The role of adjuvant chemotherapy in surgical stage I-II serous or clear cell
endometrial carcinoma: a randomized phase III trial
Principal Investigator: Frederic Amant, MD PhD
Division Gynecologic Oncology
Department of Obstetrics and Gynecology
University Hospitals Leuven
Although 20 years have past since the description of the clinicopathologic characteristics of
uterine papillary serous carcinomas (UPSC), our knowledge and understanding of the
epidemiology, pathogenesis, natural history, and optimal treatment strategies for this
aggressive variant are limited (Amant et al., 2005a). The natural history of UPSC implies
frequent involvement of the four routes of potential metastasis, including hematogenous
dissemination, lymphatic embolization, intraperitoneal spread via exfoliation, and continuous
spread. It is reasonable to suggest that treatment strategies should be predicated on the
anticipated patterns of recurrence. The treatment strategies for the four different routes of
failure might rationally require diverse or combination therapies specific for one or more of
the routes of spread. In the presence or absence of lymph node involvement and a substantial
risk for intraperitoneal or hematogenous failure, the treatment strategies might be distinctly
different. Hence, the necessity for definitive surgical management should be similar to the
ovarian epithelial cancer counterpart and should include omentectomy, systematic
lymphadenectomy (not sampling), staging biopsies in the absence of macroscopic extrauterine
disease, and perhaps when feasible cytoreduction (Jeffrey et al., 1986; Dunton et al., 1991;
Kato et al., 1995; Podratz, 2003). The diagnostic value of systematic lymphadenectomy was
again validated since 19% lymph node involvement has been reported in patients with UPSC
without myometrial invasion (Slomovitz et al., 2003). Furthermore, the importance of
performing a formal lymph node dissection is stressed by the absence of pelvic side wall
failures following observation in a population at risk for recurrence (Huh et al., 2003).
Table 1 presents a summary of the available evidence regarding the biologic behavior of
poorly differentiated endometrioid, carcinosarcoma, clear cell and serous endometrial
malignancies. Although this information is extracted from different studies with limited
numbers in some, the similarity in spread pattern between these subtypes is apparent (Abeler
et al., 1996; Boronow et al., 1984; Cirisano et al., 1999; Creasman, et al., 1987; Gallup et al.,
1989; Goff et al., 1994; Jeffrey et al., 1986; Major et al., 1993; Manolitsas et al., 2001;
Ramirez-Gonzales et al., 1987; Sartori et al., 1997; Shaw et al., 1983; Sreenan & Hart, 1995).
Furthermore, there is a tendency for lymphatic and transperitoneal spread, that puts adequate
surgical staging into perspective.
Table 1. Overview on spread pattern in different subtypes of endometrial cancer as
reported in literature n (%)
Peritoneal Adnexal Omental Pelvic lymph
Grade 3 endometrioida 86/668 (13) 41/721 (6) 3/25 (12) 78/734 (11)
Carcinosarcomab 72/373 (19) 75/512 (15) 15/96 (16) 80/423 (19)
Serousc 17/57 (13) 27/125 (22) 47/202 (23) 72/244 (30)
Clear celld 7/20 (35) 3/32 (9) 3/6 (50) 9/20 (45)
Boronow, 1984; Cirisano 1999, Creasman 1987, Amant 2005
Manolitsas 2001, Gallup 1989, Major 1993, Sartori 1997, Shaw 1983, Sreenan 1995, Amant 2005
Goff 1994, Slomovitz 2003, Cirisano 1999, Ramirez-Gonzales 1987, Amant 2005
Mixed adenocarcinomas with serous components portend a similar clinical course to that of
pure UPSC (Goff et al., 1994; Sherman 1997; Slomovitz et al., 2003). Recently, the
importance of the serous component in endometrioid EC was studied in detail and a trend
toward a worse prognosis was found to exist even if the serous component comprised 10% of
a tumor (Boruta, 2004). Therefore, there is agreement that irrespective of the magnitude of the
serous component, tumor biology of mixed tumors parallels that of pure serous carcinomas.
Taken together, these data suggest that high risk endometrial cancers spread to lymph nodes
and transperitoneally. Adequate surgical exploration therefore is important to assess stage of
disease, prognosis and need for further treatment (Amant et al., 2005a).
1.2 Study rationale
The progress in managing serous and clear cell endometrial cancer over the past decade has
been limited and the exigency for prospective clinical trials is readily apparent. Previous trials
have been flawed by the fact that surgical staging is frequently not mandatory, resulting in
similar treatment regimens for stage I and Stage III disease. This study addresses the benefit
of adjuvant chemotherapy in surgically staged high risk endometrial cancer.
1.2.1. Complete surgical staging without adjuvant treatment
Although some numbers are relatively small, recurrences in surgically stage I-II UPSC
without further treatment are described in 0-33%. Slomovitz et al. (2003) calculated that
surgical stage I UPSC without adjuvant treatment (n = 52) had a PFS of 69% and OS of 85%
after 3 years (after 5 years, PFS of 65% and OS of 63%). Huh et al. (2003) calculated a
recurrence rate in surgically staged patients without adjuvant treatment of 17% (7/40)
resulting in a DFS and OS at 5 years of 66% and 66%, respectively. Kelly et al (2005)
calculated an overall survival of approximately 70% after 3 years and 46% after 5 years in
women without further treatment (n = 41).
In a smaller study, 2/11 (18%) of surgically staged patients without adjuvant treatment
recurred (Bristow 2001). Gehrig et al. (2001) encountered 2/6 (33%) vaginal recurrences that
were treated by radiotherapy. There were no distant metastases. Grice (1998) observed no
recurrences in 9 patients respectively. Gallion et al (1989) observed 1/5 (20%) recurrences in
surgically staged patients without further treatment.
Table II. Summary of outcomes of surgical stage I-II serous endometrial cancer without
adjuvant treatment according to literature data.
n 3y DFS (%) 3y OS (%) 5y DFS (%) 5y OS (%)
Slomovitz, 2003 Stage I, 52 69 85 65 63
stage II, 5 100 100 100 100
Huh, 2003 40 66 66
Kelly, 2005 41 70 46
Grice, 1998 6 100 80
Bristow, 2001* 11 82 82
Gallion, 1989* 5 80 80
*, variable duration of follow up
1.2.2. Complete surgical staging with adjuvant chemotherapy
Whether adjuvant chemotherapy results in clinical benefit in completely staged high risk
endometrial cancer is unknown. Randomized trials are lacking and little studies include
adequately staged patients. Available data are as follows.
Recurrences in surgically stage I-II UPSC with platinum based chemotherapy vary from 0-
66%. The first suggestion in UPSC of an improved outcome after adjuvant chemotherapy was
in 10 patients who received pelvic radiotherapy and systemic treatment and who all survived
(Rosenberg et al., 1993). Elit et al. encountered 4/6 (66%) recurrences in surgical stage I
UPSC receiving cisplatin based chemotherapy (Elit et al., 2004). Recently, two observational
studies in surgical stage I UPSC showed a promising role for adjuvant chemotherapy. Dietrich
et al. (2005) studied 21 patients who received 3-6 courses paclitaxel and carboplatin. After 41
months, 1 patient recurred and all patients survived (DFS 95%, OS 100%). In a retrospective
comparison of 74 patients, Kelly et al. (2005) observed a 5-year survival of 100% (n = 32) in
the platinum based chemotherapy group and 46% (n = 41) in the group of patients who did
not receive chemotherapy. Huh et al. noted no recurrences (n = 7) in the group receiving
Table III. Summary of outcomes of surgically stage I-II serous endometrial cancer with
adjuvant chemotherapy according to literature data.
n 3y DFS (%) 3y OS (%) 5y DFS (%) 5y OS (%)
Elit, 2004 6 33
Dietrich, 2005 21 95 100
Kelly, 2005 32 97 100 100
Huh, 2003 7 100 100 100 100
Havrilesky, 13 77 89
* patients also received radiotherapy
Summarizing these data, recurrences are described both in surgical stage I-II UPSC with and
without platinum based chemotherapy, although the outcome based on retrospective series
appears to be beneficial in case chemotherapy is administered. On the other hand, in a subset
analysis for serous endometrial cancer only, Randall et al. (2006) did not encounter a benefit
in the group receiving chemotherapy. Therefore, in the absence of randomized data, this study
investigates prospectively the role of adjuvant chemotherapy in surgical stage I-II high risk
1.2.3. Should endometrial clear cell carcinoma be included?
Lumping is necessary in rare disease entities. Clear cell (CC) endometrial cancer has, similar
to UPSC, a tendency towards transperitoneal and lymphatic spread. Surgical staging for CC is
therefore identical as for UPSC.
When compared to grade 3 endometrioid endometrial cancer, both UPSC and CC predict for a
poorer survival (Hamilton, 2006). The five year disease-specific survivals for women with
UPSC, CC and G3EC were 55, 68 and 77%, respectively (p < 0.0001). We recently lumped
CC and UPSC and noted a worse outcome when compared to G3EC (Amant, 2005b).
The spread pattern and poor prognosis are shared by both UPSC and CC. These tumor
characteristics of rare disease entities allow lumping in order to enhance accrual and
2 Study Objectives
Primary end-point: disease free survival after three years
Secondary end-point: overall survival after three years
3 Overall design
3.1 Description of comprehensive surgical staging technique
Inspection and palpation of all peritoneal surfaces and biopsies of any suspect lesion should
be carried out. Peritoneal washing and biopsies from both hemidiaphragms, paracolic gutter
and pelvic sidewall should be aimed for. A hysterectomy, bilateral salpingo-oophorectomy,
cytology, pelvic lymphadenectomy and infracolic omentectomy are performed. These
surgical requirements can be fulfilled using a laparoscopic procedure. In case of
macroscopically involved pelvic nodes, macroscopically involved adnexa or growth through
the serosa of the uterus, a para-aortic lymphadenectomy below the inferior mesenteric artery
is recommended. In case a patient is referred who only underwent removal of the uterus and
ovaries and with apparent stage I-II endometrial carcinoma, a re-operation (possibly
laparoscopic procedure) is mandatory to fulfill the surgical requirements. Complete pelvic
lymphadenectomy is attained and should inform about external iliac, internal iliac, obturator
fossa and common iliac vessels as much as possible and a minimum of six nodes per side is
requested. The protocol does not allow pelvic node sampling. Paraaortic lymphadenectomy is
advised, although not mandatory.
3.2 Description of chemotherapy regime
UPSC has long been considered a chemoresistant disease. Recent work changed this idea and
several studies and clinical practice of most confirm that UPSC is chemo sensitive.
Systemic treatment has been shown to result in a better outcome when compared to
radiotherapy. Randall et al. (2006) randomized women with stage III or IV endometrial
carcinoma having a maximum of 2 cm of postoperative residual disease to whole-abdominal
irradiation (WAI) and doxorubicin (60 mg/m²)-cisplatin (50 mg/m²) chemotherapy.
Approximately 25% of tumours were UPSC or clear cell. At 60 months, 50% of patients
receiving AP were predicted to be alive and disease free when adjusting for stage compared
with 38% of patients receiving WAI (Randall, 2006).
Doxorubicin-cisplatin is considered standard treatment for advanced or recurrent endometrial
cancer and in reports addressing all types of endometrial cancer, response rate varies from 33-
81% (Seltzer, 1984; Tropé, 1984; Pasmantier, 1985; Barrett, 1993).
Responses to a combination of taxanes and carboplatin are excellent. Paclitaxel-carboplatin
showed a response rate of 78% (n=21) and 60% (n=20) in nonpapillary and UPSC cancers,
respectively (Hoskins, 2001). A response rate of 84% (16/19) was calculated in UPSC treated
with paclitaxel-carboplatin (Vaidya, 2006). A case report documented a complete response do
docetaxel-carboplatin (Kashima, 2005). These responses in combination with the overall
acceptable tolerance, support the preference of paclitaxel-carboplatin over doxorubicin-
cisplatin in the treatment of endometrial cancer.
The protocol intends to estimate in a randomized Phase III study the value of adjuvant
chemotherapy in high risk surgically stage I-IIa endometrial carcinoma.
Patients randomized to the study group receive combination chemotherapy consisting of
paclitaxel (175mg/m²)-carboplatin (AUC x 5). Chemotherapy should be administered within 6
weeks after surgery. In case of a restaging procedure, administration should occur within six
weeks of this procedure and not of the primary incomplete surgery.
3.3 Radiation therapy
In the presence of negative nodes, there is no clinical benefit of further external radiotherapy
(Podratz & Mariani, 2003). Recently, this statement was endorsed in a GOG phase II study
where clinical stages I and II UPSC or CC received adjuvant whole abdominal irradiation
(Sutton, 2006). Since over half of the treatment failures were within the radiation field, the
authors support the use of alternative modalities in early stage disease.
Brachytherapy is not endorsed in a disease with a tendency for systemic spread. However, the
protocol allows brachytherapy to the vaginal vault according to the discretion of the treating
3.4 Early stage high risk endometrial carcinoma study protocol, schematically:
Serous or clear cell or mixture
HT, BSO, cytology, adequate pelvic
lymphadenectomy, omentectomy, peritoneal
No further treatment 6 cycles paclitaxel
carboplatin (AUC 5)
4 Study population
4.1 Inclusion criteria
Patients must meet all of the following inclusion criteria:
Histological proven invasive serous or clear cell endometrial cancer (mixed
endometrial carcinomas with serous or clear cell component, irrespective of
percentage of serous or clear cells are allowed)
Adequate staging procedure including hysterectomy, bilateral salpingo-
oophorectomy, cytology, adequate pelvic lymphadenectomy, omentectomy,
FIGO surgical stage I-IIa
Patients must be fit to receive combination chemotherapy and optimal
surgical staging (see below)
Patients must have adequate bone marrow, renal, hepatic and pulmonary
WHO performance status 0 or 1
> 18 years of age
4.2 Exclusion criteria
Endometrial cancer of the following subtype: uterine leiomyosarcoma,
endometrial stromal sarcoma, carcinosarcoma, undifferentiated endometrial
cancer, endometrioid endometrial cancer (any grade)
Endometrial carcinoma with positive pelvic nodes (Stage IIIc) or evidence
for transperitoneal spread (Stage IV).
FIGO surgical stage IIb
5 Statistical analysis
A randomized Phase III trial is set up to directly compare the two treatment arms. Patients
will be randomized to receive either adjuvant chemo or no chemotherapy. The design will test
for superiority of the chemotherapy arm over the no chemo arm.
Design: Randomized Phase III.
Primary endpoint: PFS rate at 3 years.
Statistical test: Fisher exact test (2-sided)
- alpha error = 0.05
- beta error = 0.20
- Expected rate in the control arm (no chemo) = 69% PFS at 3 yrs
- Expected rate in the experimental arm (chemo) = 95% PFS at 3 yrs
Sample size: 2 x 38 patients = 76 patients in total.
The fact that one has to wait at least 3 years between randomization of the patient and the
endpoint becoming available, makes the addition of any formal interim analysis difficult.
Either the interim evaluation will have to be based on too few events and the resulting
stopping rule will almost never be met. Or the interim analysis needs to be set at a later time
point (possibly after completion of accrual) but then the result will be available too late to
prevent withholding chemotherapy to a relevant number of patients.
A more pragmatic approach is to have frequent (e.g. yearly) IDMC evaluations. A practical
approach is to compute the conditional power at each look. The conditional power reflects the
probability that the trial would end with a positive result (ie. p-value < 0.05) if the already
observed PFS rates would be extrapolated.
Advantage of this technique is that it does not involve any formal testing, hence no alpha
adjustement needs to be performed. Interpretation of the conditional power is also relatively
easy. Disadvantage is that no formal stopping rules exists for conditional power.
In addition, IDMC should also take into account toxicity profiles, treatment compliance,
protocol violations and accrual rate to decide on any changes in the further conduct of the
Comments on the statistical analysis
The hypothesized difference of 69% versus 95% PFS rate at three years comes from different
sources in literature and is rather large. It could be that this difference is an optimistic
6 Storage of tissue
Although optional, investigators are asked to store tumour tissue in liquid nitrogen or at -80°C
in order to have adequate material for future research studies.
Abeler V, Vergote I, Kjorstad K, Tropé C. Clear cell carcinoma of the endometrium.
Prognosis and metastatic pattern. Cancer 1996;78:1740-7.
Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial
cancer. Lancet 2005a;366:591-605.
Amant F, Cadron I, Fuso L, Berteloot P, de Jonge E, Jacomen G, Van Robaeys G, Neven P,
Moerman P, Vergote I. Endometrial carcinosarcomas have a different prognosis and pattern of
spread compared to high risk epithelial endometrial cancer. Gynecol Oncol 2005b;98:274-80
Barrett et al., Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced
endometrial carcinoma. Am J Clin Oncol 1993;16:494
Boronow R, Morrow C, Creasman W, Disaia P, Silverberg S, Miller A, Blessing J. Obstet
Boruta D, Gehrig P, Groben P, et al. Uterine serous and grade 3 endometrioid carcinomas: Is
there a survival difference? Cancer 2004;101:2214-21.
Bristow R, Asrari F, Trimble E, Montz F. Extended surgical staging for uterine papillary
serous carcinoma: survival outcome of locoregional (Stage I-III) disease. Gynecol Oncol
Cirisano F, Robboy S, Dodge R, Bentley R, Krigman H, Synan I, Soper J, Clarke-Pearson D.
Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial
cancers when compared to endometrioid carcinoma. Gynecol Oncol 1999;74:385-94.
Creasman W, Morrow P, Bundy B, Homesley H, Graham J, Heller P. Surgical pathologic
spread patterns of endometrial cancer. Cancer 1987;60:2035-41.
Dunton C, Balsara G, McFarland M et al. Uterine paillary serous endometrial cancer : a
review. Obstet Gynecol Survey 1991;46:97-102.
Jeffrey J, Krepart G, Lotocki R. Papillary serous adenocarcinoma of the endometrium. Obstet
Gallion H, van Nagell J, Powell D et al. Stage I serous papillary carcinoma of the
endometrium. Cancer 1989;63:2224-8.
Gallup D, Gable D, Talledo E, Otken L. A clinical-pathologic study of mixed müllerian
tumors of the uterus over a 16-year period- The Medical College of Georgia experience. Am J
Obstet Gynecol 1989;161:533-9.
Gehrig P, Groben P, Fowler W et al. Noninvasive papillary serous carcinoma of the
endometrium. Obstet Gynecol 2001;97:153-7.
Goff B, Kato D, Schmidt R et al. Uterine papillary serous carcinoma: patterns of spread.
Gynecol Oncol 1994;54:264-8.
Grice J, Ek M, Greer B et al. Uterine papillary serous carcinoma: evaluation of long-term
survival in surgically staged patients. Gynecol Oncol 1998;69:69-73.
Hamilton C, Cheung M, Osann K, et al. Uterine papillary serous and clear cell carcinomas
predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Ca
Havrilesky L, Secord A, Bae-Jump V, Ayeni T, Calingaert B, Clarke-Pearson D, Berchuck A;
Gehrig P. Outcomes in surgical stage I papillary serous carcinoma. Gynecol Oncol
Hoskins P, Swenerton K, Pike J, et al. Paclitaxel and carboplatin, alone or with irradiation, in
advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 2001;19:4048-53
Huh W, Powell M, Leath C et al. Uterine papillary serous carcinoma: comparisons of
outcomes in surgical stage I patients with and without adjuvant therapy. Gynecol Oncol
Kashima K, Aoki Y, YahataT, Tanaka K. Complete response to docetaxel and carboplatin
combination chemotherapy for a stage IV uterine papillary serous carcinoma: a case report.
Int J Gynecol Cancer 2005;15:1199-1202.
Kato D, Ferry J, Goodman A, Sullinger J, Scully R, Goff B, Fuller A, Rice L. Uterine
papillary serous carcinoma (UPSC): a clinicopathologic study of 30 cases. Gynecol Oncol
Major F, Blessing J, Silverberg et al. Prognostic factors in early-stage uterine sarcoma. Cancer
Manolitsas T, Wain G, Williams K, Freidlander M, Hacker N. Multimodality therapy for
patients with clinical stage I and II malignant mixed Müllerian tumors of the uterus. Cancer
Pasmantier et al. Treatment of advanced endometrial carcinoma with doxorubicin and
cisplatin: effects on both untreated and previously treated patients. Cancer Treat Rep
Podratz K. Uterine papillary serous carcinomas : the exigency for clinical trials. Gynecol
Ramirez-Gonzales C, Adamsons K, Mangual-Vazquez T et al. Papillary adenocarcinoma in
the endometrium. Obstet Gynecol 1987;70:212.
Randall M, Filiaci V, Muss H et al. Randomized Phase III trial of whole-abdominal
irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial
carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2006;24:36-44.
Rosenberg P, Boeryd B, Simonsen E. A new aggressive approach to high-grade endometrial
cancer of possible benefit to patients with stage I uterine papillary cancer. Gynecol Oncol
Sartori E, Bazzurini L, Gadducci A, Landoni F, Lissoni A, Maggino T, Zola P, La Face B.
Carcinosarcoma of the uterus : a clinicopathological multicenter CTF study. Gynecol Oncol
Seltzer et al., Adriamycin and cis-diamminedichloroplatinum in the treatment of metastatic
endometrial adenocarcinoma. Gynecol Oncol 1984;19:308.
Shaw R, Lynch P, Wade-Evans T. Mullerian mixed tumour of the uterine corpus: a clinical
histopathological review of 28 patients. Br J Obstet Gynaecol 1983;90:562-9.
Sherman M, Sturgeon S, Brinton L et al. Risk factors and hormone levels in patients with
serous and endometrioid uterine carcinomas. Mod Pathol 1997;10:963-8.
Slomovitz B, Burke T, Eifel P et al., Uterine papillary serous carcinoma (UPSC): a single
institution review of 129 cases. Gynecol Oncol 2003;91:463-9.
Sreenan J, Hart W. Carcinosarcomas of the female genital tract. A pathologic study of 29
metastatic tumors. Am J Surg Pathol 1995;19:666-74.
Sutton G, Axelrod J, Bundy B, et al. Adjuvant whole abdominal irradiation in clinical stage sI
and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the
Gynecologic Oncology Group. Gynecol Oncol 2006;100:349-54.
Tropé et al., Treatment of recurrent endometrial adenocarcinoma with a combination of
doxorubicin and cisplatin. Am J Obstet Gynecol 1984;149:379.
Vaidya A, Littell R, Krasner C, Duska L. Treatment of uterine papillary serous carcinoma
with platinum-based chemotherapy and paclitaxel. Int J Gynecol Cancer 2006;16(suppl
Elit L, Kwon J, Bentley J, Trim K, Ackerman I, Carey M. Optimal management for surgical
stage I serous cancer of the uterus. Gynecol Oncol 2004;92:240-6.