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Gynecologic Oncology 1
Adjuvant whole abdominal irradiation in clinical stages I and II papillary
serous or clear cell carcinoma of the endometrium: A phase II study of the
Gynecologic Oncology Group
Gregory Sutton a,*, Janice H. Axelrod b, Brian N. Bundy c, Tapan Roy d,1, Howard Homesley e,2,
Roger B. Lee f,g, Paola A. Gehrig h, Richard Zaino i
a St. Vincent Hospitals and Health Services, Division of Gynecologic Oncology, 8301 Harcourt Road, Suite 202, Indianapolis, IN 46260, USAb Gynecologic Oncology, Western Pennsylvania Hospital, Pittsburgh, PA 15224, USA
c Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USAd Cancer Institute of Cape Girardeau (St. Louis University Health Science Center), Cape Girardeau, MO 63703, USA
e Wake Forest University School of Medicine, Winston-Salem, NC 27157, USAf University of Washington School of Medicine, Tacoma General Hospital, Tacoma, WA 98405, USAg Southwest Washington Gynecologic Oncology, Tacoma General Hospital, Tacoma, WA 98405, USA
h Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7570, USAi Department of Pathology, Milton S. Hershey Medical Center of Pennsylvania State University, Hershey, PA 17033, USA
Received 23 April 2005
Available online 5 October 2005
Abstract
Objectives. To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with
whole abdominal radiotherapy.
Methods. After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal
washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day).
Results. Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight
patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent
chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients
who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2).
Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD
(3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1),
vagina (1), and unknown (1).
Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and
cutaneous (one grade 3).
Conclusions. Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or
sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Whole abdominal irradiation; Papillary serous; Clear cell; Endometrium; Adjuvant
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2005.08.037
* Corresponding author. Fax: +1 317 415 338 6749.
E-mail address: [email protected] (G. Sutton).1 Affiliate of University of Iowa Hospitals and Clinics, Iowa City, IA 52242,
USA.2 Currently: Gynecologic Oncology Network, Nashville, TN 37203, USA.
Introduction
Endometrial cancer is the most common malignancy
arising in the female reproductive tract and has the lowest
death-to-case ratio of all gynecologic cancers. Nonetheless,
an estimated 7310 women will die of advanced, recurrent,
or metastatic endometrial cancer in 2005 in the United
00 (2006) 349 – 354
www.el
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349–354350
States [1]. Extirpative surgery followed in selected cases by
pelvic radiation therapy is capable of controlling stages I
and II disease in the majority of cases. Adjuvant therapy in
stage III and localized stage IV disease has not been well-
defined, however, and the most appropriate treatment for
patients with aggressive papillary serous (PS) and clear cell
(CC) cancers awaits delineation.
Based upon early experience in treating ovarian cancer at
the MD Anderson Cancer Center, Greer and Hamburger [2]
suggested that whole abdominal radiotherapy (WAR) utilizing
a moving strip technique could be beneficial in treating patients
with endometrial cancer in whom tumors had spread to the
abdominal cavity. They reported corrected and absolute 5-year
survival rates of 80% and 63%, respectively, among 27 women
with intraperitoneally disseminated endometrial cancer. None
had residual disease greater than 2 cm in diameter, and all
received whole abdominal moving-strip radiotherapy with a
pelvic boost. Of the patients who developed recurrent disease,
three had within-field failures alone and one experienced
simultaneous abdominal and distant relapse. Toxicity was
limited to early severe enteritis, two cases of ‘‘late’’ partial
bowel obstruction, and a vaginal ulcer. Subsequent reports [3]
of substantial small bowel toxicity among patients with ovarian
cancer treated with the moving strip technique led to the
abandonment of this procedure in favor of the whole
abdominal ‘‘open field’’ procedure presently used.
Hendrickson et al. [4] first demonstrated that PS cancers
of the endometrium were associated with an extraordinary
risk of relapse characterized by upper abdominal failures
that were fatal in the vast majority of patients. They were
the first investigators to suggest the use of adjuvant upper
abdominal radiotherapy in this disease entity.
The Gynecologic Oncology Group (GOG) initiated a
study in 1986 to determine progression-free survival (PFS)
and overall survival (OS) among patients with advanced
endometrial cancer of all histologic types treated with whole
abdominal irradiation (WAI) and pelvic (and, in the case of
para-aortic metastases, para-aortic) boosts (GOG Protocol
94) [5]. Also included in that study were patients with
stages I and II PS and CC cancer of the endometrium.
This report summarizes PFS, OS, and sites of recurrence
among patients with clinical stages I and II PS and CC
carcinomas of the endometrium who received WAI.
Methods and materials
In this study, eligible patients were to have pathologically confirmed
primary endometrial cancer with clinical stage I/II disease without vaginal
involvement, parenchymal liver metastases, lung metastases, or spread to
extraperitoneal sites, excluding retroperitoneal lymph nodes. It was required
that PS or CC histology involves greater than 50% of tumor volume.
Patients were ineligible if they had received pelvic or abdominal
radiation or chemotherapy or were found to have inadequate hematologic
(WBC <3000/Al, platelets <100,000 Al, or granulocytes <1500 cells/mm3),
renal (creatinine >2.0 mg%), or hepatic function (bilirubin or AST >2�normal). Also ineligible were patients with GOG performance status of 4,
and those with a previous or concomitant malignancy except non-melanoma
skin cancer. Participating institutions obtained approval of the study from
their Institutional Review Board prior to enrolling any patient on the study.
Patients provided written informed consent in accordance with institutional,
state, and federal regulations, prior to the initiation of study therapy.
Pathology review
Peritoneal washings were obtained from the pelvis and cytologically
evaluated for malignant cells. The uterus was evaluated for size, location of
tumor, depth of myometrial invasion, histologic type, and grade of tumor.
Lymph nodes and adnexa were also evaluated for the presence and location
of metastases. For each patient entered on study, all slides were reviewed
centrally by the GOG Pathology Committee to document histological
parameters and confirm eligibility.
Surgery
Patients were required to undergo total abdominal hysterectomy, bilateral
salpingo-oophorectomy, pelvic washings, and selective para-aortic and pelvic
lymph node sampling. Omentectomy was not required; however, careful
inspection of the omentum as well as removal of sections of the omentum with
gross metastases was necessary. Patients who had received previous therapy
with hormonal agents were permitted, as were those with recurrent endometrial
cancer, if all other protocol requirements were met.
Radiation therapy
Radiation was to be initiated within 8 weeks of surgery. Treatment was
delivered by megavoltage equipment ranging from that of cobalt-60 to
maximum 25 MeV photons. Minimal source-skin distance was 80 cm, and
dose rates between 30 and 200 cGy per minute at midplane were required.
Patients were treated with parallel opposed fields (open field technique) to the
whole abdomen and pelvis.
The abdomen was to be treated first to a dose of 3000 cGy in 20 fractions of
150 cGy each. A decrease in the daily fraction to 125 cGy was permitted if
gastrointestinal symptoms or leukopenia precluded the use of the higher dose.
After WAI, the pelvis was to be boosted to a midplane dose of 1980 cGy at 180
cGy per fraction for eleven treatments. The combined WAI and total pelvic
irradiation required 6 to 7 weeks.
The whole abdominal field extended from 1 cm above the top of the
diaphragm to the bottom of the obturator foramina. The lateral border extended
1.0 to 1.5 cm beyond the lateral peritoneal margin. Full thickness PA kidney
blocks were used throughout therapy. The left heart above the diaphragm and
portions of the lower lateral pelvic fields and femoral heads were blocked. The
pelvic field extended from the L5–S1 interspace superiorly to the bottom of the
obturator foramina inferiorly. The lateral margins were 1.5 cm lateral to the
medial rim of the ilium. In patients with para-aortic metastases, the boost field
was bounded by the L5–S1 interspace inferiorly and the superior margin of the
abdominal field superiorly, and the lateral extent was 8 cm wide. Interruptions in
treatment exceeding 2 weeks disqualified patients from continuing protocol
therapy.
Radiation therapy quality control was supervised by the Radiologic Physics
Center under the sponsorship of the American Association of Physicists in
Medicine. An accuracy of T3% in source output and T5% in prescribed dose
delivery was required.
Statistical considerations
Evaluation parameters included PFS, OS, and frequency and severity of
adverse effects. Progression-free survival was defined as the date from study
entry to the date of reappearing or increasing disease or the date of last contact.
Overall survival was defined as the observed length of life from study entry to
death or to date of last contact.
Life tables and medians were computed using the method of Kaplan and
Meier. Differences in PFS or OS by patient characteristics were evaluated using
the log-rank test. The Pearson Chi-square test was used to identify correlations
between the two major categories of cell type and patient/disease characteristics.
The Wilcoxon Rank Sum test was used for age at diagnosis and cell type
categories.
Table 2
Adverse events (n = 33a)
Toxicity Grade
1 2 3 4
Hematologic 9 6 2 1
Gastrointestinal 11 13 3 3
Genitourinary 3 2 1 0
Cardiovascular 0 1 0 0
Pulmonary 5 1 0 0
Hepatic 1 0 0 0
Fever 3 1 0 0
Cutaneous 6 0 1 0
Lymphatics 2 1 0 0
Other 2 3 0 0
a 1 PS patient refused protocol therapy after registration.
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349–354 351
Results
Population
Two hundred seventy-four patients were enrolled in the
original study between December 1986 and February 1994. Of
these, 58 were ineligible for the following reasons: inadequate
surgery (20), wrong cell type (22), disease more advanced than
was permitted by protocol criteria (3), failed the criteria for
advanced stage (4), second primary malignancy (8), and
primary that was not endometrial (1). One patient who received
no radiation therapy and another patient who had recurrent
disease were inevaluable.
Among 214 evaluable patients in GOG Protocol 94, 180
with stage III/IV disease have been reported separately [5]; 34
had stage I/II PS (n = 21) or CC (n = 13) cancer; this group is
the subject of this report (Table 1). In the patients with stages I
and II disease, the median age of those with PS cancer was 68
(range: 51–83) years compared with a median age of 63
(range: 46–86) years for patients with CC cancers. The relative
frequency of GOG performance status of 0 was 43% and 62%
and for patients with PS and CC cancers, respectively. Two of
21 (10%) patients with PS cancers and four of 13 (31%) of
those with clear cell cancers were nonwhite.
Treatment
Because no patient had para-aortic metastases, none
received a boost to this area. One patient refused all
radiotherapy and was not treated. One patient received pelvic
Table 1
Patient characteristics (n = 34)
Characteristic No. (%)
Cell type
Clear cell 13 38.2
Papillary serous 21 61.8
Age
<50 3 8.8
51–60 4 11.8
61–70 16 47.1
71–80 9 26.5
>80 2 5.9
GOG performance status
0 17 50.0
1 16 47.1
2 1 2.9
3 0 0.0
Race
White 28 82.4
Black 5 14.7
Other 1 2.9
Gradea
1 0 0.0
2 8 24.2
3 25 75.8
a Histologic grade unknown for one patient.
radiotherapy only, and two received doses other than pre-
scribed (one patient had 3319 cGy to the abdomen/1620 cGy to
the pelvis, and another patient had 1200 cGy to the abdomen/
3570 cGy to the pelvic region). Among the 30 patients who
received the prescribed RT doses, 2 completed treatment in 35
days or less, 3 finished in 36–42 days, and 22 (73%)
completed RT in 43–49 days. For three patients, treatment
duration was �50 days.
Toxicity
Adverse events are displayed in Table 2. Nausea and
diarrhea were the most common acute gastrointestinal (GI)
toxicities. The three patients experiencing grade 3 GI toxicity
had bowel obstructions; all were successfully resolved by
surgery. One of the three received only pelvic radiation. The
other two received radiation therapy dose and timing per
protocol, although one received a vaginal cuff boost (protocol
violation). Three patients experienced grade 4 toxicity; one had
nausea, vomiting, and diarrhea resulting in termination of her
radiation therapy and hospitalization. After temporary relief
with steroid therapy, she was released, only to be readmitted 3
weeks later; she expired (ruled treatment-related) the following
day. Another patient had numerous food intolerances and, 6
months post-radiotherapy, had surgical resection to correct a
bowel obstruction; 1 month later, she experienced a grade 3
bladder fistula. This patient was NED at 63 months. The third
patient required a Cantor tube to resolve bowel obstruction and
suffered with chronic anorexia due to severe radiation proctitis
and colitis; this patient died of her disease at 32 months on
study. The latter two patients completed their radiation therapy
per protocol.
Patterns of failure
Of 21 patients with PS carcinoma, one refused radiotherapy
after registration and died of disease at 35.2 months. A second
patient received a vaginal boost, constituting a major protocol
violation. Shewas alive without disease at 10 years and 5months
after therapy. Of the remaining patients, 7 died of disease from
9.6 to 32.0 months. Other deaths included one attributable to
toxicity, one intercurrent death, one patient with a pelvic
Table 3
Sites of relapse
Sites No. (%)
NED 22 64.7
Recurred
Vagina 2 5.9
Pelvis 2 5.9
Abdomen 2 5.9
Abdomen + pelvis 1 2.9
Retroperitoneal nodes 0 0.0
Lung 4 11.8
Unknown 1 2.9
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349–354352
recurrence at 49 months who died of complications of second-
line systemic chemotherapy, and two deaths of unknown cause.
Sites of recurrence for all patients are illustrated in Table 3.
Among treated patients, sites of recurrence included lung alone
(2), lung and vagina (1), abdomen and pelvis (1), vagina alone
(1), and abdomen alone (2). Time to recurrence ranged from 2.8
to 28.9 months.
Of 13 patients with CC carcinoma, one received pelvic
radiotherapy only and died with intercurrent disease 7.8
months following therapy. An additional five patients died,
three died of disease, one of intercurrent disease, and one of
unknown cause. Sites of recurrence for disease-related deaths
were lung (1), vagina (1), and unknown (1). Time to recurrence
ranged from 6.1 to 21.7 months.
Progression-free and overall survival
Figs. 1 and 2 illustrate PFS and OS, respectively, for PS/CC
patients.
Eight of 21 (38%) patients with stage I/II PS cancer were
alive without disease 59.6 months to 12.8 years after study
entry. PFS for the PS group was 38.1% at 5 years (the last
failure occurred at 49.1 months). Of 13 patients with CC
carcinoma, 7 (54%) were alive without disease 59.9 to 8 years
Fig. 1. Progression-free s
and 9 months after treatment. PFS for the CC group was 53.9%
at 5 years (the last failure occurred at 40.6 months).
Discussion
In 1982, Hendrickson et al. [4] first described uterine
papillary serous carcinoma and demonstrated associated long-
term survival far inferior to that of a control group of patients
with poorly differentiated endometrial cancers of similar stage.
Clear cell carcinoma of the endometrium is also felt to be a rare
but aggressive variant by many authors [6,7] and for these
reasons patients with stages I and II papillary serous and clear
cell carcinomas of the endometrium were included in the
present study of adjuvant whole abdominal radiotherapy.
Clear cell carcinoma
Abeler et al. [8] identified 181 patients with clear cell
carcinoma of the endometrium in the tumor registry of the
Norwegian Radium Hospital between 1970 and 1982, repre-
senting just 3.1% of all endometrial cancers seen during that
interval. Of these, 155 (86%) patients had disease clinically
limited to the uterus and cervix. The mean age of subjects in
this study was 66.2 years, compared with 62.1 years for
patients with adenocarcinoma of the endometrioid type. The
majority of patients in this study received surgery plus
radiotherapy (80.1%), and 64.8% of those received pelvic or
pelvic plus aortic fields; none were treated with WAR. Sixty-
nine (44.5%) of 155 patients experienced relapses, and
actuarial crude survival for stage I and stage II cases was
about 50%. Twenty-four of 75 patients of all stages had relapse
in the pelvis only; 21 of 51 with extrapelvic failure had an
upper abdominal component. These authors concluded that
their ‘‘. . .findings argue against the use of adjuvant pelvic
radiotherapy in patients with endometrial clear cell carcino-
ma.’’ They suggested that cisplatin-based chemotherapy might
be the most efficient type of therapy.
urvival by cell type.
Fig. 2. Survival time by cell type.
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349–354 353
In a later study, Malpica et al. [9] reported 21 patients with
stage I/II clear cell carcinomas of the endometrium with an
average age of 66 years. All but three of these patients were
treated with abdominal hysterectomy and bilateral salpingo-
oophorectomy with or without lymph node sampling. Twelve
(57.1%) patients received preoperative and two (9.5%)
postoperative radiotherapy; three patients with stage II disease
were treated with radiotherapy without surgery because they
were poor surgical candidates. A single patient received
adjuvant combination chemotherapy and was alive at more
than 5 years follow-up. Two patients with stage I disease
developed abdominal failures at 3 and 10 months, and a third
had a pelvic relapse at 7.5 years. Overall, one of eight patients
with stage I disease and three of seven with resected stage II
disease (26.7%) developed recurrences with a pelvic compo-
nent despite radiotherapy; two additional patients with stage I
cancer developed abdominal failures. These authors concluded
that clear cell carcinomas of the endometrium were dissimilar
to papillary serous cancers and behaved more like grade III
endometrioid tumors. Although there was no specific recom-
mendation for adjuvant therapy, they did suggest that long
follow-up was important because of observed late failures.
Taken together, these reports and the current study of
patients with surgical stage I/II disease would suggest that
patients with early stage clear cell carcinomas of the
endometrium may have a better outlook than their counterparts
with papillary serous cancer.
Papillary serous cancers
Nearly all early reports demonstrated poor survival in
patients with stages I and II papillary serous carcinomas of
the uterus, a finding confirmed by the present study which
was initiated in 1986. Typical were the findings of Ward et al.
[10] who, in 1990, published a 3-year survival rate of 47% in
patients with localized disease. In a later report, these authors
[11] showed that aggressive surgical staging, including upper
abdominal biopsies and omentectomy, increased the propor-
tion of patients with true stage IV disease from 2% to 73%.
They suggested, much as was the case in stage I ovarian
cancer, that poor outcomes in early studies reflected under-
staging. In fact, occult omental involvement has been reported
in 22–25% [12,13] of patients with papillary serous cancers.
Subsequent authors have demonstrated excellent survival in
appropriately staged stages I and II papillary serous cancers of
the uterus with either adjuvant pelvic radiotherapy [14] or
even surgery alone [15]. In the present study, it should be
recalled that ‘‘. . .careful inspection of the omentum was
required, as well as removal of sections of the omentum with
gross metastases.’’ Total or infracolic omentectomy was not
required in the study. It is conceivable that some microscopic
omental metastases could have been missed during staging,
although microscopic metastases would potentially have been
sensitive to whole abdominal radiotherapy. Although three
failures in the present group of patients with papillary serous
cancers occurred in the lung or had a pulmonary component,
five arose within the treatment fields. However, in a study of
radiation with or without chemotherapy in 29 patients with
early stage papillary serous cancers of the uterus in which
omentectomy was required and completed, 66% still had
abdominal, vaginal, or pelvic failures, and 5-year survival was
52% [16].
In summary, both for papillary serous and clear cell
histologies, there is a need in stages I and II cases to
evaluate other adjuvant approaches, namely chemotherapy,
chemoradiotherapy or sequential chemotherapy, and radiation
therapy.
Acknowledgments
This study was supported by National Cancer Institute grants
to member institutions of the Gynecologic Oncology Group
(GOG). The following GOG institutions participated in this
study: University of Alabama at Birmingham (CA 12484),
Oregon Health Sciences University, Duke University Medical
Center (CA 12534), Abington Memorial Hospital, University of
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349–354354
Rochester Medical Center (CA 12482), Walter Reed Army
Medical Center (CA 23501), Wayne State University (CA
12477), University of Southern California at Los Angeles (CA
37535), University of Mississippi Medical Center (CA 13633),
Colorado Gynecologic Oncology Group, P.C. (CA 15975),
University of California at Los Angeles (CA 13630), University
of Miami School of Medicine (CA 37234), Milton S. Hershey
Medical Center (CA 16386), Georgetown University Hospital
(CA 16938), University of Cincinnati, University of North
Carolina School of Medicine (CA 23073), University of Iowa
Hospitals and Clinics (CA 19502), University of Texas
Southwestern Medical Center at Dallas (CA 28160), Indiana
University Medical Center (CA 21720), Wake Forest University
School of Medicine (CA 21946), Albany Medical College (CA
27469), University of California Medical Center at Irvine (CA
23765), Tufts-New England Medical Center (CA 37569), Rush-
Presbyterian-St. Luke’s Medical Center (CA 12485), Stanford
University Medical Center (CA 35640), State University of
New York Downstate Medical Center (CA 34477), Eastern
Virginia Medical School (CA 40296), The Cleveland Clinic
Foundation, Johns Hopkins Oncology Center, State University
of New York at Stony Brook, Eastern Pennsylvania Gynecol-
ogy/Oncology Center, P.C., Washington University School of
Medicine, Memorial Sloan-Kettering Cancer Center, Cooper
Hospital/University Medical Center, Columbus Cancer Coun-
cil, University of Massachusetts Medical Center, Women’s
Cancer Center, and University of Oklahoma.
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