Changing Concepts in the Management of Endometrial Cancer

Until the late 1980s endometrial carcinoma was a clinically
staged disease. After finding evidence that clinical staging was
inaccurate, the International Federation of Gynecology and Obstetrics
(FIGO) modified the staging system in 1988 to reflect surgicopathologic
information [1-3]. This move resulted in a substantial change
in the clinical management of endometrial cancer.

Epidemiology

Carcinoma of the uterus is the most common malignant lesion
arising in the female genital tract. The Surveillance, Epidemiology,
and End Results (SEER) program of the National Cancer Institute
estimated that there were 32,800 cases in 1995 with 5,900 deaths
[4]. The peak incidence of endometrial carcinoma is between the
ages of 50 and 70 years, with more than 70% of all cases occurring
in postmenopausal women. Approximately 70% to 80% of patients
present with clinical stage I disease, and the remaining 20% to
30% are equally divided between stages II, III, and IV [4,5].

Several risk factors for endometrial cancer are well defined.
Obesity is associated with up to a 10-fold increase in relative
risk [6]. Women with prolonged, unopposed exposure to estrogen
are at increased risk of developing endometrial cancer. Obesity,
nulliparity, late menopause, and polycystic ovary disease all
predispose women to the development of uterine cancer by this
mechanism [7]. Women who have estrogen-secreting tumors or who
are taking exogenous estrogen therapy are at heightened risk of
developing endometrial cancer. The addition of progesterone to
estrogen ablates this increased risk [8]. Medical conditions associated
with an increased risk include diabetes, hypertension, arthritis,
and hypothyroidism [6].

Recently, an increase in the incidence of uterine cancer was noted
with adjuvant tamoxifen (Nolvadex) administration in the setting
of breast cancer. Tamoxifen-treated women enrolled in the National
Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial
had a 7.5 relative risk of developing endometrial cancer. The
annual hazard rate of endometrial cancer as a first event was
1.2 per 1,000 patients-years in the tamoxifen recipients, and
these tumors did not appear to carry a worse prognosis when compared
to cases occurring after placebo treatment. The authors concluded
that, if patients receive close routine gynecologic follow-up,
the benefit of adjuvant hormonal therapy still outweighs the risk
of developing uterine cancer [9].

Figo Staging

In 1988, endometrial cancer was changed to a surgically staged
disease (Table 1). The clinical staging system is now reserved
for inoperable patients (Table 2). This change followed the example
of ovarian cancer, in which more accurate surgical assessment
of disease guides the clinician in providing optimal therapy.
Clinical staging of endometrial cancer clearly underestimated
the extent of disease [2,10]. The Gynecologic Oncology Group (GOG)
evaluated a large number of clinical stage I endometrial cancers
and found that 23% had disease outside the uterus. Only 24% of
clinical stage II cancers were pathologically confirmed as stage
II [10].

If pathologic staging is more accurate, will this have an impact
on treatment and ultimate outcome? Many prognostic factors have
been described. Only tumor grade and histologic cell type are
generally available preoperatively. Although tumor grade is highly
predictive of nodal metastases, it is far from accurate. Without
additional surgically derived information, a large number of patients
either would receive unnecessary adjuvant therapy or would be
denied potentially beneficial adjuvant treatment. Knowledge of
the extent of disease allows therapy to be individualized, enabling
patients with poor prognostic factors to receive more aggressive
therapy. Whether this information will ultimately influence survival
remains to be determined.

Prognostic Factors

Clinical stage remains the most important prognostic factor. However,
as almost all patients present with clinical stage I disease,
it has become important to define other indicators of prognosis
among this heterogeneous patient group. Most of the information
about these prognostic factors comes from large prospective surgical
trials carried out by the GOG [10-12] (Tables 3 and 4).

The depth of myometrial invasion through the uterine wall is a
powerful predictor of prognosis that directly correlates with
the incidence of extrauterine disease. Also, tumor grade is as
important as clinical stage in predicting both FIGO surgical stage
and overall survival. High-grade tumors are more often associated
with deep myometrial invasion and lymph node positivity. Grade
3 lesions predict a high incidence of pelvic recurrence (relative
risk, 15) and distant metastases [12,13]. Lymphovascular space
involvement has consistently been associated with poor prognosis
in the GOG studies [3,10,12]. Spread to the cervix or lower uterine
segment appears to increase the risk of recurrence and extrauterine
disease, but it is difficult to isolate this feature, as patients
with involvement of these structures often have deeply invasive,
high-grade tumors [12].

Squamous elements in an adenocarcinoma have an adverse impact
on prognosis. The prognosis of these mixed tumors is determined
by the grade of the squamous component [14]. Clear cell and papillary-serous
types of endometrial carcinomas represent less than 10% of cases.
Regardless of stage, patients with these histologies have extremely
poor survival with frequent systemic failures [15].

Lastly, advanced age and being of a non-Caucasian race are associated
with a poor prognosis [16].

Some authors divide advanced-stage disease (stages III and IV)
into favorable and unfavorable categories. Extrauterine spread
limited to peritoneal fluid and/or the adnexa (stage IIIA) has
a favorable outcome compared to stages IIIC or IV [17]. The number
of metastatic sites involved strongly predicts abdominal and distant
failure rates [12,18]. Patients with extrauterine disease of any
type tend to have worse outcomes than those with localized disease.

Many recent investigations have focused on other markers of prognosis,
some of which are now included in prospective GOG trials. Ploidy,
S-phase fraction, DNA index, and proliferative index show promise
as prognostic factors [19]. DNA content and neu-oncogene amplification
are being analyzed for their prognostic value by the GOG. Serum
tumor markers, such as CA-125 and CA-15-3, may help predict the
risk of extrauterine spread [20]. Steroid-receptor concentration
correlates with the degree of differentiation [19]. Progesterone-receptor
positivity appears to predict response to hormonal therapy in
the setting of advanced disease [21].

Surgical Therapy and Staging

All medically operable patients with stage I disease, regardless
of grade, should undergo total abdominal hysterectomy and bilateral
salpingo-oophorectomy for both therapeutic and staging purposes.
The intra-abdominal incision should be large enough to allow adequate
surgical exploration and possible nodal sampling if indicated.
Peritoneal fluid is obtained for cytologic analysis before surgical
exploration. The uterus and adnexae are removed en bloc via an
extrafascial hysterectomy [5].

In certain cases, a pelvic and periaortic lymph node sampling
is performed at the time of surgical exploration. The selective
lymphadenectomy outlined by the GOG includes excision of pelvic
nodal tissue from the distal half of the common iliac arteries,
anterior and medial external iliac arteries and veins, and the
obturator fat pad anterior to the obturator nerve. The periaortic
lymph node dissection includes excision of nodal tissue over the
distal vena cava from the level of the inferior mesenteric artery
to the mid-common iliac arteries [22]. Some centers perform a
complete lymphadenectomy, whereas others biopsy only palpable
abnormalities [23]. A Wertheim hysterectomy should be considered
for clinical stage II patients.

Which Patients Require Nodal Sampling?

Despite the abundance of information available regarding surgical
staging, there is no consensus as to which patients should undergo
lymph node sampling. Clinical stage I patients with low-grade
tumors are at low risk for nodal metastasis and generally do not
require nodal sampling. The same holds true for patients who have
a tumor with no or minimal myometrial invasion, unless the tumor
is high grade [5]. Some centers rely on frozen sections and perform
nodal sampling in low-grade tumors only if there is extensive
myometrial invasion.

Magnetic resonance imaging can provide a preoperative estimate
of myometrial invasion, as well as identify possible nodal involvement
[24]. Whether or not this information can be used to guide the
decision regarding the need for nodal sampling remains to be determined.

The American College of Gynecology recommends that pelvic and
periaortic nodal sampling be considered in patients with suspicious
adenopathy, high-grade tumors, or tumors of any grade invading
into the middle third or greater of the myometrium or cervix [25].

Role of Laparoscopic Surgery

There is currently a great deal of interest in laparoscopic surgery
for endometrial cancer, and this is under investigation by the
GOG. Operative laparoscopy and vaginal hysterectomy can both treat
endometrial cancer and provide surgicopathologic staging while
avoiding an abdominal incision. Childers et al at the University
of Arizona have described this procedure in 59 patients. Only
5% required conversion to laparotomy. Although the procedure took
longer than the traditional abdominal approach, hospital stays
were significantly shorter. Unfortunately, laparoscopic surgery
is not applicable to the obese patient [26].

Radiation Therapy

Stage I Disease

Historically, patients with stage I endometrial adenocarcinoma
were treated with a combination of surgery and radiation. Typically,
radiation therapy was given preoperatively, followed by an extrafascial
hysterectomy; then, depending on the pathologic assessment, some
patients required additional external-beam pelvic radiation. The
rationale behind this approach was the belief that preoperative
radiation could sterilize occult metastases, reduce dissemination
at surgery, result in fewer complications compared with postoperative
therapy, and avoid the potential for hypoxia in the target volume.
This approach has yielded excellent outcomes, with 5-year survival
rates of 85% to 90% [27].

Complications using preoperative implantation alone are low (3%)
[27]. An increase in the incidence of complications is seen in
patients who subsequently receive additional postoperative radiation.
Some authors have reported fewer late complications with preoperative
radiation compared with postoperative radiation alone [27]. No
prospective randomized trial has been performed to confirm the
theoretical advantages of preoperative therapy.

Disadvantages of preoperative radiation include the unnecessary
treatment of patients at "low risk" for recurrence and
the potential for destroying potential prognostic pathologic information.
Currently, the most favored therapeutic approach is to tailor
postoperative adjuvant therapy to prognostic factors.

Low-Risk Patients--Some studies have divided patients into
defined risk groups (Table 5). Various authors have defined a
"low-risk" group consisting of patients with disease
confined to the uterus, grade 1 or 2 histology, and less than
50% penetration through the myo-metrial wall [12,13,28,29]. These
features predict a low risk of recurrence (Table 6).

It is accepted that adjuvant external-beam radiation is not necessary
for low-risk patients. The possible benefit of adjuvant vaginal
cuff irradiation alone is more controversial. A number of centers
have reported pelvic recurrence rates in the range of 0% to 4%
following adjuvant vaginal cuff irradiation [13,30,31]. Recent
reviews by Carey et al and Elliot et al reported pelvic recurrence
rates of 3% and 4.9%, respectively, without adjuvant therapy [29,32].
Given these low recurrence rates, it is difficult to document
a clinically significant benefit of adjuvant vaginal cuff irradiation
in this low-risk group.

High-Risk Patients--The definition and treatment of a "high-risk"
group are more controversial (Table 7). Most authors agree that
patients with grade 3 tumors or with more than 50% myometrial
penetration of any grade fall into a high-risk group. The GOG
surgical staging trial demonstrated that grade 3 histology, deep
myometrial penetration, and vascular space involvement are independent
poor prognostic factors [12].

Very few studies have analyzed recurrence rates without adjuvant
radiation in high-risk patients. Aalders et al reported the results
of a prospective randomized trial of adjuvant pelvic radiation
in patients with early-stage endometrial cancer. All patients
received vaginal cuff irradiation. A significant reduction in
local recurrence rates was seen with the addition of external-beam
radiation compared with vaginal cuff irradiation alone (1.9% vs
6.9%). The greatest benefit occurred in patients who had grade
3 tumors with more than 50% myometrial penetration [13]. The GOG
surgical staging trial suggested that adjuvant radiation improved
locoregional recurrence rates over surgery alone (31.8% vs 16%),
although risk factors were not balanced [12]. Carey et al reported
a high local recurrence rate in 36 high-risk patients who were
not treated per protocol with adjuvant pelvic radiation (14.3%
vs 3.9%) [29].

The use of adjuvant external-beam radiation in this defined patient
group has resulted in excellent outcomes, with 5-year survival
rates ranging from 80% to 90% [29-32]. Some studies have reported
no difference in survival in high-risk patients given adjuvant
external- beam radiation when compared to a low-risk group. Other
reports have described a worse outcome, mainly due to higher distant
relapse rates [29,32].

In the era of surgical staging, the role of adjuvant radiation
is not as well defined. In the majority of studies outlined above,
surgical staging was not performed. Adjuvant radiation recommendations
were based on intrauterine factors only. The risk of pelvic recurrence
with high-risk intrauterine factors and negative surgical staging
is unknown. Does negative surgical staging define a group of patients
who do not need adjuvant therapy? The GOG surgical-pathologic
correlation study found that even when sampled nodes were negative,
deep myometrial invasion and high tumor grade remained predictive
of recurrence [12]. Patients in this risk category who did not
receive adjuvant radiation were more likely to suffer a local
failure [12].

Currently, the GOG is analyzing the results of a randomized trial
of adjuvant pelvic external-beam radiation therapy vs observation
in surgically staged patients (stages IB, IC, IIA occult, and
IIB occult of all grades). Perhaps this study will help define
the role of adjuvant pelvic radiotherapy in surgically staged
patients. This study did not assess vaginal cuff treatment.

Current Recommendations--In conclusion, patients with low-risk
stage I endometrial cancer probably do not need adjuvant therapy.
Patients with high-risk stage I disease, as defined above, have
been shown to benefit from adjuvant pelvic radiation in terms
of a reduction in locoregional failure rate. The impact of radiation
on survival rates and the development of distant metastases is
less clear. Whether surgical staging can define patients in this
group who may benefit more from other therapeutic strategies remains
to be determined.

Stage II Disease

Patients with occult stage II endometrial cancer (microscopic
involvement of the cervix) are generally treated in a fashion
similar to stage I patients, with adjuvant radiation tailored
to prognostic factors. Morrow et al have reported a higher local
recurrence rate in stage II compared with stage I endometrial
carcinoma. These investigators noted a tendency for stage II patients
to develop vaginal vault recurrences, suggesting a role for adjuvant
vaginal cuff irradiation [12]. Locoregional recurrence tended
to be the predominant site of failure for these patients who did
not receive adjuvant radiation.

Treatment for patients with gross cervical involvement (clinical
stage II disease) consists of either preoperative radiation to
both the primary tumor and pelvic nodes followed by extrafascial
hysterectomy, or radical hysterectomy followed by adjuvant radiation
in some cases [33]. Although results are similar with the two
approaches, complications are lower with the former [33]. Survival
rates for clinical stage II disease range from 70% to 85%.

Stage III Disease

The treatment of stage III patients must be individualized. The
outcome for occult stage III endometrial cancer is better than
for clinical stage III, unless the latter can be maximally debulked
[18]. The GOG surgical staging review found that positive periaortic
or pelvic nodes, vascular space involvement, and malignant peritoneal
cytology denoted poorer survival [12]. Also, the number and sites
of extrauterine involvement are prognostic. Involvement of the
adnexa alone is more favorable than involvement of other sites
[18].

The adjuvant treatment options for occult or debulked stage III
patients include pelvic radiation, extended-field radiation, whole-abdominal
radiation, and/or systemic therapy. The 5-year survival rate using
adjuvant pelvic radiation alone for this group ranges from 40%
to 70% [18]. The patterns of recurrence include local in 10% to
30% of patients, abdominal in 5% to 20%, and distant in 20% to
35% [18].

Stage IIIC patients with positive periaortic nodes should be considered
for postoperative radiation to the pelvis and periaortic area
(extended-field radiation). Small studies have shown a 5-year
survival rate of 30% to 45% with this approach [34]. The recognition
of a significant number of intra-abdominal relapses led to the
study of whole-abdominal radiation in stage III disease [35].
A recent GOG pilot study prospectively treated maximally debulked
stage III and IV patients with whole-abdominal radiation [36].
The in-field failure rates were similar to historical trials using
adjuvant pelvic radiation alone (15% to 30%) [18,36]. Early results
from this GOG pilot study show a 3-year survival rate of 31% with
a 6% incidence of late gastrointestinal morbidity [36].

In summary, although radiation may benefit some subgroups of patients
with stage III disease, such as those with involvement of few
extrauterine metastatic sites, better strategies for systemic
management are needed. New approaches currently being evaluated
include combined chemoradiation and new chemotherapy regimens,
as discussed below.

Stage IV Disease

The results of treatment of stage IV disease are poor, with survival
rates of 5% to 15%. If maximum debulking (less than 2 cm residual
disease) can be achieved, patients are candidates for either whole-abdominal
radiation or systemic treatment strategies. There are some reports
of improved outcomes with these approaches [35,36].