Adjuvant Chemotherapy on Endometrial Carcinoma

I.

Introduction

Endometrial cancer is also known as adenocarcinoma of the endometrium, uterine

cancer or womb cancer. This is a malignant growth of the lining (endometrium) of the
womb (uterus) classified by the World Health Organization as C54. It is distinct from
sarcomas (tumours of the uterine muscle). It is the seventh commonest cancer in women
worldwide with approximately 290,000 cases annually and about 75,000 related deaths
(Ferlay 2004; Ferlay 2010). It affects at least 1.5% of western women in their lifetime. The
chance of surviving uterine cancer depends on the stage of the cancer when it is first
diagnosed.
Endometrial carcinoma (EC) is the tenth most common and the second most
common gynecologic malignancy in women in the world. Surgery is the primary treatment
involving a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and
para-aortic lymphadenectomy, and pelvic washings, with five year survival rates of 78% .
Randomized trials by Post-operative Radiation therapy in endometrial cancer (PORTEC)
and Gynecological Oncology Group 99 (GOG-99) have shown significant reduction of the
risk of pelvic and vaginal recurrence by adjuvant radiotherapy, although a survival benefit
is not yet proven . Thus radiotherapy remains mainstay of adjuvant treatment.
The prognosis of early-stage endometrial cancer is favorable, even when treated
using surgery alone, whereas recurrent cases or advanced cases (stage III or IV) with
progression beyond the uterus have a poor prognosis, and therapy for such cancers is still
in the exploratory stages. Stage I and II cases are sometimes treated with adjuvant therapy
to prevent recurrence after surgical therapy; however, the treatment options for these cases
remain controversial. The boundaries encompassing intermediate risk cases may be
approached in several ways, and it would be difficult to say that any consensus has been
reached, although examples often include stage IIB (FIGO stage 1988) and higher, stage
IC endometrioid adenocarcinoma, all grade 3 (poorly-differentiated) endometrioid
adenocarcinoma, non-endometrioid adenocarcinoma, and marked lymphovascular space

invasion). Radiation therapy and chemotherapy are the two primary modalities of
postoperative adjuvant therapy for patients with these types of endometrial cancer
characterized by a poor prognosis or a risk of recurrence.
The role of chemotherapy alone in postoperative management of EC has remained
controversial. Large randomized trial of Gynecologic Oncology Group (GOG 122) has
shown the improvement in both progression free survival (PFS) and overall survival (OS)
at 52 months with the use of adjuvant chemotherapy alone compared with adjuvant
radiotherapy in stage III and IV patients (without evidence of hematogenous metastases)
after surgery. Contrary, two large randomized trials have shown that adjuvant
chemotherapy alone was not better than adjuvant radiotherapy alone with no difference in
PFS and OS rates in patients with early stage EC. Benefit of sequential adjuvant
chemotherapy and radiotherapy was seen in advanced stage endometrial carcinoma by
NSGO/EORTC and MaNGO studies with 36% reduction in the risk for relapse (hazard
ratio (HR) 0.64, 95% confidence interval (CI) 0.41-0.99; p 0.04). However, both trials of
sequential adjuvant treatment failed to see any significant differences in the OS.
Theoretically, adjuvant chemotherapy after surgery may delay the curative radiotherapy
which may result in locoregional control. The aim of our study was to evaluate impact of
sequential chemotherapy and radiotherapy in patients with early stage endometrial
carcinoma with adverse features.

II.

Classification of endometrial carsinoma

Clinically significant prognostic indicators in patients with endometrial cancer are
FIGO stage, histopathologic tumour type, tumour grade, depth of myometrial invasion,
extent of lymph vascular space involvement, and patient age. These factors form the basis
for subsequent treatment planning and follow-up.
Published studies have frequently categorized stage I endometrial cancer patients as
low-risk, intermediaterisk, and high-risk for recurrence on the basis of surgical pathologic
findings. Recommendations for adjuvant therapy are based on the estimated risk for
disease recurrence. Although the exact definition of risk for patients with stage I disease

varies between studies, the low-risk group is generally defined as pathologic stage IA,
grade 1 and 2 endometrioid adenocarcinoma, with no or minimal myometrial invasion.
The 5-year risk of recurrence for patients in this low-risk category is between 2% and
10%. The stage I intermediate-risk group has been defined differently in various
randomized trials as shown in Table 2. Generally speaking, this includes patients with
grade 1 or 2 adenocarcinoma with more than 50% invasion or grade 3 tumours with
superficial invasion and the presence of extensive lymph vascular space invasion in the
uterine specimen. Being age 60 or over is also a risk factor. The 5-year risk of recurrence
for patients in this group is as high as 20% to 25%. The high-risk group includes all
patients with deep cervical stromal involvement or stages III and IV disease, including all
aggressive histologies such as serous or clear cell.1 Treatment options for advanced stage
endometrial cancer (stage II with deep cervical stromal invasion to 4 cm) should be
individualized and may include chemotherapy, radiotherapy, or a combination of both. The
5-year risk of recurrence for patients in this risk group is between 30% and 65%. The 5year survival rate for this group is up to 58% for stage III and up to 15% for stage IV.

Tabel 1; staging for endometrial cancer based on FIGO

Tabel 2; Risk Stratification of Endometrial Cancer

III.

Adjuvant Therapy
a. Adjuvant Therapy in Low-risk Endometrial Cancer
The use of adjuvant therapy for endometrial cancer depends on the patient's
estimated risk of recurrence. Typically, patients are categorized as low, intermediate or
high risk for recurrence based on prognostic variables such as age, tumor grade and
depth of invasion. Low-risk patients include those women with stage IA grade 1 and 2
tumors and stage IB grade 1 tumors. Intermediate risk includes the remainder of
patients with stage I and II lesions.
Adjuvant treatment tends to be recommended in a step-wise fashion, with more
aggressive modalities suggested for patients with higher risk disease. However simple
this seems, the adjuvant treatment of endometrial cancer has historically been a
contentious issue. In one analysis, the risk of recurrence for women with stage IA and
IB grade 1 or 2 tumors was 3.2% at 10 years. Given the favorable prognosis of this
group, adjuvant therapy is usually withheld. The addition of vaginal brachytherapy is
well tolerated, and, even in lower risk patients, can decrease the risk of local
recurrence, though it has not been shown to improve overall survival.
b. Adjuvant Therapy in Intermediate-risk Endometrial Cancer
The optimal adjuvant treatment, if any, for women with intermediate-risk
endometrial cancer is one of the most controversial areas in gynecologic oncology.
While adjuvant whole pelvic radiotherapy for intermediate-risk endometrial cancer

that is confined to the uterus is widely prescribed, the survival benefit of such
treatment has not been convincingly demonstrated. In a large study of
comprehensively staged women with endometrial cancer treated at the University of
Alabama (AL, USA) survival was excellent whether adjuvant radiation was
administered or not. To date, three randomized trials have addressed this issue.
Investigators from the Norwegian Radium Hospital (Oslo, Norway) examined 540
women with stage I endometrial cancer. All patients underwent surgical resection and
vaginal brachytherapy and were randomized to whole pelvic radiation versus no
further treatment. Pelvic control was improved with the addition of radiotherapy, but
there were no survival differences at 5 years. The Postoperative Radiation Therapy in
Endometrial Cancer (PORTEC) trial randomly assigned 715 women with stage IB
grade 2-3 tumors or stage IC grade 1-2 tumors who underwent hysterectomy to whole
pelvic radiotherapy versus observation. After 10 years of follow-up there was a
reduction in vaginal recurrences from 15 to 4% but no difference in survival. Finally,
researchers from the US GOG randomized 392 patients with stages IB, IC, IIA or
occult IIB endometrial cancer to whole pelvic radiation or observation. Unlike the
prior two studies, all patients in GOG protocol 99 underwent surgical staging with
comprehensive lymphadenectomy. Again, radiation appeared to improve local control
and disease-free survival, but did not affect overall survival.
All three randomized trials suggest that radiotherapy may improve local control
and decrease the risk of vaginal and pelvic relapses without altering long-term
survival. The failure of pelvic radiotherapy to alter survival results from the fact that
the majority of recurrences for women with stage I endometrial occur at the vaginal
cuff. A high percentage of women with vaginal cuff recurrences can be salvaged with
radiation at the time of recurrence. In total, 73% of women in the P-ORTEC trial with
isolated vaginal recurrences were salvaged. However, the findings from these three
trials must be interpreted with caution. All three of the reported trials included large
numbers of patients at a relatively low risk for death from endometrial cancer.
Therefore, these reports may lack the power to detect a true survival advantage in
those women most likely to die from their tumors.

Given the limitations of these reports, investigators have attempted to define

subgroups of patients who may benefit from radiotherapy. Results from two published
reviews suggest that the only patients who may benefit from whole pelvic externalbeam radiotherapy are women with stage IC grade 3 tumors. A review of 21,249
patients from the US National Cancer Institute's Surveillance, Epidemiology, and End
Results (SEER) database suggested that, while radiotherapy did not improve survival
in patients with low-risk disease, radiation was associated with a survival advantage
for patients with stage IC, grade 1 or 3 tumors. In a Cochrane Collaboration review of
adjuvant radiotherapy for stage I endometrial cancer, external-beam radiotherapy
resulted in a 72% reduction in pelvic relapses, an absolute reduction of 6%, with a
number needed to treat of 16.7 to prevent one locoregional recurrence. Despite the
improvement in pelvic control, radiation did not translate into a reduction in distant
metastatic disease or improve overall survival. A subgroup analysis by the authors
demonstrated a trend towards a reduction in death in patients with multiple high-risk
factors (stage IC and grade 3 tumors). A second meta-analysis of available data
suggested that only women with stage IC, grade 3 tumors derived benefit from
adjuvant radiation. External-beam radiotherapy had no effect on survival for
intermediate-risk patients and actually increased mortality in women with low-risk
disease.
Pelvic radiotherapy, particularly after surgical lymphadenectomy, is associated
with appreciable toxicity. Hematologic, gastrointestinal, genitourinary and cutaneous
toxicities are common with pelvic radiotherapy. Late complications were documented
in 25% of patients in the radiotherapy arm of the PORTEC trial. In an attempt to
decrease the morbidity of pelvic radiotherapy while preserving the benefit of pelvic
control associated with radiation, several groups have investigated adjuvant vaginal
brachytherapy. Vaginal brachytherapy delivers radiotherapy to the vaginal cuff, the
region at highest risk for recurrence. Vaginal brachytherapy is most commonly
delivered in the outpatient setting using high dose rate applicators. Observational
studies have noted acceptable rates of local control with minimal morbidity for
patients with low- and intermediate-risk tumors. In a series of 164 patients with stage

IB-II tumors, 5-year survival was 87% with a relapse rate of 9%. No grade 3 or 4
toxicities were encountered. A randomized trial (PORTEC-2) comparing externalbeam radiotherapy to vaginal brachytherapy for subsets of patients with stage IB-IIA
tumors is currently ongoing.
Certain groups of patients with endometrial cancer confined to the uterine corpus
are at particularly high risk for recurrence. Among 99 patients with stage IC grade 3
tumors, all of whom received external-beam radiotherapy, locoregional recurrences
were noted in 14%, while distant metastases were observed in 31%. Overall survival
for these patients was only 58%. The high rate of systemic metastases and poor
survival suggest that these patients may benefit from systemic therapy. Given the
success of cytotoxic chemotherapy for advanced-stage endometrial cancer, several
groups have begun trials that incorporate chemotherapy into the treatment of women
with intermediate-risk endometrial cancer. In 1996, the GOG opened protocol 156 to
compare postoperative radiation therapy with adjuvant chemotherapy, with
doxorubicin and cisplatin for intermediate-risk patients. The trial was closed however,
due to lack of accrual. The Japanese Oncology Group recently published a randomized
controlled trial of postoperative whole pelvic radiation versus chemotherapy with
cisplatin, doxorubicin and cyclophosphamide in patients with intermediate- and highrisk endometrial cancers. In their cohort of 385 women with IC-IIIC endometrial
cancers, no significant differences were found in progression-free or overall survival
between the two treatment arms. However, in a subgroup of women (IC, grade 3 age
>70 years, stage II or IIIA) chemotherapy appeared to improve survival. Italian
investigators did not identify a survival difference for stage IC, grade 3, IIA or III
endometrial cancer patients treated with either external-beam radiotherapy or
combination chemotherapy. Clearly, the idea of treating high-intermediate-risk
endometrial cancer is appealing and we will likely see further investigations of
chemotherapy alone as well as chemotherapy in combination with radiotherapy.
Another area under investigation is the use of chemotherapy in conjunction with
radiotherapy. It appears that women treated with chemotherapy alone have a high risk
of relapse within the pelvis. Mundt and coworkers reported significant pelvic relapse

rates when using adjuvant chemotherapy alone in patients with high-risk or advancedstage endometrial cancer. Overall, 40% of women experienced a pelvic relapse at 3
years and, in 31% of the patients, the pelvis was the first or only site of recurrence.
Pelvic radiotherapy could thus control pelvic disease while chemotherapy could target
occult systemic disease. The GOG initially attempted to define the role of
chemotherapy in combination with radiotherapy for women with early-stage disease. A
cohort of 181 patients with stage I and II endometrial cancer that underwent surgery
followed by radiation was randomized to either doxorubicin or observation. While
there was no difference in survival, the trial suffered from severe methodological flaws
and the authors concluded that the utility of adjuvant chemotherapy remained
unknown.
Several small trials have investigated different postoperative combinations of
radiotherapy and chemotherapy in various subgroups of intermediate- and high-risk
patients. These trials offer important insights for the treatment and design of future
protocols. A small Italian study of 23 patients with stage IC grade 3 or stages IIB-IIIC
underwent adjuvant treatment with paclitaxel and concurrent pelvic radiation therapy.
Overall survival was 81% at 3 years with a median time to relapse of 19 months. In a
similar design, Greven and colleagues reported on 46 patients with two or three
endometrial adenocarcinoma with greater than 50% myometrial invasion, stromal
invasion of the cervix, or extrauterine disease confined to the pelvis and/or positive
peritoneal cytology who underwent postoperative adjuvant treatment with pelvic
radiation therapy, subsequent vaginal brachytherapy and concurrent cisplatin and
paclitaxel. Survival at 4 years was 85%. No recurrences were reported amongst
women with stage IC disease. Given the appeal of combination therapy we will likely
see further dual modality trials in the future.
c. Adjuvant Therapy in High-risk & Advanced-stage Endometrial Cancer
The diagnosis of advanced endometrial cancer rs a relatively poor prognosis.
Traditionally, treatment for women with stage III endometrial cancer has relied on
radiotherapy while women with stage IV disease have been treated with palliative
chemotherapy. There has been a gradual shift towards incorporating chemotherapy into

the treatment of women with stage III and IV endometrial cancer. This shift is based
largely on the results of GOG protocol 122. In this trial, 396 women with stage III or
IV disease were randomized to postoperative whole abdominal radiation versus
chemotherapy with doxorubicin and cisplatin. Patients in the chemotherapy group had
a statistically significant increased progression-free (42 vs 38%) and overall survival
(53 vs 42%). Both acute and chronic toxicities were higher in women who received
chemotherapy. While survival was relatively poor in both groups, this trial has sparked
renewed interest in chemotherapy for endometrial cancer.
Historically, the literature on chemotherapy for advanced endometrial cancer has
grouped women with advanced disease with patients with recurrent tumors. Certainly,
many of these trials suffer from the inclusion of a heterogenous group of subjects. The
most active agents for endometrial cancer appear to be doxorubicin and cisplatin.
Response rates to single-agent doxorubicin alone are generally in the range of 17-25%.
Two prospective randomized trials have demonstrated a superior response rate to
doxorubicin and cisplatin as compared with doxorubicin alone, however, survival rates
for the two regimens were similar. This combination regimen has served as the control
arm in many subsequent trials.
Recent interest has focused on the incorporation of paclitaxel into regimens for
the treatment of advanced disease. When combined with either cisplatin or carboplatin,
response rates of greater than 40% have been reported. Given this provocative data,
doxorubicin plus paclitaxel was investigated by the GOG (GOG 163) as an alternative
to doxorubicin and cisplatin for women with advanced or recurrent disease. The two
doublets were similar with regards to both response and survival. The authors failed to
find a difference in progression-free or overall survival among the two groups. The
most recent GOG trial compared doxorubicin plus cisplatin to a regimen of
doxorubicin, cisplatin and paclitaxel. The three drug regimen demonstrated a
statistically significant improvement in response rate, progression free and overall
survival as expected, toxicity was much higher with the three drug regimen. The GOG
is currently conducting a trial (GOG 209) comparing paclitaxel and carboplatin to
doxorubicin, cisplatin and paclitaxel in women with advanced or recurrent disease.

The results are anxiously awaited as paclitaxel and carboplatin has emerged as the
standard of care in many centers, despite the lack of published data supporting it's
superiority to doxorubicin and cisplatin.
As for women with intermediate-risk disease there has been an interest in
examining multimodality therapy for advanced-stage disease. This is particularly true
for women with stage IIIC tumors with disease metastatic to the lymph nodes.
Combination therapy again offers the benefit of systemic control with chemotherapy
and enhanced pelvic control with radiotherapy. Secord and colleagues retrospectively
examined 356 women with stage III and IV endometrial cancer and stratified patients
based on whether they received adjuvant radiation, chemotherapy or combination
therapy. Combination therapy was associated with an improved survival. The GOG
recently completed a prospective trial of radiotherapy in combination with either
cisplatin and doxorubicin or cisplatin, doxorubicin and paclitaxel for women with
stage III and IV completely resected endometrial cancer. The two regimens appeared
equivalent.
IV.

Adjuvant Chemotherapy for advanced or recurrent endometrial cancer

Although adjuvant External-beam radiation therapy (EBRT) can be expected to be
effective to a certain extent for advanced or recurrent endometrial cancer, chemotherapy
with anti-tumor agents is also being additionally performed in Europe and the US. After
many changes in regimens, AP therapy (combining doxorubicin and cisplatin) is currently
the standard therapy. The changes in regimens are summarized below. From the 1970s to
the 1980s, doxorubicin monotherapy was reported to result in a response rate of 20% to
42%10), and a good response rate of 45% to 60% was reported in a subsequent phase II
study combining cisplatin with doxorubicin. These two drugs therefore came to be
positioned as key drugs in chemotherapy for endometrial cancer. In the 1990s, the
Gynecologic Oncology Group (GOG) in the US and the European Organization for
Research and Treatment of Cancer (EORTC) conducted phase III randomized comparative
studies on doxorubicin vs. doxorubicin + cisplatin (AP therapy) in both the GOG107
and EORTC55872 trials, respectively, and the response rates of 25% vs. 42% in the

GOG107 study and 43% vs. 17% in the EORTC55872 study demonstrated the efficacy of
AP therapy. Although no significant differences in OS were found in the GOG-107 study,
AP therapy was shown to be superior in the EORTC55872 study. On the other hand, CAP
(cyclophosphamide + doxorubicin + cisplatin) therapy is also being used for endometrial
cancer in Japan, where chemotherapy is more often performed as a postoperative therapy.
However, cyclophosphamide was not found to result in significant differences in the
response rate in phase II studies of CAP therapy and AP therapy, while the GOG48 study
on doxorubicin vs. doxorubicin + cyclophosphamide (AC therapy) also revealed no
significant differences in the response rate, response period, or OS, thus contradicting the
usefulness of concomitant cyclophosphamide for endometrial cancer;AP therapy has come
to be acknowledged as the standard chemotherapy for endometrial cancer in Japan as well.
Radiation therapy and chemotherapy are thus the primary modalities of therapy that
should be used after surgery for endometrial cancer.
1. Single-agent adjuvant chemotherapy experience
In the last 20 years there has been a more focused effort to identify active single
agents in endometrial cancer. Most of these tumors have been high grade. For a
particular chemotherapy drug to be regarded as effective, it should induce response in
at least 15% of patients in the study.
a. Anthracyclines
Doxorubicin has emerged as the most efficacious medication shown by data from
three disease-specific trials (Table 1 ). Among 161 patients there was a 12%
complete response rate and a 26% overall response rate. Epirubicin, an
anthracycline analogue, also appears to be active, but so far it has not found
acceptance as a component in combination chemotherapy regimens. Idarubicin
and mitoxantron appear to have no activity.
TABLE 1. Single-Agent Chemotherapy in Endometrial Cancer: Anthracyclines

DOX = Doxorubicin; Epir = epirubicin

b. Cisplatin
The second most effective single agent appears to be cisplatin, and possibly also
carboplatin (Table 2 ). The Gynecologic Oncology Group studies found that
cisplatin appeared to be more effective in patients not previously exposed to
cytotoxic chemotherapy, and in fact Seski and colleaguesfound that with a dose
greater than 50 mg/m2, the drug had to be discontinued in one third of the patients
because of dose-related toxicity. There appears to be little value in exceeding this
dose in patients with endometrial cancer. In patients who had no previous cytotoxic
chemotherapy, the complete response rate for single-agent cisplatin chemotherapy
was 6% with an overall response rate of 29%, compared to 4% and 29%,
respectively, for carboplatin. Cisplatin remains the preferred agent because of its
lack of hematologic toxicity.

TABLE 2. Single-Agent Chemotherapy in Endometrial Cancer: Cisplatin and

Carboplatin

*Second-line

chemotherapy

CBDCA = carboplatin; CDDP = cisplatin

c. 5-Fluorouracil
5-Fluorouracil (5-FU) is a third agent that shows activity in endometrial cancer,
with a response rate of 23% among 43 patients. More frequently, 5-FU has been
used as a component of combination chemotherapy either with melphalan or lately
with leucovorin.
d. Cyclophosphamide
Cyclophosphamide is a drug with long-time use in metastatic or recurrent
endometrial cancer, usually in combination regimens. It was initially administered
with Adriamycin and then with added cisplatin when this medication became
available. There is, however, evidence that as a single agent it is not effective. In
1976, DeVita and colleagues found a 21% response rate of single-agent
cyclophosphamide among 33 patients from five broad-based phase II studies.
However, Horton and co-workers found no response in 19 patients using a dose of
cyclophosphamide 600 mg/m2. A phase III study by the Gynecologic Oncology
Group failed to show a therapeutic advantage when cyclophosphamide was added
to cisplatin and doxorubicin. The efficacy of cyclophosphamide in endometrial
cancer, therefore, remains in doubt.

e. Paclitaxel (Taxol)
More recently there has been great interest in the use of paclitaxel in endometrial
cancer. In a phase II study by the Gynecologic Oncology Group, there were 4
complete and 6 partial responses in 28 patients given 250 mg/m2 of Taxol over a
24-hour period administered every 3 weeks. The progression-free interval and
overall survival, however, were not given. This 35% response rate for Taxol is
better than that of other drugs used as single agents and is promising evidence to
support its use in combination with cisplatin and perhaps doxorubicin also.
f. Other Single-Agent Chemotherapy
Ifosfamide is another drug that has been examined for use in endometrial cancer.
Barton and associates had 2 responders among 16 patients, and Sutton and
colleagues found an 8.6% response rate in 23 patients with previously untreated
endometrial

cancer. Hexamethymelamine

(altretamine)

has

only

limited

usefulness, partly because toxicity precluded prolonged administration. Seski and

co-workers found a 30% response rate with a medial duration of response of 3.5
months, while a Gynecologic Oncology Group study had 3 patients (7%) with an
objective response among 34 patients. None of the other drugs examined so far has
been recognized as useful in endometrioid endometrial cancer at this time. This
includes etoposide and methotrexate.
2. Combination Chemotherapy
Right from the time that Adriamycin and then cisplatin became available, they
were given in combination in recurrent or initially metastatic endometrial carcinoma.
However, there have been few prospective trials comparing single agents with
combination chemotherapy or comparing one combination with another.
1. Melphalan and 5-Fluorouracil, With or Without a Progestin

Among the first combination chemotherapy regimens reported was melphalan with
5-FU and the progestin medroxyprogesterone. Cohen and associates obtained an
objective response in six of seven patients with advanced or recurrent disease
previously treated with surgery and radiation. Five of the patients had grade 2 and
3 histology, and the duration of response ranged from 16 to more than 64 months, a
truly remarkable result considering that the patients with the longest duration of
response had grade 3 histology. Piver and colleagues treated 50 analogous patients
using the same regimen and found a 48% overall response rate and a 20%
complete response rate. In that study, however, the median progression-free
survival was only 5 months.
2. Adriamycin, Cyclophosphamide, and 5-Fluorouracil
The other combination chemotherapy initially reported on was Adriamycin,
cyclophosphamide, and 5-FU together with medroxyprogesterone. Unfortunately,
the grade of tumor was not included. Only one patient had prior chemotherapy
with melphalan and 5-FU. All seven patients showed a response, and this was
sustained for more than 3 months in four patients. Perhaps some of the response
was due to the progestin; this is a problem in assessing results in all patients with
endometrial cancer given cytotoxic chemotherapy and hormonal therapy
simultaneously.
The Mount Sinai group reported a further 29 patients treated with the same
combination and obtained a 44% objective response rate with a median duration of
survival of 11 months. By 1984 a Gynecologic Oncology Group study reported by
Cohen and co-workers showed a 16% complete and a 22% partial response rate
among 77 patients. A further 131 patients given melphalan, 5-FU, and
medroxyprogesterone had a 17% complete and a 19% partial response rate. The
grade of the tumor was not stated in the manuscript, nor was the duration of
response, so in this study it is difficult to assess the effect of omitting the progestin.
3. Doxorubicin and Cyclophosphamide

In 1977 Muggia and associates showed a response in six of eight patients with
recurrent, high-grade endometrial carcinoma treated with doxorubicin and
cyclophosphamide (Table 3). They suggested that cytotoxic therapy may have a
place in the primary treatment of advanced or recurrent high-grade endometrial
cancer in which progestins are unlikely to be effective. Campora and
colleaguesobtained a 46% response rate with the same medications with a median
survival of 10 months. The most important study of the combination of
doxorubicin with cyclophosphamide was performed by the Gynecologic Oncology
Group, who compared doxorubicin alone with doxorubicin and cyclophosphamide.
The objective response rate with combined cyclophosphamide-doxorubicin was
66%, compared to a 35% response rate for doxorubicin alone. The median
progression-free survival was 6.2 months for the combination and 3.9 months for
doxorubicin alone. The median survival for both groups was 9 months. These
paradoxical data support the practice of giving combination therapy rather than
single-agent chemotherapy. It would appear that a relatively inactive single agent
such as cyclophosphamide may enhance the effectiveness of an active single agent
when given in combination with it. Intellectually this is difficult to accept, and
supportive in vitro studies would clearly be of interest. Nevertheless, the majority
of investigators currently continue to use cyclophosphamide in combination with
doxorubicin and cisplatin.

TABLE 3. Doxorubicin-Cyclophosphamide in Endometrial Cancer

CTX = cyclophosphamide; DOX = doxorubicin

Cisplatin and Doxorubicin
Trop and co-workers reported on the use of doxorubicin and cisplatin in 19
patients with recurrent endometrial cancer and 1 patient with initial metastatic
cancer, all treated primarily with this combination. The dose of each drug was 50
mg/m2, and treatment cycles were every 4 weeks. There was an objective response
rate of 60%, with two complete remissions and a median survival period for those
with partial remission of greater than 11 months. Seltzer and associates gave the
same doses in nine patients, but administered the drug every 3 weeks, and these
patients had significant toxicity. There were two partial responses and one
complete response. Deppe and colleagues treated 19 patients with the same doses,
also every 3 weeks, and had 7 patients with a partial response, an overall response
rate of 36%, and a median survival of 36 months. There was no significant toxicity
in this study. Pasmantier and co-workers achieved a 92% response rate in 12
patients who had received no prior chemotherapy and a 50% response rate in 4
patients who had received prior chemotherapy. The median survival was 10
months. The drugs were administered every 28 days on an outpatient basis. These
encouraging findings were substantiated by a prospective randomized study of the
Gynecologic Oncology Group reported by Thigpen and associates. In 223 patients,
there was a 35% response rate with single-agent doxorubicin and a 67% response

rate with doxorubicin plus cisplatin. However, the progression-free survival was
only 6 months and there was no survival advantage for the combination.
4. Cisplatin, Doxorubicin, and Cyclophosphamide
All

other

reported

trials

of

doxorubicin

and

cisplatin

also

include

cyclophosphamide (Table 4 ) and frequently a progestin, usually megestrol

(CAP+M). Hoffman and colleagues had 4 patients with a complete response and 1
with a partial response among 15 patients, giving an overall response rate of 33%.
The median survival was 15 months for responders and 5 months for
nonresponders, but the median progression-free survival for responders was only 7
1/2 months. All 15 patients had endometrioid endometrial carcinoma, 7 grade 3,
and 6 grade 2. The dose of doxorubicin was 30 mg/m 2, cisplatin 50 mg/m2, and
cyclophosphamide 250 mg/m2, escalated to 500 mg/m2 in the absence of toxicity.
Turbow and co-workers had 9 responders (47%) among 19 patients treated with
CAP. Two of these were complete responses, and seven were partial responses.
Seventeen patients had adenocarcinoma and three had serous papillary tumors.
Twelve of the patients had grade 3 tumors. These authors found better survival
with good performance status and believed the cyclophosphamide added toxicity
and no therapeutic benefit. Lovecchio and associates evaluated CAP+M in 15
patients and found a 60% response rate with a tumor-free progression interval of 8
months and a mean survival of 12 months. Hancock and colleagues used CAP in
18 patients with a 56% objective response rate; 5 (28%) of these patients had a
complete response. All of these patients had hormone-resistant tumors. Neither of
the last two reports discussed tumor grade or tumor type. Edmonson and coworkers treated 16 patients with progestin-refractory endometrial cancer with CAP
chemotherapy given every 4 weeks. Five patients (31%) had a partial response,
and two patients survived for 2 years. This Mayo Clinic study concluded that more
effective agents need to be found to make this therapy worthwhile. Burke and
associates reported on a CAP study from the MD Anderson Cancer Center in
which 42 patients with advanced and 60 patients with recurrent endometrial cancer
were studied. The drugs were given every 28 days. Of 87 patients with measurable

disease, 12 (14%) had a complete clinical response and 27 (31%) a partial

response. Both groups responded similarly, but the median duration of response
was only 4.8 months. It was concluded that enthusiasm for this therapy should be
tempered by the brief duration of response. Fung and colleagues reported on 44
patients treated with CAP-medroxyprogesterone; 15 had measurable disease with a
53% response rate. The median survival for the whole group was 31 months. The
volume of tumor was considered to be the factor most important in determining
survival. Histologic grade did not predict response, although many patients had
low-grade tumors. Dunton and co-workers treated 25 patients with CAP
chemotherapy every 3 weeks and found a 47% response rate among 17 evaluable
patients. The group included serous papillary tumors and nine grade 3
endometrioid carcinomas. The 2-year disease-free survival was 20%.
TABLE 4. Cyclophosphamide, Doxorubicin, and Cisplatin, With or Without
Megestrol, in Endometrial Cancer

CTX = cyclophosphamide; CDDP = cisplatin; DOX = doxorubicin; NS = not

significant; q 4 = every 4 weeks.
3. Primary Adjuvant Chemotherapy
In 1994 two reports appeared in the literature advocating the use of adjuvant
chemotherapy with CAP as primary treatment in advanced endometrial carcinoma.
Smith and associates assessed the effect of adjuvant CAP in stage IC and II carcinoma
of the endometrium with more than 60% myometrial invasion and in completely
resected stage III and IV carcinomas before planned radiation therapy. Of the 47
women, 8 had grade 2 and 29 grade 3 histology; however, the series included 8
patients with serous papillary tumors, 2 with clear cell carcinomas, and 6 with
adenosquamous histologies. The 2-year progression-free survival was 72.5% for
nonserous-histology cancers and 22% for serous papillary cancers. The authors
concluded that CAP chemotherapy followed by radiation appeared to offer survival
advantage for patients with endometrioid histology when compared with historic
controls.
Burke and colleagues treated 62 patients with endometrial cancer at high risk for
recurrence by virtue of (1) more than 50% myometrial invasion, (2) grade 3 histology,
(3) completely resected extrauterine tumor, and (4) clear cell and serous histology.
Recurrence occurred in 48% of 29 patients with extrauterine disease and in 24% of 33
patients with disease confined to the uterus. The median time of recurrence was 13

months. The authors admitted that CAP chemotherapy did not prevent distant failure
but did appear to provide a survival advantage.
4. Other Platinum Combination
Although methotrexate as a single agent had not found favor in endometrial
cancer, Long and co-workers treated 30 patients with advanced or recurrent carcinoma
of the endometrium with methotrexate, vinblastine, doxorubicin, and cisplatin.
Regression of tumor was noted in 67% of patients, with a complete response in 8
patients (7%). The median overall survival was 10 months, and the median survival of
responders was 11 months. There was significant toxicity, and there were two
treatment-related deaths. The authors nevertheless stated in their discussion that this
combination compared favorably with cisplatin and doxorubicin alone. In most
investigators' hands, however, the two drugs doxorubicin and cisplatin have little
severe toxicity, and their conclusion does not appear justified.

V.

Summary
The treatment of endometrial cancer is rapidly evolving. An extensive body of
literature exists which, upon critical review, has shaped the current treatment paradigms.
New minimally invasive surgical techniques have helped to reduce the operative
morbidity for endometrial cancer. An emerging body of data has helped to better stratify
women with intermediate-risk endometrial cancer. New interest has emerged on
incorporating cytotoxic chemotherapy into the adjuvant treatment of endometrial cancer.
Despite these advances, significant questions remain regarding the optimal adjuvant
regimens for women diagnosed with all stages of endometrial cancer.
Cytotoxic chemotherapy is effective in high-grade endometrioid endometrial cancer
that is either recurrent or extensive at the time of diagnosis. It is interesting that the
administration of prior pelvic radiation, which many of the patients presenting with
recurrence have received, does not appear to affect the administration of the cytotoxic

chemotherapy or prejudice response, which seems to be the same as in patients receiving

primary chemotherapy for advanced disease. The response rates appear to exceed those
achieved primarily with progestational agents, and this is likely to be most true for poorly
differentiated tumors. Combination chemotherapy appears preferable to the use of single
agents, and it is likely that cisplatin with doxorubicin and paclitaxel will be the preferred
combination. If the use of Adriamycin or Taxol, is precluded by cardiac damage, then 5FU and leucovorin are acceptable alternatives. The combination of 5-FU and cisplatin has
not yet been explored.
Advocacy for the use of cytotoxic chemotherapy needs, however, to be tempered by
the recognition that the duration of response is brief and may be so brief as not to justify
the administration of these necessarily toxic drugs to an elderly patient population, who
frequently already have poor quality of life and in whom the chemotherapy does not
confer significant survival advantage. The use of granulocyte colony-stimulating factor is
just beginning to be explored, but it is unlikely to change the response duration
significantly. If the performance status of the patient is good and there is desire for
therapy, then the administration of chemotherapy appears justified, provided the patient
and her family recognize the limitations of treatment. Performance status, rather than age,
is the critical determinant. Besides considering the requirements of managed care and the
financial aspects of significantly expensive treatment with a very brief duration of benefit,
both the physician and the patient need to be sure that the disadvantages of such therapy
do not outweigh the advantages of such a brief prolongation of life.
Many problems regarding adjuvant therapy for endometrial cancer remain. (1)
Which patients receive the highest benefit from adjuvant therapy? (2) Is there a definite
consensus regarding the criteria for grouping patients according to the risk of recurrence?
(3) Which chemotherapy regimen should be certified as the gold standard regimen for
adjuvant therapy (4) Which combination of radiation therapy and chemotherapy is best?
To answer these questions, before designing a trial concept, a worldwide consensus on the
criteria for risk groups needs to first be obtained. In addition, to interpret the results of
various adjuvant therapy trials, careful attention to the kind of surgery that the patients
have received and the percentages of grade 3 endometrioid adenocarcinoma and

aggressive pathological subtypes (serous, clear cell, undifferentiated, and so on) is needed.
We have collected information regarding the percentages of pelvic lymphadenectomy,
paraaortic lymphadenectomy, grade 3 endometrioid adenocarcinoma or aggressive
pathological subtypes, and informations about surgical stage distribution, treatment
compliance, and adverse effects. Sufficient information regarding the patient conditions
after surgery and just before receiving adjuvant therapy is needed. For example, some
trials with low percentages of pelvic or paraaortic lymphadenectomy, trials with high
percentages of G3 or aggressive pathological subtypes, and trials with high percentages of
advanced stage patients tend to favor chemotherapy, since these patient groups tend to
have higher possibilities of micrometastases that cannot be identified using imaging.