [25] do not appear appli-

cable. Consistent with these observations, the preliminary

data from Gynecologic Oncology Group 122 suggest a

more favorable response with systemic cytotoxic therapy

than with whole abdominal radiotherapy [26].

In the present analysis, we observed the occurrence of

concomitant primary recurrences at multiple sites. Overall,

27% of all recurrences had multiple sites of primary

declaration (Fig. 3). When multiple risk factors are

identified, patients should be considered at risk for multiple

sites of recurrence and thus may be considered potential

candidates for multimodality therapy (i.e., systemic cyto-

toxic therapy and radiotherapy) (Table 1). On the basis of

the present study and multiple previous publications on

endometrial cancer from our institution, we recently

developed guidelines for the surgical (Table 4) and post-

operative treatment of patients with endometrial cancer at

Mayo Clinic.

Complete surgical staging was not performed in all the

patients in our series; however, of the patients operated on

during the 13-year study period (1984–1996), the defini-

tions of risk groups for different sites of recurrence were

forwarded, taking into account the completeness of staging

in the statistical analyses [3–5]. We believe that complete

surgical staging permits the accurate determination of lymph

node and peritoneal (when appropriate) involvement with

disease and is necessary for a more precise definition of

patients at risk for hematogenous, lymphatic, and peritoneal

recurrence (Tables 1 and 4).

During the 13-year period of our study, all the patients

received state-of-the-art therapy. Therefore, the observed

rate and patterns of recurrence are representative of the

relapses one would anticipate in patients with endometrial

cancer managed with traditional modality-based therapy.

In this retrospective assessment of outcomes, radiotherapy

was the main adjuvant modality administered to patients

considered at risk for recurrence. For this reason, the

observed rate of primary lymphatic (6%) and abdominal

recurrences (6%) may have been underestimated because

of the locoregional effect of adjuvant radiotherapy.

However, the rate of primary hematogenous recurrence

(9%) is likely representative of that observed in an

untreated population.

On the basis of the identified factors predictive of

recurrence via one of the three main routes of dissemination

(Table 1), 35% of the overall population of patients with

endometrial cancer referred to our institution were declared

at risk for posttreatment recurrence. This at-risk group

accounted for 89% of all recurrences and had a 46%

probability of having a recurrence by 5 years despite

receiving traditional modality-based therapy (Fig. 1). With

a 46% recurrence rate for the at-risk patients (35% of the

population) among the expected 40,320 cases of newly

diagnosed endometrial cancer in 2004, about 6500 recur-

rences would be predicted, which approximates the number

of deaths (n = 7090) estimated to be caused by this disease

during 2004. Therefore, to maximize outcomes, approx-

imately one third of the patients with endometrial cancer in

the United States (i.e., about 14,000 patients for 2004 [1])

would potentially benefit from enrollment in clinical trials

addressing target-based adjuvant therapy. Innovative target-

based algorithms should be incorporated in the development

of future prospective multimodality clinical trials predicated

on the site or sites of recurrence.

Acknowledgments

Supported by the Mayo Cancer Center (P30CA15083)

and the Rochester Research Committee, Mayo Foundation.

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