Treatment planning in endometrial cancer Review Article

Transcription

Cancer Therapy Vol 1, page 373
Cancer Therapy Vol 1, 373-391, 2003.
Treatment planning in endometrial cancer
Review Article
Angiolo Gadducci*, Stefania Cosio, Andrea Riccardo Genazzani
Department of Procreative Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa,
Italy
__________________________________________________________________________________
*Correspondence: Angiolo Gadducci, Department of Procreative Medicine and Child Development, Division of Gynecology and
Obstetrics, University of Pisa, Via Roma 57, 56127 Pisa, Italy; Tel: 39 50 992609; Fax: 39 50 553410; e-mail:
[email protected]
Key Words: Endometrial cancer, Surgery, Radiotherapy, Chemotherapy, Endocrine therapy
Abbreviations: Federation of Gynecology and Obstetrics, (FIGO); Gynecologic Oncology Group, (GOG); Doxorubicin, (DOX);
cisplatin, (CDDP); Epirubicin, (EPIDOX); carboplatin, (CBDCA); cyclophosphamide, (CTX); paclitaxel, (TAX); European
Organization for Research and Treatment of Cancer, (EORTC); relative risk, (RR); Confidence interval, (CI); medroxyprogesterone
acetate, (MPA); gonadotrophin-releasing hormone, (GnRH); selective estrogen receptor modulator, (SERM); Post Operative Radiation
Therapy in Endometrial Cancer, (PORTEC)
Received: 18 December 2003; Accepted: 29 December 2003; electronically published: December 2003
Summary
Endometrial cancer is the most common gynecological cancer in the western world. Whenever possible surgery is
the initial treatment for both early and advanced disease. Surgery consists of laparotomy, peritoneal washing, total
extrafascial hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection.
Modified radical hysterectomy is performed in cases with macroscopic cervical involvement, vaginal hysterectomy
is taken into consideration in specific clinical conditions, and laparoscopic-assisted vaginal hysterectomy is still
investigational. Intensive surgical staging, including peritoneal biopsies and omentectomy besides pelvic and paraaortic lymphadenectomy, is warranted in non-endometrioid tumors. In patients with advanced disease at surgical
exploration tumor debulking should be attempted whenever possible. Current guidelines of postoperative
management are based on surgical stage and prognostic pathological variables assessed on surgical samples. Highrisk , early stages as well as more advanced stages should receive adjuvant treatment including irradiation and /or
platinum-based chemotherapy. This latter should consist of the combination of doxorubicin or epirubicin +
cisplatin + paclitaxel or single-agent carboplatin according to patient age and performance status. The lack of
benefit associated with an intensive follow-up is mainly due to the limited chance of cure of recurrent endometrial
cancer patients, with the exception of those with disease limited to the vagina. Interesting fields of research are
represented by the assessment of investigational agents able to interfere with the activity of proto-oncogenes, oncosuppressor genes, mismatch repair genes, and molecules involved in tumor invasiveness and angiogenesis.
often associated with endometrial atypical hyperplasia,
and generally have a good prognosis, whereas type-2 nonendometrioid carcinomas (i.e. serous papillary and clear
cell carcinomas) are estrogen- independent, arise in an
atrophic endometrium, affect older women, and display a
high biological aggressiveness with poor clinical outcome.
The recurrence rate of these latter is extremely high and
the most frequent extra-pelvic sites of relapse are the
upper abdomen, lungs and liver (Trope et al, 2001).
Molecular pathogenesis is quite different for the two
variants (Sherman et al, 1995; Matias-Guiu et al, 2001;
Prat, 2002). Four different genetic abnormalities may
occur in endometrioid carcinomas (microsatellite
instability and mutations in the PTEN, k-RAS and betacatenin genes), whereas nonendometrioid carcinomas
often display p53 gene mutations and loss of
heterozygosity on several chromosomes. Occasionally a
I. Introduction
Endometrial cancer is the most common
gynecological cancer in the western world. In the United
States every year 36,100 new cases are diagnosed and
approximately 6,500 women die of this malignancy
(Greenlee et al, 2000). Of the 6,088 endometrial cancer
patients assessed by the International Federation of
Gynecology and Obstetrics (FIGO) Annual Report n. 24,
2.8% were younger than 40 years of age, 9.9% were 40-49
years old, 25.6% were 50-59 years old, 33.3% were 60-69
years old, and 28.4% were 70 years or older (Creasman et
al, 2001).
Two different clinico-pathological and biological
types of endometrial cancer can be considered (Sherman et
al, 1995; Matias-Guiu et al, 2001; Prat, 2002). Type-1
endometrioid carcinomas are estrogen-dependent, are
373
Gadducci et al: Treatment planning in endometrial cancer
nonendometrioid carcinoma may develop as a result of
dedifferentiation of a preexisting endometrioid carcinoma;
in such a case, the tumor exhibits overlapping clinical,
morphologic, immunohistochemical and molecular
features of the two types (Matias-Guiu et al, 2001).
Endometrial cancer spreads by direct extension
(myometrium, cervix, vagina, adnexa, and more rarely,
bladder
and
rectum),
lymphatic
spread,
and
hematogeneous spread (Oram, 1990). Lymphatic trunks
drain mainly into the pelvic and para-aortic nodes, and less
frequently into the groin nodes through vessels lying in the
round ligament (Boronow et al, 1984; Oram, 1990; Ayhan
et al, 1994; Benedetti Panici et al, 1998). In a prospective
trial performed by Ayan et al (1994) on 183 patients with
clinical stage I disease submitted to systematic
lymphadenectomy, pelvic and para-aortic metastases were
found in 15.3% and 9.3% of the cases, respectively. In a
study of the Gynecologic Oncology Group (GOG), paraaortic metastases were detected in 2% of patients with
negative pelvic nodes compared to 67% of those with
positive pelvic nodes (Boronow et al, 1984).
In 1988 the FIGO Committee on Gynecologic
Oncology changed the staging of endometrial cancer from
a clinical to a surgical-pathologic staging that requires an
accurate histopathologic examination of the surgical
sample aimed to assess the true extension of the disease
and to define a series of prognostic variables (Mikuta,
1993) (Table 1). Each case is graded histologically as G1,
G2 or G3, according to whether nonsquamous or
nonmorular solid growth pattern involves <5%, 6-50%, or
>50% of the glandular component (Mikuta, 1993;
Creasman et al, 2001). Significant nuclear atypia increases
the histologic grade one step. In serous papillary, clear cell
and adenosquamous carcinomas, the nuclear grade takes
precedence.
Adenocarcinoma
with
squamous
differentiation is graded according to the nuclear grade of
the glandular component.
An accurate surgical staging shows that
approximately 15-20 % of patients with tumor apparently
confined to the uterine body have a subclinical extension
of the disease to the cervix, adnexa, lymph nodes or
peritoneum (De Palo et al, 1993). The high operability rate
of endometrial cancer makes this staging system a viable
one, which provides information about the need for
additional treatment. Patients who are treated primarily
with radiation therapy should be staged according to the
clinical staging system adopted by FIGO in 1971.
Table 2 reports the most important surgicalpathological prognostic variables, most of which are
included in the 1988 FIGO staging system (Mikuta, 1993).
Among the 5,694 surgically staged patients reported in the
FIGO Annual Report n. 24, 5-year survival was 88.9% for
stage Ia, 90.0% for stage Ib, 80.7% for stage Ic, 79.9% for
stage IIa, 72.3% for stage IIb, 63.4% for stage IIIa, 38.8%
for stage IIIb, 51.1% for stage IIIc, 19.9% for stage IVa,
and 17.2% for stage IVb (Creasman et al, 2001). Survival
was related to the degree of differentiation for any stage
and to histological type. For instance 5-year survival
ranged from 92.0% for grade G1 to 74.0% for grade G3
among stage I patients, from 78.6% for grade G1 to 44.4%
for grade G 3 among stage IIIa patients, and from 61.2% for
grade G 1 to 44.0% for grade G3 among stage IIIc patients.
In the same series 5-year survival was 79.7% for
endometrioid carcinoma, 79.1% for adenosquamous
carcinoma, 72.9% for mucinous carcinoma, 54.3% for
serous papillary carcinoma, and 63.2 % for clear cell
carcinoma. The aggressive biological behaviour, and in
particular the higher frequency to extrauterine spreading,
helps to explain the poorer survival of serous papillary and
clear cell carcinomas (Cirisano et al, 2000; Trope et al,
2001). Several authors reported that uterine papillary
serous carcinoma can relapse also in patients with tumor
confined to the endometrium or to an endometrial polyp
(Silva and Jenkins, 1990; Lee and Belinson, 1991;
Carcangiu and Chambers, 1992; Suzuki et al, 1999).
Lymph node involvement is related to several
pathological variables such as histological grade,
myometrial invasion, histological type, lymph-vascular
space involvement, tumor size, cervical extension,
peritoneal cytology, and adnexal metastases (Creasman et
al, 1987; Feuer and Calanog, 1987; Morrow et al, 1991;
Bell et al, 1997). In a GOG study including 621 stage I
endometrial cancer patients positive pelvic and para-aortic
node rate ranged from 3% and 2% for grade G1 to 18%
and 11% respectively for grade G3, and from 1% and 1%
for tumors confined to endometrium to 25% and 17%
respectively for tumors invading myometrium deeply
(Creasman et al, 1987).
The prognostic relevance of peritoneal cytology in
patients with endometrial cancer apparently confined to
the uterine body, but that are classified in stage IIIa only
for the presence of neoplastic cells in peritoneal fluid or
washing is still debated (Turner et al, 1989; Grimshaw et
al, 1990; Grigsby et al, 1992; Kadar et al, 1992; Vecek et
al, 1993; Kennedy et al, 1993; Kashimura et al, 1997;
Ebina et al, 1997; Obermair et al, 2001; Takeshima et al,
2001; Luo et al, 2001; Kasamatsu et al, 2003) (Table 3).
Conversely positive peritoneal cytology is a poor
prognostic factor in patients with extrauterine disease
(Kadar et al, 1992; Ebina et al, 1997; Takeshima et al,
2001). For instance according to Kadar et al (1992) if the
tumor had spread to the adnexa, lymph nodes or
peritoneum, positive peritoneal cytology had a detrimental
effect on 5-year survival, decreasing it from 73 to 13%.
Similarly Ebina et al (1997) reported that in stages IIIc and
IV the prognosis was significantly poorer for patients with
positive than for those with negative peritoneal cytology.
Hirai et al (2001) investigated the malignant potential
of endometrial cancer cells in peritoneal washing in 50
patients with clinical stage I–II disease in whom positive
peritoneal cytology was found at surgery. A tube for
cytologic analyses was inserted into the peritoneal cavity
when closing the abdomen, and afterwards the peritoneal
cavity was irrigated with physiologic saline and washings
were obtained through the tube seven and fourteen days
after surgery. Persistence of positive peritoneal cytology
was observed in 4 out of 7 patients with adnexal
metastases, none of the 9 patients with nodal disease, and
1 of 34 patients with disease confined to the uterus, for a
total of 10% (5 of 50).
374
Table 1. FIGO surgical staging of endometrial cancer (Rio de Janeiro, 1988)
Stage
Ia
Ib
Ic
IIa
IIb
IIIa
Tumor limited to the endometrium (G1, G2, G3)
Invasion to < half of myometrium (G1, G2, G3)
Invasion to > half of myometrium (G1, G2, G3)
Endocervical glandular involvement only (G1, G2, G3)
Cervical stromal involvement (G1, G2, G3)
Involvement of uterine serosa and/or adnexae and/or positive peritoneal
cytology (G1, G2, G3)
Vaginal involvement (G1, G2, G3)
Metastases to pelvic and/or para-aortic lymph nodes (G1, G2, G3)
Involvement of bladder and/or rectal mucosa (G1, G2, G3)
Distant metastases (including intra-abdominal and groin lymph node
metastases) (G1, G2, G3)
IIIb
IIIc
IVa
IVb
G1, grade 1; G2, grade 2; G3, grade 3
Table 2. Surgical-pathological risk factors of endometrial cancer
Intra-uterine risk factors
1. Depth of myometrial invasion
2. Histologic grade
3. Histology
4. Cervical extension
5. Lymph vascular space involvement
Extra-uterine risk factors
1. Pelvic and para-aortic node metastases
2. Adnexal involvement
3. Penetration of uterine serosa
4. Positive peritoneal cytology
Table 3. Independent prognostic significance of positive peritoneal cytology in endometrial cancer confined to the uterine
body
NO
Grimshaw et al, 1990
Lurain et al, 1991
Vecek et al, 1993
Ebina et al, 1997
Takeshima et al, 2001
Kasamatsu et al, 2003
YES
Turner et al, 1989
Grigsby et al, 1992
Kennedy et al, 1993
Kashimura et al, 1997
Luo et al, 2001
Obermair et al, 2001
In the other 45 (90%) patients no malignant cells were
found in any of the washings. These data seem to suggest
that endometrial cancer cells found in the peritoneal cavity
usually disappear within a short time and have a low
malignant potential. Only malignant cells from particular
cases, such as adnexal metastases, appear to be capable of
independent growth and could represent a risk factor for
recurrence.
et al, 1983; Chen, 1989; Vardi et al, 1992; Lanciano et al,
1993; Gretz et al, 1996; Boronow, 1997). However the
lack of resection of the upper vagina does not seem to
have a strong impact on survival (la Vecchia et al, 1983).
Different surgical procedures can be performed to assess
retroperitoneum, ranging from biopsies of enlarged nodes
only to selective node sampling from multiple sites to
systematic pelvic and para-aortic lymphadenectomy
(Chuang et al, 1995; Kilgore et al, 1995; Onda et al, 1997).
In the experience of Kilgore et al (1995) the chance to
detect microscopic metastases was related to the number
of sampled pelvic sites and to the number of removed
nodes.
Maximal surgical cytoreduction should be
recommended for patients with advanced endometrial
cancer, since the achievement of a residual disease <1 cm
appears to be an independent prognostic variable for
survival (Goff et al, 1994; Chi et al, 1997; Bristow et al,
II. Surgery
Whenever possible surgery is the initial treatment for
both early and advanced endometrial cancer (Bremond et
al, 2001). The standard surgical approach consists of
laparotomy, peritoneal washing, extrafascial hysterectomy,
bilateral salpingo-oophorectomy, partial colpectomy, and
pelvic and para-aortic lymph node dissection (Oram,
1990; Boronow et al, 1984; De Palo et al, 1993; la Vecchia
375
2000, 2001; Ayhan et al, 2002). For instance in the series
of Bristow et al (2000), including 65 patients submitted to
primary surgery for stage IVb endometrial cancer, median
survival was 34.3 months for patients with residual disease
<1 cm compared to 11.0 months (p=0.0001) for those with
larger residum). As for the former, the patients with
microscopic residual disease had a significant better
survival compared to those with macroscopic residuum.
Similarly, among the 37 patients with stage IVb
endometrial cancer treated by Ayhan et al (2002), median
survival was 25 months for the patients with residuum
<1cm compared to 10 months (p=0.01) for those with
bulkier residual disease.
Intensive
surgical
staging
(also
including
omentectomy and peritoneal biopsies) similar to that
required for ovarian cancer is warranted for serous
papillary and clear cell carcinoma of the endometrium
(Gallion et al, 1989; Bancher-Todesca et al, 1998;
Cirisano et al, 2000; Chan et al, 2003).
It is uncertain whether lymph node dissection itself
gives a clinical benefit (Candiani et al, 1990; Chuang et al,
1995; Kilgore et al, 1995; Fanning et al, 1996; Massi et al,
1996; Onda et al, 1997; Orr et al, 1997; Bar-Am et al,
1998; Larson et al, 1998; Podratz et al, 1998; Mohan et al,
1998; Trimble et al, 1998; Mariani et al, 2000; Seago et al,
2001; Rittenberg et al, 2003). Cumulative data from the
literature showed the development of recurrent disease in
20 (6.6%) out of 305 patients who had been submitted to
systematic lymphadenectomy for medium risk endometrial
cancer, who had negative nodes and who had not
undergone postoperative pelvic irradiation (Fanning et al,
1996; Orr et al, 1997; Podratz et al, 1998; Larson et al,
1998; Mohan et al, 1998). Only 5 of these 20 recurrences
were loco-regional. Subsequent studies confirmed that
whole pelvis irradiation can be safely omitted in patients
with FIGO stage Ic or stage I grade G3 endometrial cancer
if nodal status is known (Seago et al, 2001; Rittenberg et
al, 2003). Therefore systematic lymphadenectomy could
avoid adjuvant external irradiation in medium risk patients
with histologically proven negative lymph nodes.
The therapeutic relevance of lymphadenectomy has
been long debated (Candiani et al, 1990; Chuang et al,
1995; Kilgore et al, 1995; Massi et al, 1996; Onda et al,
1997; Larson et al, 1998; Mohan et al, 1998; Podratz et al,
1998; Mariani et al, 2000). For instance, both Candiani et
al (1990) and Massi et al (1996) failed to detect a
difference in survival between patients who had undergone
pelvic lymphadenectomy and those who had not.
Conversely, Kilgore et al (1995) showed a survival benefit
for patients undergoing multiple site pelvic lymph node
sampling compared with those not receiving such
procedure. Mariani et al (2000) assessed 137 endometrial
cancer patients with an high risk of para-aortic metastases
due to deep myometrial invasion or palpable pelvic nodes
or adnexal involvement, and 51 patients who had positive
pelvic or para-aortic nodes. Among the former 5-year
survival was 85% for patients who had undergone paraaortic lymphadenectomy compared to 71% (p=0.06) for
those who had not, and among the latter 5-year survival
was 77% for patients who had undergone this surgical
procedure compared to 42% (p=0.05) for those who had
not.
Piver II-III radical hysterectomy is sometimes
performed in endometrial cancer patients, and particularly
in those with macroscopic involvement of the uterine
cervix (Rutledge, 1974; Boothby et al, 1989; Boente et al,
1995, Mariani et al, 2001; Sartori et al, 2001). The
rationale for this operation is that the removal of
parametria provides more adequate free surgical margins
when endometrial cancer has spread to the cervix (Sartori
et al, 2001). In 1995 a study performed on specific
diagnostic and therapeutic options in endometrial cancer
by means of a questionnaire sent to several leading centres
for gynecologic oncology in Western Europe, revealed
that Piver II-III hysterectomy was routinely performed in
6.2% of 81 institutions, never used in 11.1%, and adopted
for specific conditions (such as FIGO stage >I, younger
age, poorly differentiated tumor) in 82.7% of the centres
(Maggino et al, 1995). As for the elective surgical
management in stage II disease, radical hysterectomy was
considered to be the treatment of choice in 79.5% of the
institutions.
Rutledge (1974) reported that 5-year survival was not
significantly different between endometrial cancer patients
who underwent extended hysterectomy and those treated
with simple hysterectomy, even though, among stage I
patients, the local recurrence rate was lower in the radical
surgery group. In the study of Bonte et al (1995) on
patients with stage II disease, pelvic recurrence rate was
6% among the 33 patients submitted to radical
hysterectomy and 14% among the 37 submitted to
extrafascial hysterectomy. The retrospective analysis of
203 stage II endometrial cancer cases treated in five
different Italian gynecologic oncology centres detected
that 5-year and 10-year survivals were significantly better
in the 68 patients who had undergone radical hysterectomy
compared to the 135 who had undergone simple
hysterectomy (94% versus 79%, and, respectively, 94%
versus 74%, p=0.03) (Sartori et al, 2001). Vaginal
hysterectomy may be considered a reasonable alternative
to the abdominal approach in specific clinical conditions,
such as obesity, old age, uterine prolapse, poor
performance status, and high anesthesiological risk
(Maggino et al, 1995; Massi et al, 1996; Chan et al, 2001).
In the series of Massi et al (1996) including stage I
endometrial cancer patients, 5-year and 10-year-survivals
were superimposible in the 180 patients who underwent
vaginal hysterectomy (90% and 87%, respectively) and in
the 147 who underwent abdominal hysterectomy (91% and
90%, respectively). Vaginal operation can be
complemented
by
extraperitoneal
pelvic
lymphadenectomy according to a modification of Mitra’s
technique, that is a fast procedure applicable in high-risk
surgical patients under spinal anesthesia (Massi et al,
2000), as well as by a laparoscopic staging (Gemignani et
al, 1999; Eltabbakh et al, 2001; Malur et al, 2001;
Eltabbakh, 2002; Fram, 2002; Holub et al, 2002;
Langebrekke et al, 2002; Occelli et al, 2003).
In particular laparoscopic assisted vaginal
hysterectomy has been recently considered as a technically
acceptable and safe surgical procedure for early
376
endometrial cancer in the hands of experienced operators.
It is associated with a longer operating time, but with a
less blood loss, a shorter hospitalisation and equivalent
clinical outcomes when compared to abdominal
hysterectomy (Gemignani et al, 1999; Eltabbakh et al,
2001; Malur et al, 2001; Eltabbakh, 2002; Holub et al,
2002; Fram, 2002; Occelli et al, 2003). For instance a
retrospective review of Eltabbakh (2002) on women with
clinical stage I endometrial cancer showed that the 100
patients who underwent laparoscopy and the 86 who
underwent laparotomy had similar 2-year and 5-year
recurrence-free survivals (93% versus 94%, and 90%
versus 92%, respectively), as well as similar 2-year and 5year overall survivals (98% versus 96% and 92% versus
92%, respectively). Both groups were similar with regard
to age, lymphadenectomy, surgical stage, tumor grade,
histology, and postoperative radiation therapy, and
moreover there was no apparent difference with regard to
the sites of recurrence between the two groups. However
in low-risk endometrial cancer patients treated by
laparoscopic assisted vaginal hysterectomy an higher
incidence of vaginal cuff recurrences or positive peritoneal
cytology has been sometimes reported, and some cases of
port-site recurrences have been described, probably due to
the intraoperative dissemination of tumor cells enhanced
by the use of intrauterine manipulator (Wang et al, 1997;
Zayyan and Kazmi, 1998; Muntz et al, 1999; Sonoda et al,
2001; Vergote et al, 2002; Chu et al, 2003). For instance,
in a large series of low risk endometrial cancer patients
Sonoda et al (2001) found a positive peritoneal cytology in
10.3% of the 131 patients treated with laparoscopic
assisted vaginal hysterectomy compared to 2.8% of the
246 patients who underwent abdominal hysterectomy.
Therefore, the routine use of laparoscopic assisted vaginal
hysterectomy should be undertaken with caution, as the
long-term risks for recurrence and survival have yet to be
defined in large, randomised controlled trials (Chu et al,
2003).
As for recurrent endometrial cancer, intensive
surgery has been sometimes suggested for women with
large pelvic or abdominal relapse (Scarabelli et al, 1998).
In carefully selected cases of isolated central recurrences
pelvic exenteration is the only potential option for cure
(Morris et al, 1996; Barakat et al, 1999; Chi and Barakat,
2001). In the series of Morris et al (1996), including 20
patients with recurrent endometrial cancer who underwent
exenteration with curative intent, the estimated 5-year
disease-free survival was 45%. Twelve (60%) patients
experienced major complications, the most common of
which was neovaginal flap necrosis, and 1 (5%) patient
died of surgical complications. Barakat et al (1999)
reassessed 44 patients with central recurrence after surgery
with or without radiotherapy who underwent pelvic
exenteration. Major postoperative complications occurred
in 35 (80%) patients and included urinary/intestinal tract
fistulas, pelvic abscess, septicemia, pulmonary embolism,
and stroke. Median survival for the entire group of patients
was 10.2 months, but 9 (20%) achieved long-term survival
(>5 years). Further investigation into the techniques of
intraoperative radiotherapy could increase the pool of
patients to whom a salvage surgery may be sometimes
offered (Chi and Barakat, 2001).
III. Radiotherapy
Exclusive radiotherapy consisting of both external
beam irradiation and uterovaginal brachytherapy is
undertaken only in selected cases unsuitable for surgical
management due to medical contraindications or advanced
age (Rose et al, 1993; Rouanet et al, 1993; Fishman et al,
1996; Thomas et al, 2001; Peiffert et al, 2003). In patients
with early tumor this treatment modality can obtain a local
control rate of about 80-90% (Peiffert et al, 2003).
Fishman et al (1996) assessed 54 patients with clinical
stage I and II endometrioid carcinoma who were deemed
medically inoperable and exclusively received radiation
therapy, and a cohort of 108 operable patients adjusted for
age, clinical stage, and grade as a control group. The 5year actuarial cancer-specific survivals for patients with
stage I inoperable, stage II inoperable, stage I operable,
and stage II operable disease were 80, 85, 98, and 100%,
respectively.
External pelvic irradiation is the most common
adjuvant treatment in endometrial cancer, able to reduce
loco-regional recurrences without improving overall
survival (Aalders et al, 1980; Roberts et al, 1999;
Creutzberg et al, 2000; Straugh et al, 2003; Creutzberg et
al, 2003). In the randomised study of Aalders et al (1980)
enrolling 540 stage I patients, vaginal-pelvic recurrence
rate was 1.9% in patients who received adjuvant
intravaginal irradiation plus external pelvic irradiation
compared to 6.9% (p<0.01) in those who received
adjuvant intravaginal irradiation alone, whereas distant
metastases developed in 9.9% of the former and in 5.4%
of the latter. Thus, the 5-year survival was not improved
by external irradiation. A more detailed analysis led to the
conclusion that only patients with poorly differentiated
tumors which infiltrate more than half of the myometrial
thickness, might benefit from additional external
radiotherapy. In the GOG 99 trial comparing surgery
versus surgery plus external irradiation in patients with
intermediate-risk stage endometrial cancer, loco-regional
recurrence rate was 1.6% in the patients who had
radiotherapy compared to 8.5% in those who had no
further treatment, whereas survivals were not significantly
different (Roberts et al, 1999). In the multicenter
randomised PORTEC [Post Operative Radiation Therapy
in Endometrial Cancer] study enrolling 715 patients with
intermediate-risk stage I disease, adjuvant external pelvic
irradiation reduced loco-regional recurrence rate (4%
versus 14%, p<0.001) and increased treatment
complication rate (25% versus 6%, p<0.0001) compared to
surgery alone, whereas deaths for cancer (9% versus 6%),
5–year survivals (81% versus 85%), and 8-year actuarial
survivals (71% versus 77%) were unchanged (Creutzberg
et al, 2000; Creutzberg et al, 2003). As pelvic radiotherapy
appears to improve loco-regional control without a
survival benefit, its use should be limited to those patients
at sufficiently high risk (15% or over) for recurrence in
order to maximize local control and relapse-free survival
(Creutzberg et al, 2003).
377
Vaginal vault brachytherapy alone has been used as
postoperative treatment in patients with low risk (stage Ib
G1, G2) disease (Alektiar et al, 2002) or in patients with
medium risk (stage I G3 or stage Ic) disease with
histologically proven negative lymph nodes (Seago et al,
2001; Rittenberg et al, 2003), but the clinical benefit of
this adjuvant therapy versus surgery alone has not yet been
defined. Moreover, there is no definitive suggestion that
the addition of a vaginal vault brachytherapy boost to
external beam irradiation is beneficial for pelvic control or
disease-free survival of stage I or II endometrial cancer
patients and prospective randomised trials designed to
study external beam irradiation alone versus external beam
irradiation plus vaginal brachytherapy are unlike to show a
positive result (Greven et al, 1998).
Little data are currently available about extendedfield irradiation in patients with positive para-aortic nodes
(Feuer and Calanog, 1987; Corn et al, 1992; Rose et al,
1992; De Palo et al, 1993; Hicks et al, 1993; Rotman et al,
1993). In the study of Feuer and Calanog (1987) this
treatment obtained a 5-year survival of 66.7% in patients
with microscopic aortic metastases compared to 16.7% in
those with macroscopic aortic metastases. Rose et al
(1992) gave extended field irradiation to 17 out of 26
patients with para-aortic involvement, and found that 9
(53%) of them were alive with no evidence of disease with
a median survival of 27 months, whereas 87.5% of the 8
patients treated with chemotherapy or progestins died after
a median time of 13 months. By assessing 19 patients with
positive para-aortic nodes, Hicks et al (1993) detected a 5year disease-free survival of 27% in patients treated with
pelvic plus para-aortic irradiation compared to 0% in those
who received pelvic irradiation plus hormonotherapy.
Para-aortic irradiation could be effective particularly in the
control of microscopic disease even after surgical
debulking; however, this procedure is sporadically used in
the clinical practice for both the risk of severe bowel
complications and the suggestion that para-aortic node
involvement is associated with systemic spread of disease
(Corn et al, 1992; Rotman et al, 1993).
The role of whole abdomen irradiation in selected
patients is still debated (Martinez et al, 1988; Small et al,
2000; Smith et al, 2000; Lee et al, 2003; Martinez et al,
2003). Recently Lee et al (2003) reported that whole
abdomen irradiation with a cumulative dose of 3000 cGy
plus supplementary doses to partial abdominal volumes
can eradicate small peritoneal deposits after surgical
cytoreduction. This treatment modality has been evaluated
also in patients with uterine serous papillary and clear cell
carcinoma (Smith et al, 2000; Martinez et al, 2003). Smith
et al (2000) assessed 22 patients with FIGO Stage III-IV
endometrioid carcinoma and 26 patients with FIGO Stage
I-IV serous papillary or clear cell carcinoma treated
postoperatively with whole abdomen irradiation (median
dose: 3000 cGy to the upper abdomen and 4980 cGy to the
pelvis, respectively). Patients with endometrioid
carcinoma had 3-year disease-free and 3-year overall
survival of 79% and 89%, respectively, compared with
47% and 68% in the group of patients with serous
papillary or clear cell carcinoma. Stage I-II patients with
serous papillary or clear cell carcinoma had 3-year
disease-free survival and overall survival of 87%
compared with 32% and 61% in those with stage III and
IV disease. The 3-year actuarial major complication rate
was 7%, with no treatment-related deaths. These data
appear to suggest that whole abdomen irradiation is a safe,
effective treatment for patients with optimally debulked
advanced stage endometrioid or early stage serous
papillary or clear cell carcinoma. Martinez et al (2003)
gave postoperative whole abdomen irradiation with a
pelvic/vaginal boost to 132 patients with stage I-III
endometrial carcinoma at high risk for abdomen-pelvic
recurrence, including serous-papillary and clear cell
histology. The 5- and 10-year cause-specific survival was
77% and 72% for the entire group, 75% and 70% for
adenocarcinoma, and 80% and 74% for serous papillary
and clear cell carcinoma, and the long-term complication
rate was acceptable (chronic grade 3/4 gastrointestinal
toxicity in 14% and grade 3 renal toxicity in 2% of the
cases, respectively).
Concurrent chemo-radiation in endometrial cancer is
still investigational (Reisinger et al, 1996; Frigerio et al,
2001; Sood et al, 2002).
Radiotherapy has been widely used for the
management of loco-regional recurrences of surgically
treated endometrial cancer patients (Aalders et al, 1980;
Ackerman et al, 1996; Pai et al, 1997; Hart et al, 1998;
Nag et al, 2000; Wylie et al, 2000; Jhingran et al, 2003).
The size of recurrence (<2cm versus >2 cm) is a strong
predictor of local control (Wylie et al, 2000). However,
the chances of survival are generally poor, with the
exception of the patients with recurrent disease limited to
the vagina (Hart et al, 1998). Infact external beam
irradiation
followed
by
low-or
high-dose-rate
brachytherapy may be curative for women with isolated
vaginal recurrence (Aalders et al, 1980; Pai et al, 1997;
Wylie et al, 2000; Jhingran et al, 2003). Intracavitary
brachytherapy should be restricted to patients with
nonbulky (<0.5 cm thick) disease, whereas patients with
bulky recurrences should be treated with interstitial
techniques (Nag et al, 2000). In the study of Jhingran et al
(2003) including 91 patients treated with radiotherapy for
vaginal recurrence after definitive surgery for endometrial
cancer, 5-year-local control rate and 5-year overall
survival were 75% and 43%, respectively. A total
radiotherapy dose >8000 cGy was a significant predictor
of local control, whereas the combination of external
pelvic irradiation plus brachytherapy versus single
modality therapy was a significant predictor of both local
control and survival. It is worth noting that a high
percentage of patients with radiotherapy-induced local
control subsequently died of disease for the development
of distant recurrence. According to Corn et al (1997) the
women who recur locally have nearly a fourfold risk of
failing distantly compared to those who remain locally
controlled.
IV. Pharmacological treatment
Both chemotherapeutic and hormonal agents have
been employed in endometrial cancer (Table 5).
378
1996), and paclitaxel (TAX) (Ball et al, 1996; Lissoni et
al, 1996; Lincoln et al, 2003). The majority of responses to
single agents are partial and short-lived, with response
durations ranging between 3 and 6 months (Muss, 1994)
Cumulative data from several clinical studies detected an
overall response rate of 34% for the combination of DOX
+ CTX (Muggia et al, 1977; Seski et al, 1981; Campora et
al, 1990; Thigpen et al, 1994). A GOG randomised trial
showed that response rates were 30% for DOX + CTX and
22% for single-agent DOX (p=0.06) (Thigpen et al, 1994).
Trope et al (1984) found that chemotherapy including
DOX 50 mg/m 2 + CDDP 50 mg/m 2 produced an objective
response of 60% in 20 patients with recurrent endometrial
cancer. Another GOG randomised study on 297 patients
revealed that CDDP + DOX compared to single-agent
DOX had a higher response rate (45% versus 27%) but a
similar survival (with a median of about 9 months)
(Thigpen et al, 1993; Muss, 1994). Conversely a similar
trial conducted by the European Organization for Research
A. Chemotherapy
Doxorubicin (DOX) and cisplatin (CDDP) are the
most commonly used chemotherapeutic drugs (Thigpen et
al, 1989, 1994; Muss, 1994; Thigpen et al, 1995; Trope
and Kristensen, 1997) (Table 4). Data from cumulative
series showed an objective response in 26% of 161
patients treated with D0X, and in 24% of 124 patients
treated with CDDP (Muss, 1994; Thigpen et al, 1995;
Trope and Kristensen, 1997). Epirubicin (EPIDOX)
seemed to have the same activity of DOX (Thigpen et al,
1995; Trope and Kristensen, 1997), and carboplatin
(CBDCA) produced a response rate of 17-30% (Long et
al, 1988; Green et al, 1990; van Wijk et al, 2003). For
instance in the study of van Wijk et al (2003) CBDCA
achieved an objective response in 17% of 47 evaluable
patients, and, in detail, in 24% of the 33 patients who
received CBDCA as first-line chemotherapy. Other drugs
with an objective response rate higher than 20% are 5fluorouracil (De Vita et al, 1976), cyclophosphamide
(CTX) (Horton et al, 1978), ifosfamide (Sutton et al,
Table 4. Drugs used in the treatment of endometrial cancer
Chemotherapeutic agents
Doxorubicin
Cisplatin
Epirubicin
Carboplatin
5-fluorouracil
Cyclophosphamide
Paclitaxel
Progestins:
Hormonal agents
medroxyprogesterone acetate
hydroxyprogesterone caproate
megestrol acetate
Tamoxifen
Gn-RH analogues
Aromatase inhibitors (anastrozole, letrozole)
SERM (arzoxifene)
Table 5. Surgical treatment of endometrial cancer
TAH+ BSO, total abdominal hysterectomy and bilateral salpingo- oophorectomy;
G1, grade 1; G2, grade 2; G3, grade 3; M0, tumor limited to the endometrium;
M1, invasion to < half of myometrium; M2, invasion to > half of myometrium
379
and Treatment of Cancer (EORTC) on 154 patients
detected an improved median survival for CDDP + DOX
arm (13 months versus 8 months, p=0.036) (Aapro et al,
1994).
The combination of CDDP +DOX or EPIDOX +
CTX, with or without progestins, has been largely
employed in advanced or recurrent endometrial cancer,
with an objective response rate ranging between 31% and
60%, a median duration of response of 4-10 months, and a
median survival of 7-15 months (Lovecchio et al, 1984;
Turbow et al, 1985; Hancock et al, 1986; Edmondson et al,
1987; Hoffman et al, 1989; Burke et al, 1991; Dunton et
al, 1991; Gadducci et al, 1999). The analysis of the
relationship between dose intensity of chemotherapy and
response in advanced endometrial cancer showed that
CTX is relatively inactive when used in combination
regimens (Levin and Hryniuk, 1987). Therefore CTX
could be omitted from chemotherapy regimens for
endometrial cancer, and the combination of CDDP plus
DOX could be considered as the standard of care for
patients with advanced or recurrent disease (Thigpen et al,
1995; Trope and Kristensen, 1997). In a recent randomised
GOG trial including 342 patients with stage III, IV, or
recurrent endometrial cancer, no significant benefit in
terms of response rate, progression-free survival, overall
survival, or toxicity profile was observed with circadian
timed chemotherapy consisting of DOX 60 mg/m2 at 6:00
am + CDDP 60 mg/m2 at 6:00 pm. compared to standard
DOX 60 mg/m2+ CDDP 60 mg/m2 (Gallion et al, 2003).
As for TAX, in a phase II GOG trial this agent at the
dose of 250 mg/m2 (24 hour-infusion) obtained an
objective response rate of 36% (with a complete response
rate of 14%) in 28 patients with advanced and recurrent
endometrial cancer (Ball et al, 1996). TAX 175 mg/m2 (3
hour-infusion) (Lincoln et al, 2003) achieved a complete
response in 10.5% and a partial response in 26.3% of 19
patients previously treated with CDDP + DOX + CTX
(Lissoni et al, 1996). By giving TAX to patients with
persistent or recurrent endometrial cancer who have failed
prior chemotherapy, Lincol et al (2003) found that 3
(6.8%) out of the 44 evaluable patients obtained a
complete response and 9 (20.5%) had a partial response
for an overall response rate of 27.3%. The median overall
survival was 10.3 months. The combination of TAX with a
platinum compound seems to achieve promising results
even in the serous papillary histotype (Resnik and Taxy,
1996; Vasuratna et al, 1998; Eltabbakh et al, 1999; Le et
al, 1999; Hoskins et al, 2001; Fleming et al, 2002; Niwa et
al, 2002). In a randomised GOG study enrolling 266
patients with advanced or recurrent endometrial cancer,
the combination of DOX 45 mg/m2 + CDDP 50 mg/m2 +
TAX 160 mg/m2 (3-hour infusion) obtained an
improvement in response rates (57% versus 33%,
p<0.001), a decrease in recurrence risk (relative risk
[RR]= 0.57; Confidence interval [CI 95%]= 0.43-0.75,
p<0.001], and a nonsignificant decrease in death risk (RR
= 0.79; CI 95%= 0.59-1.07) compared to the combination
of DOX 60 mg/m2 + CDDP 50 mg/m2 (Fleming et al,
2002).
The topoisomerase I inhibitor, topotecan, is being
investigated for the treatment of endometrial cancer
(Miller et al, 2002; Holloway, 2003; Wadler et al, 2003).
Single-agent topotecan has been found to achieve an
objective response in 9% of 22 previously treated patients
(Holloway, 2003) and in 20% of 40 chemotherapy-naive
patients (Wadler et al, 2003). This agent is active also
against uterine papillary serous carcinoma (Miller et al,
2002).
The are no conclusive data about the effectiveness of
adjuvant chemotherapy in patients with high-risk
endometrial cancer (Morrow et al, 1990; Burke et al, 1994;
Onda et al, 1997; Bancher-Todesca et al, 1998; Maggi et
al, 1999; Tomioka et al, 1999; Pustilnik and Burke, 2000;
Mundt et al, 2001). In a GOG trial including 181 patients,
5-year survival was not significantly different in patients
who received adjuvant external beam irradiation alone
compared to those who had adjuvant irradiation plus DOX
(72% versus 63%) (Morrow et al, 1990). Burke et al
(1994) gave 6 cycles of adjuvant therapy consisting of
CDDP + DOX + CTX to 62 high risk patients, and
reported actuarial 3-year survivals of 46% and 82%,
respectively, for patients with and those without extrauterine spread of disease. Onda et al (1997) observed a 5year survival of 75% in 20 patients with histologically
proven para-aortic nodes who received 3 cycles of
postoperative platinum-based chemotherapy followed by
pelvic plus para-aortic irradiation. Tomioka et al (1999)
reported a 5-year survival of 83% in a series of 83 high
risk patients who underwent adjuvant chemotherapy with
CDDP + DOX + CTX, which was similar to the survival
of an historical control group including 68 patients who
received adjuvant pelvic irradiation. Among 340 patients
with high risk endometrial cancer (stage Ic grade G3, stage
IIa-b grade G3, stage III) enrolled in a multicenter Italian
study there was no difference in recurrence rate between
patients who received adjuvant chemotherapy consisting
of CDDP + DOX + CTX and those who received external
pelvic irradiation (29.1% versus 27.3%) (Maggi et al,
1999). Mundt et al (2001) assessed 43 high risk
endometrial cancer patients (most of whom had Stage IIIIV disease or unfavourable histology) who received
chemotherapy consisting primarily of CDDP and DOX as
sole postoperative treatment. After a median follow-up of
27 months, 29 (67.4%) women relapsed, and in detail, 17
(39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. Nine (31%) of the 29 relapsed patients
developed pelvic recurrence as their only (n.6) or first site
(n.3) of recurrence. Since pelvic recurrence is common in
high risk stage I-IV endometrial cancer patients after
adjuvant chemotherapy alone, the authors suggest the use
of adjuvant irradiation after chemotherapy.
B. Endocrine therapy
Progestins have been long used in the treatment of
advanced or recurrent endometrial cancer. Kauppila
(1984) reviewed 1,068 patients treated with
medroxyprogesterone acetate (MPA), megestrol acetate, or
hydroxyprogesterone caproate in different trials and found
an overall response rate of 34%, with an average duration
of response ranging from 16 to 28 months and an average
survival ranging from 18 to 33 months. However
380
subsequent clinical studies, based on more stringent
criteria for response assessment, reported lower response
rates ranging from 11.2% to 15.8% with no difference
according to the type of progestin (Piver et al, 1980;
Podratz et al, 1985). In a randomised GOG trial 299
women with advanced or recurrent endometrial cancer
were randomly allocated to receive oral MPA either 200
mg daily or 1000 mg daily (Thigpen et al, 1999). The 145
patients receiving low-dose progestins experienced 25
complete and 11 partial responses, for an overall response
rate of 25%. Among the 154 patients treated with highdose progestins, there were 14 complete and 10 partial
responses, for an overall response rate of 15%. Median
progression- free survival and median survival were 3.2
and 11.1 months, respectively for the low-dose group, and
2.5 and 7 months, respectively for the high-dose group.
According to this study oral MPA 200 mg daily is a
reasonable initial approach for advanced or recurrent
endometrial cancer, particularly for those lesions that are
well-differentiated and/or have a high progesterone
receptor content (>50 fmol/mg cytosol protein).
The majority of progestin-sensitive tumors are
represented by well differentiated carcinomas. For
instance in the series of Podratz et al (1985), an objective
response was obtained by 40% of patients with grade 1
tumors according to Broders, compared to 17.5% of
patients with grade 2 tumors, 2.4% of those with grade 3
tumors, and 0% of those with grade 4 tumors. Hormone
receptor status (Kauppila, 1984; Thigpen et al, 1999),
interval between primary treatment and hormonal therapy
and tumor burden (Podratz et al, 1985) are predictors of
the response to progestins.
The role of progestins as adjuvant treatment in early
endometrial cancer has been long debated (Malkasian and
Decker, 1978; MacDonald et al, 1988; Vergote et al, 1989;
De Palo et al, 1993; Martin-Hirsch et al, 2000). The
Cochrane Gynaecological Cancer Group recently
performed a cumulative analysis of the 4,351 patients
included in six clinical trials assessing the role of adjuvant
progestagens following primary surgery for endometrial
cancer (Martin-Hirsch et al, 2000). Three studies enrolled
only women with stage I disease, whereas three included
patients with more advanced disease. The analysis showed
that progestin therapy does not significantly reduce the
risk of recurrence (RR= 0.81, CI 95%= 0.65-1.01) and of
endometrial cancer related death (RR= 0.88, CI 95%=
0.71-1.1) and increases the risk of non-endometrial cancer
related death (RR= 1.33, CI 95%= 1.02-1.73). Therefore
adjuvant progestin therapy does not improve patient
survival (RR= 1.05; CI 95%= 0.88-1.24).
As for tamoxifen, in a recent GOG study including
68 patients with advanced or recurrent disease this agent
achieved 3 complete and 4 partial responses, with an
overall response rate of 10%, a median progression-free
survival of 1.9 months and a median overall survival of
8.8 months (Thigpen et al, 2001). Therefore tamoxifen has
a modest activity against endometrial cancer and does not
warrant further investigation as single agent for this
disease. It is well known that tamoxifen can increase
progesterone receptor content in endometrial cancer (Nola
et al, 1999), and experimental studies on human
endometrial cancer transplanted into nude mice revealed
that sequential administration of tamoxifen and MPA
induces a greater tumor regression than MPA alone (Zaino
et al, 1985). However, clinical studies on alternating
treatment with tamoxifen and MPA gave unsatisfactory
results in advanced or recurrent endometrial cancer (Kline
et al, 1987; Fiorica et al, 2000; Pandya et al, 2001). For
instance an Eastern Cooperative Oncology Group study
failed to detect any difference in response rate between the
20 patients treated with megestrol acetate and the 42
patients who received sequential therapy with megestrol
acetate and tamoxifen (20% versus 19%) (Pandya et al,
2001).
After the discovery of gonadotrophin-releasing
hormone (GnRH) receptors in endometrial cancer, some
authors investigated whether GnRH agonists were able to
exert an anticancer activity in patients with this
malignancy and found objective response rates ranging
from 0% to 28% (Jeyarajah et al, 1996; Covens et al,
1997; Asbury et al, 2002). For instance in a GOG study
goserelin acetate obtained 2 complete and 3 partial
responses among 40 evaluable patients with recurrent
disease, with an overall response rate of 11%, a median
progression-free survival of 1.9 months and a median
overall survival of 7.3 months (Asbury et al, 2002). The
activity of goserelin acetate in endometrial cancer is
insufficient to warrant further study of the single agent,
but elucidation of the mechanism of action of this drug
may allow more effective use in conjunction with other
agents in the future.
Little data are currently available about aromatase
inhibitors and selective estrogen receptor modulators
(SERM)s in endometrial cancer (Rose et al, 2000; Berstein
et al, 2002; Chan, 2002; Elit and Hirte, 2002; Burke and
Walker, 2003; McMeekin et al, 2003). In the study of
Rose et al (2000) anastrozole achieved an objective
response in 9% of 23 patients with advanced or recurrent
disease who had received no more than one prior hormone
therapy regimen. Median progression-free survival and
overall survival were 1 month and 6 months, respectively.
Letrozole is currently under evaluation (Elit and Hirte,
2002; Berstein et al, 2002).
The third-generation SERM arzoxifene, that opposes
the action of estrogen on the breast and endometrium but
exerts an estrogen-agonist effect on bone and lipid profile,
obtained one complete response and 8 partial responses
among 29 evaluable patients, with an overall response rate
of 31% and a median duration of response of 13.9 months
(Burke and Walker, 2003; McMeekin et al, 2003). All 9
responses occurred in progestagen-sensitive patients.
Toxicity was minimal, with no grade 3-4 toxic effects. The
high response rate and the extremely favourable toxicity
profile make this agent warranting further evaluation.
V. Guidelines for management
A. Patients suitable for primary surgery
1. Surgery
Whenever possible surgery is the initial treatment
both for early and advanced endometrial cancer. Surgery
for patients with clinically early disease consists of
381
laparotomy, peritoneal washing, total extrafascial
hysterectomy and bilateral salpingo-oophorectomy (Table
5). Pelvic and para-aortic lymphadenectomy is required
for patients with suspicious nodes at surgical exploration
and is recommended for patients with higher risk of nodal
metastases, such as those with macroscopic extrauterine
disease or those with disease apparently confined to the
uterine body but with grade G3 tumor (assessed on
preoperative biopsy) or with deep myometrial invasion
(assessed on preoperative trans-vaginal ultrasound and/or
magnetic resonance or on intra-operative frozen sections).
Modified radical hysterectomy is performed in cases with
macroscopic cervical involvement, vaginal hysterectomy
is taken into consideration in specific clinical conditions
(i.e obesity, old age, significant uterine prolapse, poor
performance status, and high anesthesiological risk), and
laparoscopic-assisted vaginal hysterectomy is still
investigational. Intensive surgical staging, including
peritoneal biopsies and omentectomy besides pelvic and
para-aortic lymphadenectomy, is warranted in patients
with non-endometrioid tumors.
In patients with advanced disease at surgical
exploration tumor debulking should be attempted
whenever possible.
The planning of postoperative treatment should be
different in patients with endometrioid and with nonendometrioid tumors.
No well defined postoperative therapy can be
suggested for patients assigned to stage IIIa only for
positive peritoneal cytology. The need for an adjuvant
treatment should be based on pathological findings on
uterine sample (tumor grade, myometrial invasion,
cervical involvement) as well as on patient age and
performance status. If an adjuvant treatment is taken into
consideration, it should consist of platinum-based
chemotherapy aimed to reduce the risk of peritoneal and
distant recurrences.
Patients with stage IVb disease for intra-abdominal
or groin metastases should undergo platinum-based
chemotherapy.
Platinum-based chemotherapy should consist of the
combination of DOX (or EPIDOX) + CDDP ± TAX (3hour infusion) or single-agent CBDCA according to
patient age and performance status.
3. Postoperative
endometrioid tumors
treatment
of
non-
Whereas patients with stage Ia tumors need no
further treatment, patients with stage Ib-IIb disease as well
as those with stage IIIa disease for positive peritoneal
cytology should receive platinum-based regimens (Table
8). The use of TAX in combination with platinum-based
chemotherapy is particularly recommended in these
tumors that often display p53 mutations.
Patients with stage IIIa disease for invasion of the
serosa of the uterine body or adnexal involvement and
those with stage IIIb disease should undergo platinumbased chemotherapy followed by external pelvic
irradiation. Patients with stage IIIc disease should receive
platinum-based chemotherapy followed by pelvic + paraaortic irradiation.
Stage IVb patients should be treated with platinumbased chemotherapy.
2. Postoperative treatment of endometrioid
tumors
No further treatment is required for patients with
stage Ia any grade disease, for patients with stage Ib grade
G 1-2 disease, for patients with stage IIa grade G1-2 disease
with no or superficial myometrial invasion, and for
patients with stage Ib grade G3 disease or stage Ic any
grade disease or stage IIa disease with grade G3
differentiation or with deep myometrial invasion who had
histologically proven negative nodes after pelvic and paraaortic lymphadenectomy (Table 6). Conversely adjuvant
external pelvic irradiation is warranted for patients with
stage Ib grade G3 disease or stage Ic any grade disease or
stage IIa disease with grade G3 differentiation or deep
myometrial invasion not submitted to adequate
lymphadenectomy, as well as for patients with stage IIb
disease.
Stage III include patients with very different clinical
conditions (Table 7). Patients with stage IIIa disease for
invasion of the serosa of the uterine body or adnexal
involvement could be treated with external pelvic
irradiation or platinum-based chemotherapy followed by
external pelvic irradiation. Patients with stage IIIc disease
should receive pelvic + para-aortic irradiation according to
the site of positive nodes or platinum-based chemotherapy
followed by external beam irradiation. Controlled clinical
trials are warranted to test the clinical benefit of the
addition of chemotherapy to radiotherapy in these subsets
of patients. Adjuvant external pelvic irradiation followed
by vaginal brachytherapy should be given to patients with
stage IIIb disease.
B. Patients
surgery
unsuitable
for
primary
No stardard therapeutic approach has been defined
for patients with clinically advanced endometrial cancer at
presentation not manageable with primary surgery.
Patients with clinical stage IIIb disease with
extensive spread to vaginal walls should be treated with
external pelvic irradiation plus brachytherapy or,
alternatively,
with
neoadjuvant
platinum-based
chemotherapy followed by individualized surgery or
external pelvic irradiation plus brachytherapy
Patients with clinical stage IVa disease should undergo
neoadjuvant platinum-based chemotherapy followed by
pelvic exenteration or external pelvic irradiation.
Patients with clinical stage IVb disease should be
treated with platinum–based chemotherapy, followed, in
responsive cases, by individualized surgery or irradiation
on primary tumor.
382
VI. Follow-up
recurrence
and
pattern
papers have recently assessed in detail a large amount of
information about the follow-up and the detection of
recurrence in patients with clinically early disease (Lurain
et al, 1991; Podczaski et al, 1992; Shumsky et al, 1997,
1994, Berchuck et al, 1995, Reddoch et al, 1995; Agboola
et al, 1997; Gadducci et al, 2000; Morice et al, 2003).
of
There is no agreement in the literature about the
examinations to carry out in the post-treatment
surveillance of patients with endometrial cancer. Some
Table 6. Postoperative treatment of endometrioid endometrial cancer (surgical stage I-II)
G1, grade 1; G2, grade 2; G3, grade 3; M0, tumor limited to the endometrium; M1, invasion to < half of myometrium; M2,
invasion to > half of myometrium; N, lymph nodes
Table 7. Postoperative treatment of endometrioid endometrial cancer (surgical stage III-IV)
383
Table 8. Postoperative treatment of non-endometrioid endometrial cancer
Stage Ia
Stage Ib-IIb
Stage IIIa positive peritoneal cytology
Stage IIIa
Uterine serosa or
adnexal involvement
Stage IIIb
no further treatment
chemotherapy
Chemotherapy
Chemotherapy followed
by external pelvic irradiation
Chemotherapy followed
by external pelvic irradiation
Chemotherapy followed by
external pelvic +/-aortic
irradiation
Chemotherapy
Stage IIIc
Stage IVb
highly selected cases (isolated lung or abdominal or lymph
node metastases). External beam irradiation may be used
with the aim of palliation in patients with bone or lymph
node metastases.
Recurrence rates ranged from 11 to 19% approximately,
and the majority of relapses involved distant sites and
generally developed within 2-3 years of primary treatment
(Table 9). Table 10 reported the examinations that
revealed the recurrent disease in asymptomatic patients.
Conclusions
Current data from the literature failed to show that
routine surveillance could give a survival benefit for
endometrial cancer patients (Podczaski et al, 1992;
Shumsky et al, 1994; Berchuck et al, 1995; Reddoch et al,
1995; Agboola et al, 1997; Gadducci et al, 2000). For
instance Shumsky et al (1994) found 1 case of recurrence
every 206 routine examinations, and observed no survival
difference between the relapsed patients detected on
follow-up examinations and those who were symptomatic.
In the series of Podczaski et al (1992) survival after
recurrence was related to the site of the recurrence, the
time interval from initial surgery to recurrence, and
whether postoperative pelvic irradiation was used but not
to the presence or absence of symptoms. Similarly in our
series (Gadducci et al, 2000) survival was similar in
asymptomatic women in whom the relapse was
occasionally detected by follow-up examinations, and in
symptomatic ones.
The cornerstone of treatment of endometrial cancer
is represented by extrafascial abdominal hysterectomy
with bilateral salpingo-oophorectomy. Pelvic and paraaortic lymphadenectomy may provide additional
prognostic information, but its therapeutic relevance is still
under debate. However, the surgical assessment of the
retroperitoneum may avoid adjuvant pelvic irradiation in
early stage, medium risk patients with histologically
proven negative nodes. An intensive surgical staging
similar to that performed in ovarian cancer is warranted
for non-endometrioid tumors. Optimal surgical
cytoreduction may offer a survival benefit in patients with
stage IV disease. Current guidelines of postoperative
management are based on surgical stage and prognostic
pathological variables assessed on surgical samples. Highrisk early stages as well as more advanced stages should
receive adjuvant treatment consisting of irradiation and /or
platinum-based chemotherapy. In patients that cannot
undergo surgery, exclusive radiotherapy should be
performed.
The lack of benefit associated with an intensive
follow-up is mainly due to the limited chance of cure of
recurrent endometrial cancer patients, with the exception
of those with disease limited to the vagina (Berchuck et al,
1995; Ackerman et al, 1996; Pai et al, 1997; Hart et al,
1998; Gadducci et al, 2000; Wylie et al, 2000; Creutzberg
et al, 2003; Jhingran et al, 2003; Sartori et al, 2003). For
instance, in the series of Berchuck et al (1995) 50% of the
12 women with isolated vaginal recurrence were salvaged
compared to 6% of the 34 patients with other patterns of
failure.
In the PORTEC study Creutzberg et al (2003)
reported a 3-year survival of 73% for patients with vaginal
relapse, 8% for those with pelvic relapse, and 14% for
those with distant failure.
Since most relapses involve distant sites and no
effective therapy is usually available for these cases, the
earlier detection of recurrent disease allowed by an
intensive follow-up program has a limited chance to
VII. Treatment of recurrent disease
In patients not previously submitted to adjuvant
radiotherapy, isolated vaginal recurrence can be managed
with satisfactory cure rates with external beam irradiation
followed by high-dose-rate brachytherapy, and central or
lateral pelvic recurrence may be treated with limited
chance of cure with external pelvic irradiation or with
platinum-based chemotherapy followed by external pelvic
irradiation. Pelvic exenteration may represent the only
potential option for cure for carefully selected patients
with isolated central pelvic failures who have exhausted
other treatment modalities. However this ultraradical
surgery can be seldom taken into consideration for patient
age, habitus and performance status.
Patients with distant recurrences should receive
platinum-based chemotherapy. Progestins may represent
an alternative therapeutic option for patients with welldifferentiated tumours, high progesterone receptor content,
and long disease-free interval. Cytoreductive surgery
before or after systemic treatment can be performed in
384
Table 9. Rates and sites of recurrence in patients with early stage endometrial cancer
Reference
patients
Patients with recurrence
Sites of recurrences
Distant
Local
Dostant
264
33 (12.5%)
3
27
3
300
47 (15.6%)
16
29
2
317
53 (16.7%)
25
28
398
44** (11.1%)
15
16
8
133
24 (18.0%)
6
17
1
recurrent disease but complete follow-up data were available only for 39 of them
Local
Lurain et al, 1991
Podczaski et al, 1992
Shumsky et al, 1994
Reddoch et al, 1995
Gadducci et al, 2000
** 44 patients developed
+
Table 10. Examinations that detected recurrent disease in asymptomatic patients with relapsed endometrial cancer
Reference
Patients
Recurred
patients
Asymptomatic
Physical Chest
PAP
US
CT
other
Recurred
exam
x-ray
test
patients
Podczaski et al, 1992
300
47
24
14*
10*
1
Shumsky et al, 1994
317
53
13
5
6
2
Reddoch et al, 1995
398
44**
23
13
1
1
2
6
Gadducci et al, 2000
133
24
13
3
1
1
3
5
* one patient with concomitant local and distant failure had both an abnormal physical examination and an abnormal chest
X-ray
** 44 patients developed recurrent disease but complete follow-up data were available only for 39 of them
US: ultrasound; CT: computed tomography
Alektiar KM, McKee A, Venkatraman E, McKee B, Zelefsky
MJ, Mychalczak BR, Hoskins WJ, Barakat RR. (2002)
Intravaginal high-dose-rate brachytherapy for Stage IB
(FIGO Grade 1, 2) endometrial cancer. Int J Radiat Oncol
Biol Phys 53, 707-713.
Asbury RF, Brunetto VL, Lee RB, Reid G, Rocereto TF.
Gynecologic Oncology Group (2002). Goserelin acetate as
treatment for recurrent endometrial carcinoma: a
Gynecologic Oncology Group study. Am J Clin Oncol 25,
557-560.
Ayhan A, Taskiran C, Celik C, Yuce K, Kucukali T. (2002) The
influence of cytoreductive surgery on survival and morbidity
in stage IVB endometrial cancer. Int J Gynecol Cancer 12,
448-453.
Ayhan A, Tuncer R, Tuncer ZS, Yuce K, Kucukali T. (1994)
Correlation between clinical and histopathologic risk factors
and lymph node metastases in early endometrial cancer (a
multivariate analysis of 183 cases). Int J Gynecol Cancer 4,
306-309.
Ball HG, Blessing JA, Lentz SS, Mutch DG. (1996) A phase II
trial of taxol in advanced and recurrent adenocarcinoma of
the endometrium. Gynecol Oncol 62, 278-281.
Bancher-Todesca D, Neunteufel W, Williams KE, Prainsack D,
Breitenecker G, Friedlander ML, Hacker NF. (1998)
Influence of postoperative treatment on survival in patients
with uterine papillary serous carcinoma. Gynecol Oncol 71,
344-347.
Barakat RR, Goldman NA, Patel DA, Venkatraman ES, Curtin
JP. (1999) Pelvic exenteration for recurrent endometrial
cancer. Gynecol Oncol 75, 99-102.
Bar-Am A, Ron IG, Kuperminc M, Gal I, Jaffa A, Kovner F,
Wigler N, Inbar M, Lessing J. (1998) The role of routine
pelvic lymph node sampling in patients with stage I
endometrial carcinoma: Second thoughts. Acta Obstet
Gynecol Scand. 77, 347-350.
Bell JG, Minnick A, Reid GC, Judis J, Brownell M. (1997)
Relationship of nonstaging pathological risk factors to lymph
improve patient survival.
Interesting fields of research are represented by the
assessment of new hormonal drugs, such as SERMs
(Chan, 2002; Burke and Walker, 2003; McMeekin et al,
2003) and antisense estrogen receptor oligodeoxyribonucleotides (Taylor et al, 2002), and of investigational
agents able to interfere with the activity of protooncogenes, onco-suppressor genes, mismatch repair genes,
and molecules involved in tumor invasiveness and
angiogenesis (Elit and Hirte, 2002; Fujiwaki et al, 2002;
Santin et al, 2002). For instance Santin et al (2002)
suggested the administration of trastuzumab to patients
with uterine serous papillary l cancer that often shows
HER-2/neu overexpression. Further developments in
understanding the molecules involved in tumor growth and
spreading will allow the synthesis of specific and selective
inhibitors (Fujiwaki et al, 2002).
References
Aalders J, Abeler V, Kolstad P, Onsrud M. (1980) Postoperative
external irradiation and prognostic parameters in stage I
endometrial carcinoma: clinical and histopathologic study of
540 patients. Obstet Gynecol 56, 419-427.
Aapro M, Bolis G, Chevallier B, van der Burg MEL, Poveda A,
de Oliveira C, Pawinski A, Sahmoud T, Pecorelli S. (1994)
An EORTC-GCCG randomized phase II trial of doxorubicin
(DOX) versus DOX-cisplatin (CDDP) in endometrial
carcinoma. Proc Am Soc Clin Oncol 13, 275 (abstract 885).
Ackerman I, Malone S, Thomas G, Franssen E, Balogh J, Dembo
A. (1996) Endometrial carcinoma--relative effectiveness of
adjuvant irradiation vs therapy reserved for relapse. Gynecol
Oncol 60, 177-183
Agboola OO, Grunfeld E, Coyle D, Perry GA. (1997) Costs and
benefits of routine follow-up after curative treatment for
endometrial cancer. CMAJ 157, 879-886.
385
node metastasis and recurrence in clinical stage I endometrial
carcinoma. Gynecol Oncol 66, 388-392.
Benedetti Panici P, Maneschi F, Cutillo G, D’ Andrea G, Manci
N, Rabitti C. (1998) Anatomical and pathological study of
retroperitoneal nodes in endometrial cancer. Int J Gynecol
Cancer 8, 322-327.
Berchuck A, Anspach C, Evans AC, Soper JT, Rodriguez GC,
Dodge R, Robboy S, Clarke-Pearson DL. (1995) Postsurgical
surveillance of patients with FIGO stage I/II endometrial
adenocarcinoma. Gynecol Oncol 59, 20-24.
Berstein L, Maximov S, Gershfeld E, Meshkova I, Gamajunova
V, Tsyrlina E, Larionov A, Kovalevskij A, Vasilyev D.
(2002) Neoadjuvant therapy of endometrial cancer with the
aromatase inhibitor letrozole: endocrine and clinical effects.
Eur J Obstet Gynecol Reprod Biol 105, 161-165.
Boente MP, Orandi YA, Yordan EL, Miller A, Graham JE,
Kirshner C, Wilbanks GD. (1995) Recurrence patterns and
complications in endometrial adenocarcinoma with cervical
involvement. Ann Surg Oncol 2, 138-144.
Boothby RA, Carlson JA, Neiman W, Rubin MM, Morgan MA,
Schultz D, Mikuta JJ, (1989) Treatment of stage II
endometrial cancer. Gynecol Oncol 33, 204-208.
Boronow RC, Morrow CP, Creasman WT, Disaia PJ, Silverberg
SG, Miller A, Blessing JA. (1984) Surgical staging in
endometrial cancer: clinical-pathologic findings of a
prospective study. Obstet Gynecol 63, 825-832.
Boronow RC. (1997) Surgical staging of endometrial cancer:
evolution, evaluation, and responsible challenge--a personal
perspective. Gynecol Oncol 66, 179-189.
Bremond A, Bataillard A, Thomas L, Achard JL, Fervers B,
Fondrinier E, Lansac J, Bailly C, Hoffstetter S, Basuyau JP,
d'Anjou J, Descamps P, Farsi F, Guastalla JP, Laffargue F,
Rodier JF, Vincent P, Pigneux J (2001) Federation Nationale
des Centres de Lutte Contre le Cancer. Standards, Options
and Recommendations for the surgical management of
carcinoma of the endometrium. Bull. Cancer. 88, 181-198.
Bristow RE, Duska LR, Montz FJ. (2001) The role of
cytoreductive surgery in the management of stage IV uterine
papillary serous carcinoma. Gynecol Oncol 81, 92-99.
Bristow RE, Zerbe MJ, Rosenshein NB, Grumbine FC, Montz
FJ. (2000) Stage IVB endometrial carcinoma: the role of
cytoreductive surgery and determinants of survival. Gynecol
Oncol 78, 85-91.
Burke TW, Gershenson DM, Morris M, Stringer CA, Levenback
C, Tortolero-Luna G, Baker VV. (1994) Postoperative
adjuvant cisplatin, doxorubicin, and cyclophosphamide
(PAC) chemotherapy in women with high-risk endometrial
Burke TW, Stringer CA, Morris M, Freedman RS, Gershenson
DM, Kavanagh JJ, Edwards CL. (1991) Prospective
treatment of advanced or recurrent endometrial carcinoma
with cisplatin, doxorubicin, and cyclophosphamide. Gynecol
Oncol 40, 264-267.
Burke TW, Walker CL. (2003) Arzoxifene as therapy for
endometrial cancer. Gynecol Oncol 90, S40-46.
Campora E, Vidali A, Mammoliti S, Ragni N, Conte PF. (1990)
Treatment of advanced or recurrent adenocarcinoma of
endometrium with doxorubicin and cyclophosphamide. Eur
J Gynaecol Oncol 11, 181-183 .
Candiani GB, Belloni C, Maggi R, Colombo G, Frigoli A,
Carinelli SG. (1990) Evaluation of different surgical
approaches in the treatment of endometrial cancer at FIGO
stage I. Gynecol Oncol 37, 6-8.
Carcangiu ML, Chambers JT. (1992) Uterine papillary serous
carcinoma: A study on 108 cases with emphasis on the
prognostic significance of associated endometrioid
carcinoma, absence of invasion, and concomitant ovarian
Chan JK, Lin YG, Monk BJ, Tewari K, Bloss JD, Berman ML.
(2001) Vaginal hysterectomy as primary treatment of
endometrial cancer in medically compromised women.
Obstet Gynecol 97, 707-711.
Chan JK, Loizzi V, Youssef M, Osann K, Rutgers J, Vasilev SA,
Berman ML. (2003) Significance of comprehensive surgical
staging in noninvasive papillary serous carcinoma of the
endometrium. Gynecol Oncol 90, 181-185.
Chan S. (2002) A review of selective estrogen receptor
modulators in the treatment of breast and endometrial cancer.
Semin Oncol 29, 129-133.
Chen SS. (1989) Operative treatment in stage I endometrial
carcinoma with deep myometrial invasion and/or grade 3
tumor surgically limited to the corpus uteri. No recurrence
with only primary surgery. Cancer 63, 1843-1845.
Chi DS, Barakat RR. (2001) Surgical management of advanced
or recurrent endometrial cancer. Surg Clin North. Am 81,
885-896.
Chi DS, Welshinger M, Venkatraman ES, Barakat RR. (1997)
The role of surgical cytoreduction in Stage IV endometrial
Chu CS, Randall TC, Bandera CA, Rubin SC. (2003) Vaginal
cuff recurrence of endometrial cancer treated by
laparoscopic-assisted vaginal hysterectomy. Gynecol Oncol
88, 62-65.
Chuang L, Burke TW, Tornos C, Marino BD, Mitchell MF,
Tortolero-Luna G, Levenback C, Morris M, Gershenson DM.
(1995) Staging laparotomy for endometrial carcinoma:
assessment of retroperitoneal lymph nodes. Gynecol Oncol
58, 189-193.
Cirisano FD Jr, Robboy SJ, Dodge RK, Bentley RC, Krigman
HR, Synan IS, Soper JT, Clarke-Pearson DL. (2000) The
outcome of stage I-II clinically and surgically staged
papillary serous and clear cell endometrial cancers when
compared with endometrioid carcinoma. Gynecol Oncol 77,
55-65.
Corn BW, Lanciano RM, D'agostino R Jr, Kiggundu E, Dunton
CJ, Pursen P, Greven KM. (1997) The relationship of local
and distant failure from endometrial cancer: Defining a
clinical paradigm. Gynecol Oncol 66, 411-416.
Corn BW, Lanciano RM, Greven KM, Schultz DJ, Reisinger SA,
Stafford PM, Hanks GE. (1992) Endometrial cancer with
para-aortic adenopathy: patterns of failure and opportunities
for cure. Int J Radiat Oncol Biol Phys 24, 223-227.
Covens A, Thomas G, Shaw P, Ackerman I, Osborne R, Lukka
H, Carey M, Franssen E, Roche K. (1997) A phase II study
of leuprolide in advanced/ recurrent endometrial cancer.
Gynecol Oncol 64, 126-129.
Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham
JE, Heller PB. (1987) Surgical pathologic spread patterns of
endometrial cancer. A Gynecologic Oncology Group study.
Cancer 60, 2035-2041.
Creasman WT, Odicino F, Massoineuve Beller U, Benedet JL,
Heintz APM, HYS NGAN, Sideri M, Pecorelli S. (2001)
Carcinoma of the corpus uteri. J Epidemiol Biostat 6, 45-86.
Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen
JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van
den Bergh AC, van de Steen-Banasik E, Beerman H, van
Lent M. (2000) Surgery and postoperative radiotherapy
versus surgery alone for patients with stage-1 endometrial
carcinoma: multicentre randomised trial. PORTEC Study
Group. Post Operative Radiation Therapy in Endometrial
Carcinoma. Lancet. 355, 1404-1411.
Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen
JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van
den Bergh AC, van der Steen-Banasik E, Beerman H, van
Lent M. PORTEC Study Group. (2003) Survival after
386
relapse in patients with endometrial cancer, results from a
randomized trial. Gynecol Oncol 89, 201-209.
De Palo G, Mangioni C, Periti P, Del Vecchio M, Marubini E.
(1993) Treatment of FIGO (1971) stage I endometrial
carcinoma with intensive surgery, radiotherapy and
hormonotherapy according to pathological prognostic
groups. Long-term results of a randomised multicentre study.
Eur J Cancer 29A, 1133-1140.
De Vita VT jr, Wasserman TH, Young RC, Carter SK. (1976)
Perspective on research in gynecologic oncology. Cancer
38, 509-525.
Dunton CJ, Pfeifer SM, Braitman LE, Morgan MA, Carlson JA,
Mikuta JJ. (1991) Treatment of advanced and recurrent
endometrial cancer with cisplatin, doxorubicin and
cyclophosphamide. Gynecol Oncol 41 113-116.
Ebina Y, Hareyama H, Sakuragh N, Yamamoto R, Furuya M,
Sogame M, Fujino T, Makinoda S, Fujimoto S. (1997)
Peritoneal cytology and its prognostic value in endometrial
carcinoma. Int Surg 82, 244-248.
Edmondson JH, Krook JE, Hilton JF, Malkasian GD, Everson
LK, Jefferies JA, Mailliard JA. (1987) Randomized phase II
studies of cisplatin and a combination of cyclophosphamidedoxorubicin-cisplatin (CAP) in patients with progestinrefractory advanced endometrial carcinoma. Gynecol Oncol
28, 20-24.
Elit L, Hirte H. (2002) Current status and future innovations of
hormonal agents, chemotherapy and investigational agents in
endometrial cancer. Curr Opin Obstet Gynecol 14, 67-73
Eltabbakh GH, Moody J, Garafano LL, Hammond JM. (1999)
The combination paclitaxel, carboplatin and megestrol
acetate is effective in women with recurrent uterine papillary
serous adenocarcinoma. Eur J Gynaecol Oncol 20, 18-19.
Eltabbakh GH, Shamonki MI, Moody JM, Garafano LL. (2001)
Laparoscopy as the primary modality for the treatment of
women with endometrial carcinoma. Cancer 91, 378-387.
Eltabbakh GH. (2002) Analysis of survival after laparoscopy in
women with endometrial carcinoma. Cancer 95, 1894-1901.
Fanning J, Nanavati PJ, Hilgers RD. (1996) Surgical staging and
high dose rate brachytherapy for endometrial cancer:
Limiting external radiotherapy to node-positive tumor.
Feuer GA, Calanog A. (1987) Endometrial carcinoma: Treatment
of positive paraaortic nodes. Gynecol Oncol 27, 104-109.
Fiorica J, Brunetto V, Hanjani P, Lentz S, Mannel R, Anderson
W. (2000) A phase II study (GOG 153) of recurrent and
advanced endometrial carcinoma treated with alternating
courses of megestrol acetate and tamoxifen citrate. Proc Am
Soc Clin Oncol 19, 379 (abstract 1499).
Fishman DA, Roberts KB, Chambers JT, Kohorn EI, Schwartz
PE, Chambers SK. (1996) Radiation therapy as exclusive
treatment for medically inoperable patients with stage I and
II endometrioid carcinoma with endometrium. Gynecol
Oncol 61, 189-196.
Fleming GF, Brunetto BL, Mundt AJ, Burks RT, Look KY, Reid
G. (2002) Randomized trial of doxorubicin (DOX) plus
cisplatin (CIS) versus DOX plus CIS plus paclitaxel (TAX)
in patients with advanced or recurrent endometrial
carcinoma: a Gynecologic Oncology Group (GOG) study.
Proc Am Soc Clin Oncol 21, 202 (abstract 807).
Fram KM. (2002) Laparoscopically assisted vaginal
hysterectomy versus abdominal hysterectomy in stage I
endometrial cancer. Int J Gynecol Cancer. 12, 57-61.
Frigerio L, Mangili G, Aletti G, Carnelli M, Garavaglia E,
Beatrice S, Ferrari A. (2001) Concomitant radiotherapy and
paclitaxel for high-risk endometrial cancer: first feasibility
study. Gynecol Oncol 81, 53-57.
Fujiwaki R, Iida K, Kanasaki H, Ozaki T, Hata K, Miyazaki K.
(2002) Cyclooxygenase-2 expression in endometrial cancer:
correlation with microvessel count and expression of
vascular endothelial growth factor and thymidine
phosphorylase. Hum Pathol 33, 213-219.
Gadducci A, Cosio S, Fanucchi A, Cristofani R, Genazzani AR.
(2000) An intensive follow-up does not change survival of
patients with clinical stage I endometrial cancer. Anticancer
Res 20, 1977-1984.
Gadducci A, Romanini A, Cosio S, Fanucchi A, Tanganelli L,
Ciampi B, Genazzani AR. (1999) Combination of cisplatin,
epirubicin, and cyclophoshamide (PEC regimen) in advanced
or recurrent endometrial cancer: a retrospective clinical
study. Anticancer Res 19, 2253-2256.
Gallion HH, Brunetto VL, Cibull M, Lentz SS, Reid G, Soper JT,
Burger RA, Andersen W Gynecologic Oncology Group
Study. (2003) Randomized phase III trial of standard timed
doxorubicin plus cisplatin versus circadian timed
doxorubicin plus cisplatin in stage III and IV or recurrent
endometrial carcinoma: a Gynecologic Oncology Group
Study. J Clin Oncol 21, 3808-3813.
Gallion HH, van Nagell JR Jr, Powell DF, Donaldson ES,
Higgins RV, Kryscio RJ, Pavlik EJ, Nelson K. (1989) Stage I
serous papillary carcinoma of the endometrium. Cancer 63,
2224-2228.
Gemignani ML, Curtin JP, Zelmanovich J, Patel DA,
Venkatraman E, Barakat RR. (1999) Laparoscopic-assisted
vaginal hysterectomy for endometrial cancer: clinical
outcomes and hospital charges. Gynecol Oncol 73, 5-11.
Goff BA, Goodman A, Muntz HG, Fuller AF Jr, Nikrui N, Rice
LW. (1994) Surgical stage IV endometrial carcinoma: a
study of 47 cases. Gynecol Oncol 52, 237-240.
Green JB, Green S, Albert DS, O'Toole R, Surwit EA, Noltimier
JW. (1990) Carboplatin therapy in advanced endometrial
cancer. Obstet Gynecol 75, 696-700.
Greenlee RT, Murray T, Bolden S, Wingo PA. (2000) Cancer
statistics. CA Cancer J Clin 50, 7-33.c
Gretz HF3rd, Economos K, Husain A, Lesser M, Kaplan E,
Caputo TA, Reynolds RK, Johnston CM, Pearl ML, Roberts
JA. (1996) The practice of surgical staging and its impact on
adjuvant treatment recommendations in patients with stage I
endometrial carcinoma. Gynecol Oncol 61, 409-415.
Greven KM, D'Agostino RB Jr, Lanciano RM, Corn BW. (1998)
Is there a role for a brachytherapy vaginal cuff boost in the
adjuvant management of patients with uterine-confined
endometrial cancer? Int J Radiat Oncol Biol Phys 42, 101104.
Grigsby PW, Perez CA, Kuten A, Simpson JR, Garcia DM,
Camel HM, Kao MS, Galakatos AE. (1992) Clinical stage I
endometrial cancer: prognostic factors for local control and
distant metastasis and implications of the new FIGO surgical
staging system. Int J Radiat Oncol Biol Phys 22, 905-911.
Grimshaw RN, Tupper WC, Fraser RC, Tompkins MG, Jeffrey
JF. (1990) Prognostic value of peritoneal cytology in
endometrial carcinoma. Gynecol Oncol 36, 97-100.
Hancock KC, Freedman RS, Edwards CL, Rutledge FN. (1986)
Use of cisplatin, doxorubicin, and cyclophosphamide to treat
advanced and recurrent adenocarcinoma of the endometrium.
Cancer Treat Rep. 70, 789-791.
Hart KB, Han I, Shamsa F, Court WS, Chuba P, Deppe G,
Malone J, Christensen C, Porter AT. (1998) Radiation
therapy for endometrial cancer in patients treated for
postoperative recurrence. Int J Radiat Oncol Biol Phys 41,
7-11
Hicks ML, Piver MS, Puretz JL, Hempling RE, Baker TR,
Mcauley M, Walsh DL. (1993) Survival in patients with
paraaortic lymph node metastases from endometrial
adenocarcinoma clinically limited to the uterus. Int J Radiat
Oncol Biol Phys 26, 607-711.
387
Hirai Y, Takeshima N, Kato T, Hasumi K. (2001) Malignant
potential of positive peritoneal cytology in endometrial
cancer. Obstet Gynecol 97, 725-728.
Hoffman MS, Roberts WS, Cavanagh D, Praphat H, Solomon P,
Lyman GH. (1989) Treatment of recurrent and metastatic
endometrial
cancer
with
cisplatin,
doxorubicin,
cyclophosphamide, and megestrol acetate. Gynecol Oncol
35, 75-77.
Holloway RW. (2003) Treatment options for endometrial cancer:
experience with topotecan. Gynecol Oncol 90, S28-33.
Holub Z, Jabor A, Bartos P, Eim J, Urbanek S, Pivovarnikova R.
(2002) Laparoscopic surgery for endometrial cancer: longterm results of a multicentric study. Eur J Gynaecol Oncol
23, 305-310.
Horton J, Begg CB, Arseneault J, Bruckner H, Creech R, Hahn
RG.
(1978)
Comparison
of
adriamycin
with
cyclophosphamide in patients with advanced endometrial
cancer. Cancer Treat Rep. 62, 159-161.
Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, AcquinoParsons C, Lee N. (2001) Paclitaxel and carboplatin, alone or
with irradiation, in advanced or recurrent endometrial cancer:
a phase II study. J Clin Oncol 19, 4048-4053.
Jeyarajah AR, Gallagher CJ, Blake PR, Oram DH, Dowsett M,
Fisher C, Oliver RT. (1996) Long-term follow-up of
gonadotrophin-releasing hormone analog treatment for
recurrent endometrial cancer . Gynecol Oncol 63, 47-52.
Jhingran A, Burke TW, Eifel PJ. (2003) Definitive radiotherapy
for patients with isolated vaginal recurrence of endometrial
carcinoma after hysterectomy. Int J Radiat Oncol Biol Phys
56, 1366-1372.
Kadar N, Homesley HD, Malfetano JH. (1992) Positive
peritoneal cytology is an adverse factor in endometrial
carcinoma only if there is other evidence of extrauterine
disease. Gynecol Oncol 46, 145-149.
Kasamatsu T, Onda T, Katsumata N, Sawada M, Yamada T,
Tsunematsu R, Ohmi K, Sasajima Y, Matsuno Y. (2003)
Prognostic significance of positive peritoneal cytology in
endometrial carcinoma confined to the uterus. Br J Cancer
88, 245-250.
Kashimura M, Sugihara K, Toki N, Matsuura Y, Kawagoe T,
Kamura T, Kaku T, Tsuruchi N, Nakashima H, Sakai H.
(1997) The significance of peritoneal cytology in uterine
cervix and endometrial cancer. Gynecol Oncol 67, 285-290.
Kauppila A. (1984) Progestin therapy of endometrial, breast and
ovarian carcinoma. A review of clinical observations. Acta
Obstet Gynecol Scand 63, 441-450.
Kennedy AW, Webster KD, Nunez C, Bauer LJ. (1993) Pelvic
washings for cytologic analysis in endometrial
adenocarcinoma. J Reprod Med 38, 637-642.
Kilgore LC, Partridge EE, Alvarez RD, Austin JM, Shingleton
HM, Noojin F 3rd, Conner W. (1995) Adenocarcinoma of
the endometrium, survival comparisons of patients with and
without pelvic node sampling. Gynecol Oncol 56, 29-33.
Kline RC, Freedman RS, Jones LA, Atkinson EN. (1987)
Treatment of recurrent or metastatic poorly differentiated
adenocarcinoma of the endometrium with tamoxifen and
medroxyprogesterone acetate. Cancer Treat Rep 71, 327328.
la Vecchia C, Franceschi S, Parazzini F, Colombo E, Colombo F,
Liberati A, Mangioni C. (1983) Ten-year survival in 290
patients with endometrial cancer, prognostic factors and
therapeutic approach. Br. J Obstet Gynaecol. 90, 654-661.
Lanciano RM, Corn BW, Schultz DJ, Kramer CA, Rosenblum N,
Hogan WM. (1993) The justification for a surgical staging
system in endometrial carcinoma. Radiother. Oncol 28,
189-196.
Langebrekke A, Istre O, Hallqvist AC, Hartgill TW, Onsrud M.
(2002) Comparison of laparoscopy and laparotomy in
patients with endometrial cancer. J Am Assoc Gynecol
Laparosc 9, 152-157.
Larson DM, Broste SK, Krawisz BR. (1998) Surgery without
radiotherapy for primary treatment of endometrial cancer.
Le TD, Yamada SD, Rutgers JL, DiSaia PJ. (1999) Complete
response of a stage IV uterine papillary serous carcinoma to
neoadjuvant chemotherapy with taxol and carboplatin.
Lee KR, Belinson JL. (1991) Recurrence in noninvasive
endometrial carcinoma. Relationship with uterine papillary
serous carcinoma. Am J Surg Pathol 15, 965-973.
Lee SW, Russell AH, Kinney WK. (2003) Whole abdomen
radiotherapy for patients with peritoneal dissemination of
endometrial adenocarcinoma. Int J Radiat Oncol Biol Phys
56, 788-792.
Levin L, Hryniuk W. (1987) The application of dose intensity to
problems in chemotherapy of ovarian and endometrial
cancer. Semin Oncol 14 (Suppl 4), 12-19.
Lincoln S, Blessing JA, Lee RB, Rocereto TF. (2003) Activity of
paclitaxel as second-line chemotherapy in endometrial
carcinoma: a Gynecologic Oncology Group study. Gynecol
Oncol 88, 277-281.
Lissoni A, Zanetta G, Losa G, Gabriele A, Parma G, Mangioni
C. (1996) Phase II study of paclitaxel as salvage treatment in
advanced endometrial cancer. Ann. Oncol 7, 861-863.
Long HJ, Pfeifle DM, Wieand HS, Krook JE, Edmonson JH,
Buckner JC. (1988) Phase II evaluation of carboplatin in
advanced endometrial carcinoma. J Natl. Cancer Inst. 80,
276-278.
Lovecchio JL, Averette HE, Lichtinger M, Townsend PA,
Girtanner RW, Fenton AN. (1984) Treatment of advanced or
recurrent
endometrial
adenocarcinoma
with
cyclophosphamide, doxorubicin, cis-platinum, and megestrol
acetate. Obstet Gynecol 63, 557-560.
Luo ML, Sakuragi N, Shimizu M, Seino K, Okamoto K,
Kaneuchi M, Ebina Y, Okuyama K, Fujino T, Sagawa T,
Fujimoto S. (2001) Prognostic significance of combined
conventional and immunocytochemical cytology for
peritoneal washings in endometrial carcinoma. Cancer 93,
115-123.
Lurain JR, Rice BL, Rademaker AW, Poggensee LE, Schink JC,
Miller DS. (1991) Prognostic factors associated with
recurrence in clinical stage I adenocarcinoma of the
endometrium. Obstet Gynecol 78, 63-69.
MacDonald RR, Thorogood J, Mason MK. (1988) A randomized
trial of progestogens in the primary treatment of endometrial
carcinoma. Br J Obstet Gynaecol. 95, 166-174.
Maggi R, Cagnazzo G, Atlante G, Marinaccio M. (1999) Risk
groups and adjuvant therapy in surgical staged endometrial
cancer patients. A randomized multicentre study comparing
chemotherapy with radiation therapy. In: "7th Biennial
Meeting of the International Gynecologic Cancer Society"
Rome (Italy), September 26-30, 1999 (Pecorelli S, Atlante G,
Benedetti Panici P, Mancuso S Eds) Monduzzi Editore,
International Proceedings Division, 97-101.
Maggino T, Romagnolo C, Zola P, Sartori E, Landoni F,
Gadducci A. (1995) An analysis of approaches to the
treatment of endometrial cancer in western Europe: a CTF
study. Eur J Cancer. 31A, 1993-1997.
Malkasian GD jr, Decker DG. (1978) Adjuvant progesterone
therapy for stage I endometrial carcinoma. Int J Gynaecol
Obstet 16, 48-49.
Malur S, Possover M, Michels W, Schneider A. (2001)
Laparoscopic-assisted vaginal versus abdominal surgery in
patients with endometrial cancer--a prospective randomized
trial. Gynecol Oncol 80, 239-244.
388
Mariani A, Webb MJ, Galli L, Podratz KC. (2000) Potential
therapeutic role of para-aortic lymphadenectomy in nodepositive endometrial cancer. Gynecol Oncol 76, 348-356.
Mariani A, Webb MJ, Keeney GL, Calori G, Podratz KC. (2001)
Role of wide/radical hysterectomy and pelvic lymph node
dissection in endometrial cancer with cervical involvement.
Martinez A, Podratz K, Schray M, Malkasian G. (1988) Results
of whole abdominopelvic irradiation with nodal boost for
patients with endometrial cancer at high risk of failure in the
peritoneal cavity. A prospective clinical trial at the Mayo
Clinic. Hematol Oncol Clin North Am 2, 431-446.
Martinez AA, Weiner S, Podratz K, Armin AR, Stromberg JS,
Stanhope R, Sherman A, Schray M, Brabbins DA. (2003)
Improved outcome at 10 years for serous-papillary/clear cell
or high-risk endometrial cancer patients treated by adjuvant
high-dose whole abdomino-pelvic irradiation. Gynecol
Oncol 90, 537-546.
Martin-Hirsch PL, Jarvis G, Kitchener H, Lilford R. (2000)
Progestagens for endometrial cancer. Cochrane Database
Syst Rev 2, CD001040
Massi G, Savino L, Susini T. (1996) Vaginal hysterectomy
versus abdominal hysterectomy for the treatment of stage I
endometrial adenocarcinoma. Am J Obstet Gynecol 174,
1320-1326.
Massi G, Susini T, Amunni G. (2000) Extraperitoneal pelvic
lymphadenectomy to complement vaginal operations for
cervical and endometrial cancer. Int J Gynaecol Obstet 69,
27-35.
Matias-Guiu X, Catasus L, Bussaglia E, Lagarda H, Garcia A,
Pons C, Munoz J, Arguelles R, Machin P, Prat J. (2001)
Molecular pathology of endometrial hyperplasia and
carcinoma. Hum Pathol 32, 569-577.
McMeekin DS, Gordon A, Fowler J, Melemed A, Buller R,
Burke T, Bloss J, Sabbatini P. (2003) A phase II trial of
arzoxifene, a selective estrogen response modulator, in
patients with recurrent or advanced endometrial cancer.
Mikuta JJ. (1993) International Federation of Gynecology and
Obstetrics staging of endometrial cancer 1988. Cancer 71
(Suppl), 1460-1463.
Miller DS, Blessing JA, Lentz SS, Waggoner SE. (2002) A phase
II trial of topotecan in patients with advanced, persistent, or
recurrent endometrial carcinoma: a gynecologic oncology
group study. Gynecol Oncol 87, 247-251.
Mohan DS, Samuels MA, Selim MA, Shalodi AD, Ellis RJ,
Samuels JR, Yun HJ. (1998) Long-term outcomes of
therapeutic pelvic lymphadenectomy for stage I endometrial
adenocarcinoma. Gynecol Oncol 70, 165-171.
Morice P, Levy-Piedbois C, Ajaj S, Pautier P, Haie-Meder C,
Lhomme C, Duvillard P, Castaigne D. (2003) Value and cost
evaluation of routine follow-up for patients with clinical
stage I/II endometrial cancer. Eur J Cancer 7, 985-990.
Morris M, Alvarez RD, Kinney WK, Wilson TO. (1996)
Treatment of recurrent adenocarcinoma of the endometrium
with pelvic exenteration. Gynecol Oncol 60, 288-291.
Morrow CP, Bundy BN, Homesley HD, Creasman WT,
Hornback NB, Kurman R, Thigpen JT. (1990) Doxorubicin
as an adjuvant following surgery and radiation therapy in
patients with high-risk endometrial carcinoma, stage I and
occult stage II: a Gynecologic Oncology Group Study.
Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P,
Homesley HD, Graham JE. (1991) Relationship between
surgical-pathological risk factors and outcome in clinical
stage I and II carcinoma of the endometrium: a Gynecologic
Oncology Group study. Gynecol Oncol 40, 55-65.
Muggia FM, Chia G, Reed LJ, Romney SL. (1977) Doxorubicincyclophosphamide: effective chemotherapy for advanced
endometrial adenocarcinoma. Am J Obstet Gynecol 128,
314-319.
Mundt AJ, McBride R, Rotmensch J, Waggoner SE, Yamada
SD, Connell PP. (2001) Significant pelvic recurrence in highrisk pathologic stage I--IV endometrial carcinoma patients
after adjuvant chemotherapy alone:
implications for
adjuvant radiation therapy. Int J Radiat Oncol Biol Phys
50, 1145-1153.
Muntz HG, Goff BA, Madsen BL, Yon JL. (1999) Port-site
recurrence after laparoscopic surgery for endometrial
carcinoma. Obstet Gynecol 93, 807-809.
Muss HB. (1994) Chemotherapy of metastatic endometrial
cancer. Semin Oncol 21, 107-113.
Nag S, Erickson B, Parikh S, Gupta N, Varia M, Glasgow G.
(2000)
The
American
Brachytherapy
Society
recommendations for high-dose-rate brachytherapy for
carcinoma of the endometrium. Int J Radiat Oncol Biol
Phys 48, 779-790.
Niwa K, Kometani K, Sekiya T, Nakazawa K, Kanakura Y.
(2002) Complete remission of uterine endometrial cancer
with multiple lung metastases treated by paclitaxel and
carboplatin. Int J Clin Oncol 7, 197-200.
Nola M, Jukic S, Ilic-Forko J, Babic D, Uzarevic B, Petrovecki
M, Suchanek E, Skrablin S, Dotlic S, Marusic M. (1999)
Effects of tamoxifen on steroid hormone receptors and
hormone concentration and the results of DNA analysis by
flow cytometry in endometrial carcinoma. Gynecol Oncol
72, 331-336.
Obermair A, Geramou M, Tripcony L, Nicklin JL, Perrin L,
Crandon AJ. (2001) Peritoneal cytology: impact on diseasefree survival in clinical stage I endometrioid adenocarcinoma
of the uterus. Cancer Lett 164, 105-110.
Occelli B, Samouelian V, Narducci F, Leblanc E, Querleu D.
(2003) The choice of approach in the surgical management
of endometrial carcinoma: a retrospective series of 155 cases.
Bull. Cancer 90, 347-355.
Onda T, Yoshikawa H, Mizutani K, Mishima M, Yokota H,
Nagano H, Ozaki Y, Murakami A, Ueda K, Taketani Y.
(1997) Treatment of node-positive endometrial cancer with
complete node dissection, chemotherapy and radiation
therapy. Br. J Cancer 75, 1836-1841.
Oram D. (1990) The management of cancer of the uterine corpus.
In: “Clinical Gynecological Oncology“ (Sheperd JH,
Monaghan JM, Eds), Second Edition. Oxford, Blackwell
Scientific Publications 115-139.
Orr JW, Holimon JL, Orr PF. (1997) Stage I corpus cancer: Is
teletherapy necessary? Am J Obstet Gynecol 176, 777-789.
Pai HH, Souhami L, Clark BG, Roman T. (1997) Isolated vaginal
recurrences in endometrial carcinoma, treatment results using
high-dose-rate intracavitary brachytherapy and external beam
radiotherapy. Gynecol Oncol 66, 300-307.
Pandya KJ, Yeap BY, Weiner LM, Krook JE, Erban JK,
Schinella RA, Davis TE. (2001) Megestrol and tamoxifen in
patients with advanced endometrial cancer: an Eastern
Cooperative Oncology Group Study (E4882). Am J Clin
Oncol 24, 43-46.
Peiffert D, Hoffstetter S, Charra-Brunaud C. (2003)
Brachytherapy of endometrial cancers Cancer Radiother 7,
121-131.
Piver MS, Barlow JJ, Lurain JR, Blumenson LE. (1980)
Medroxyprogesterone
acetate
(Depo-Provera)
vs.
hydroxyprogesterone caproate (Delalutin) in women with
metastatic endometrial adenocarcinoma. Cancer 45, 268272.
Podczaski E, Kaminski P, Gurski K, MacNeill C, Stryker JA,
Singapuri K, Hackett TE, Sorosky J, Zaino R. (1992)
389
Detection and patterns of treament failure in 300 consecutive
cases of "early" endometrial cancer after primary surgery.
Podratz KC, Mariani A, Webb MJ. (1998) Staging and
therapeutic value of lymphadenectomy in endometrial
cancer. Gynecol Oncol 70, 163-164.
Podratz KC, O'Brien PC, Malkasian GD Jr, Decker DG, Jefferies
JA, Edmonson JH. (1985) Effects of progestational agents in
treatment of endometrial carcinoma. Obstet Gynecol 66,
106-110.
Prat J (2002) Endometrial cancer: epidemiology, pathology, and
natural history. In: "Hormone replacement therapy and
cancer. The current status of research and practice"
(Genazzani AR Editor), The Parthenon Publishing Group:
Boca Raton, London, New York, Washington DC, 105-114.
Pustilnik T, Burke TW. (2000) Adjuvant chemotherapy for highrisk endometrial cancer. Semin Radiat Oncol 10, 23-28.
Reddoch JM, Burke TW, Morris M, Tornos C, Levenback C,
Gershenson DM. (1995) Surveillance for recurrent
endometrial carcinoma: development of a follow-up scheme.
Reisinger SA, Asbury R, Liao SY, Homesley HD. (1996) A
phase I study of weekly cisplatin and whole abdominal
radiation for the treatment of stage III and IV endometrial
carcinoma: a Gynecologic Oncology Group pilot study.
Resnik E, Taxy JB. (1996) Neoadjuvant chemotherapy in uterine
papillary serous carcinoma. Gynecol Oncol 62, 123-127.
Rittenberg PV, Lotocki RJ, Heywood MS, Jones KD, Krepart
GV. (2003) High-risk surgical stage 1 endometrial cancer:
outcomes with vault brachytherapy alone. Gynecol Oncol
89, 288-294.
Roberts JA, Zaino R, Keys H. (1999) A phase III randomized
study of surgery vs surgery plus adjunctive radiation therapy
in intermediate risk endometrial adenocarcinoma. Protocol
GOG99. Gynecol Oncol 68, 135 (abstract 258).
Rose PG, Baker S, Kern M, Fitzgerald TJ, Tak WK, Reale FR,
Nelson BE, Hunter RE. (1993) Primary radiation therapy for
endometrial carcinoma: a case controlled study. Int J Radiat
Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB.
(2000) A phase II trial of anastrozole in advanced recurrent
or persistent endometrial carcinoma: a Gynecologic
Oncology Group study. Gynecol Oncol 78, 212-216.
Rose PG, Cha SD, Tak WK, Fitzgerald T, Reale F, Hunter RE.
(1992) Radiation therapy for surgically proven para-aortic
node metastasis in endometrial carcinoma. Int J Radiat
Rotman M, Aziz H, Boronow R. (1993) Insights in para-aortic
radiation therapy for endometrial carcinoma. Int J Radiat
Rouanet P, Dubois JB, Gely S, Pourquier H. (1993) Exclusive
radiation therapy in endometrial carcinoma. Int J Radiat
Rutledge FN. (1974) The role of radical hysterectomy in
adenocarcinoma of the endometrium. Gynecol Oncol 2, 331347.
Santin AD, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J,
Roman JJ, Hutchins L, Pecorelli S, O'Brien T, Cannon MJ,
Parham GP. (2002) Overexpression of HER-2/neu in uterine
serous papillary cancer. Clin Cancer Res 8, 1271-1279.
Sartori E, Gadducci A, Landoni F, Lissoni A, Maggino T, Zola
P, Zanagnolo V. (2001) Clinical behavior of 203 stage II
endometrial cancer cases: the impact of primary surgical
approach and of adjuvant radiation therapy. Int J Gynecol
Cancer. 11, 430-437.
Sartori E, Laface B, Gadducci A, Maggino T, Zola P, Landoni F,
Zanagnolo V. (2003) Factors influencing survival in
endometrial cancer relapsing patients: a Cooperation Task
Force (CTF) study. Int J Gynecol Cancer 13, 458-465.
Scarabelli C, Campagnutta E, Giorda G, DePiero G,
Sopracordevole F, Quaranta M, DeMarco L. (1998) Maximal
cytoreductive surgery as a reasonable therapeutic alternative
for recurrent endometrial carcinoma. Gynecol Oncol 70, 9093.
Seago DP, Raman A, Lele S. (2001) Potential benefit of
lymphadenectomy for the treatment of node-negative locally
advanced uterine cancers. Gynecol Oncol 83, 282-285.
Seski JC, Edwards CL, Gershenson DM, Copeland LJ (1981)
Doxorubicin and cyclophosphamide chemotherapy for
disseminated endometrial cancer. Obstet Gynecol 58, 88-91.
Sherman ME, Bur ME, Kurman RJ. (1995) p53 in endometrial
cancer and its putative precursors: evidence for diverse
pathways of tumorigenesis. Hum Pathol 26, 1268-1274.
Shumsky AG, Brasher PMA, Stuart GCE, Nation JG. (1997)
Risk-specific follow-up for endometrial carcinoma patients.
Shumsky AG, Stuart GCE, Brasher P, Nation JG, Robertson DI,
Sangkarat S. (1994) An evaluation of routine follow-up of
patients treated for endometrial carcinoma. Gynecol Oncol
55, 229-233.
Silva EG, Jenkins R. (1990) Serous carcinoma in endometrial
polyps. Mod. Pathol 13, 120-128.
Small W Jr, Mahadevan A, Roland P, Vallow L, Zusag T,
Fishman D, Massad S, Rademaker A, Kalapurakal JA, Chang
S, Lurain J. (2000) Whole-abdominal radiation in
endometrial carcinoma: an analysis of toxicity, patterns of
recurrence, and survival. Cancer J 6, 394-400.
Smith RS, Kapp DS, Chen Q, Teng NN. (2000) Treatment of
high-risk uterine cancer with whole abdominopelvic
radiation therapy. Int J Radiat Oncol Biol Phys 48, 767778.
Sonoda Y, Zerbe M, Smith A, Lin O, Barakat RR, Hoskins WJ.
(2001) High incidence of positive peritoneal cytology in lowrisk endometrial cancer treated by laparoscopically assisted
vaginal hysterectomy. Gynecol Oncol 80, 378-382.
Sood BM, Timmins PF, Gorla GR, Garg M, Anderson PS,
Vikram B, Goldberg GL. (2002) Concomitant cisplatin and
extended field radiation therapy in patients with cervical and
endometrial cancer. Int J Gynecol Cancer. 12, 459-464.
Straughn JM, Huh WK, Orr JW Jr, Kelly FJ, Roland PY, Gold
MA, Powell M, Mutch DG, Partridge EE, Kilgore LC,
Barnes MN, Austin JM Jr, Alvarez RD. (2003) Stage IC
adenocarcinoma of the endometrium: survival comparisons
of surgically staged patients with and without adjuvant
radiation therapy. Gynecol Oncol 89, 295-300.
Sutton GP, Blessing JA, DeMars LR, Moore D, Burke TW,
Grendys EC. (1996) A phase II Gynecologic Oncology
Group Trial of ifosfamide and MESNA in advanced or
recurrent adenocarcinoma of the endometrium. Gynecol
Oncol 63, 25-27.
Suzuki M, Ohwada M, Kanai N, Sato I. (1999) Rapid death
following papillary serous carcinoma of the endometrium
without myometrial invasion. Oncol Rep. 6, 1009-1012.
Takeshima N, Nishida H, Tabata T, Hirai Y, Hasumi K. (2001)
Positive peritoneal cytology in endometrial cancer:
enhancement of other prognostic indicators. Gynecol Oncol
82, 470-473.
Taylor AH, al-Azzawi F, Pringle JH, Bell SC. (2002) Inhibition
of endometrial carcinoma cell growth using antisense
estrogen receptor oligodeoxyribonucleotides. Anticancer
Res 22, 3993-4003.
Thigpen JT, Blessing JA, DiSaia PJ, Yordan E, Carson LF, Evers
C. (1994) A randomized comparison of doxorubicin alone
versus doxorubicin plus cyclophosphamide in the
management of advanced or recurrent endometrial
390
carcinoma: a Gynecologic Oncology Group study. J Clin
Oncol 12, 1408-1414.
Thigpen JT, Blessing JA, Homesley H, Creasman WT, Sutton G.
(1989) Phase II trial of cisplatin as first-line chemotherapy in
patients with advanced or recurrent endometrial carcinoma: a
Gynecologic Oncology Group study. Gynecol Oncol 33, 6870.
Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley
HD, Manetta A, Soper JT, Given FT. (1999) Oral
medroxyprogesterone acetate in the treatment of advanced or
recurrent endometrial carcinoma: a dose-response study by
the Gynecologic Oncology Group. J Clin Oncol 17, 17361744.
Thigpen T, Blessing J, Homesley H, Malfetano J, DiSaia P,
Yordan E. (1993) Phase III trial of doxorubicin +/- cisplatin
in advanced or recurrent endometrial carcinoma: a
Gynecologic Oncology Group (GOG) study. Proc Am Soc
Clin Oncol 12, 261 (abstract 830).
Thigpen T, Brady MF, Homesley HD, Soper JT, Bell J (2001)
Tamoxifen in the treatment of advanced or recurrent
endometrial carcinoma: a Gynecologic Oncology Group
study. J Clin Oncol 15, 364-367.
Thigpen T, Vance RB, Khansur Y. (1995) The platinum
compounds in the management of carcinomas of the
endometrium and uterine cervix. Semin Oncol, 22
(Supp.12), 67-75.
Thomas L, Bataillard A, Bremond A, Fondrinier E, Fervers B,
Achard JL, Lansac J, Bailly C, Hoffstetter S, Basuyau JP,
d'Anjou J, Descamps P, Farsi F, Guastalla JP, Laffargue F,
Rodier JF, Vincent P, Pigneux J. (2001) Standards, options,
and recommendations for the radiotherapy of patients with
endometrial cancer. FNCLCC (National Federation of
Cancer Campaign Centers) and CRLCC (Regional Cancer
Campaign Centers). Cancer Radiother 5, 163-192.
Tomioka Y, Kumagai S, Fujiyoshi K, Hirai N, Sugiyama T,
Nishida T, Kamura T. (1999) Adjuvant CAP in endometrial
cancer. Adjuvant chemotherapy with cisplatin, adriamycin,
and cyclophosphamide following in patients with high-risk
endometrial cancer. In: "7th Biennial Meeting of the
International Gynecologic Cancer Society" Rome (Italy),
September 26-30, 1999 (Pecorelli S, Atlante G, Benedetti
Panici P, Mancuso S Eds) Monduzzi Editore, International
Proceedings Division, 157-161.
Trimble EL, Kosary C, Park RC. (1998) Lymph node sampling
and survival in endometrial cancer. Gynecol Oncol 71, 340343.
Trope C, Johnsson JE, Simonsen E, Christiansen H, CavallinStahl E, Horvath G. (1984) Treatment of recurrent
endometrial adenocarcinoma with a combination of
doxorubicin and cisplatin. Am J Obstet Gynecol 149, 379381.
Trope C, Kristensen G. (1997) Current status of chemotherapy in
gynecologic cancer. Semin Oncol 24, S15-S22.
Trope C, Kristensen GB, Abeler VM. (2001) Clear-cell and
papillary serous cancer: treatment options. Best Pract Res
Clin Obstet Gynaecol 15, 433-446.
Turbow MM, Ballon SC, Sikic BI, Koretz MM. (1985) Cisplatin,
doxorubicin, and cyclophosphamide chemotherapy for
advanced endometrial carcinoma. Cancer Treat Rep 69,
465-467.
Turner DA, Gershenson DM, Atkinson N, Sneige N, Wharton
AT. (1989) The prognostic significance of peritoneal
cytology for stage I endometrial cancer. Obstet Gynecol 74,
775-780.
van Wijk FH, Lhomme C, Bolis G, Scotto di Palumbo V,
Tumolo S, Nooij M, de Oliveira CF, Vermorken JB;
European Organization for Research and Treatment of
Cancer. Gynaecological Cancer Group. (2003) Phase II study
of carboplatin in patients with advanced or recurrent
endometrial carcinoma. A trial of the EORTC
Gynaecological Cancer Group. Eur J Cancer 39, 78-85.
Vardi JR, Tadros GH, Anselmo MT, Rafla SD. (1992) The value
of exploratory laparotomy in patients with endometrial
carcinoma according to the new International Federation of
Gynecology and Obstetrics staging. Obstet Gynecol 80,
204-208.
Vasuratna A, Kudelka AP, Edwards CL, Wootipoom V,
Verschraegen CF, Charnsangavej C, Kavanagh JJ. (1998)
Prolonged remission of endometrial cancer with paclitaxel
and carboplatin. Anticancer Drugs 9, 283-285.
Vecek N, Marinovic T, Ivic J, Jukic S, Nola M, DzanicCemalovic N, Vecek N Jr. (1993) Prognostic impact of
peritoneal cytology in patients with endometrial carcinoma.
Eur J Gynaecol Oncol 14, 380-385.
Vergote I, De Smet I, Amant F. (2002) Incidence of positive
peritoneal cytology in low-risk endometrial cancer treated by
laparoscopically assisted vaginal hysterectomy. Gynecol
Oncol 84, 537-538.
Vergote I, Kjorstad K, Abeler V, Kolstad P. (1989) A
randomized trial of adjuvant progestagen in early
endometrial cancer. Cancer 64, 1011-1016.
Wadler S, Levy DE, Lincoln ST, Soori GS, Schink JC, Goldberg
G. (2003) Topotecan is an active agent in the first-line
treatment of metastatic or recurrent endometrial carcinoma:
Eastern Cooperative Oncology Group Study E3E93. J Clin
Oncol 21, 2110-2114.
Wang PH, Yen MS, Yuan CC, Chao KC, Ng HT, Lee WL, Chao
HT. (1997) Port site metastasis after laparoscopic-assisted
vaginal hysterectomy for endometrial cancer: possible
mechanisms and prevention. Gynecol Oncol 66, 151-155.
Wylie J, Irwin C, Pintilie M, Levin W, Manchul L, Milosevic M,
Fyles A. (2000) Results of radical radiotherapy for recurrent
endometrial cancer. Gynecol Oncol 77, 66-72.
Zaino RJ, Satyaswaroop PG, Mortel R. ( 1985) Hormonal therapy
of human endometrial adenocarcinoma in a nude mouse
model. Cancer Res 45, 539-541.
Zayyan KS, Kazmi NT. (1998) Port site metastasis after
laparoscopic-assisted vaginal hysterectomy for endometrial
cancer: possible mechanisms and prevention. Gynecol Oncol
70, 154-155.
391
392

Treatment planning in endometrial cancer Review Article

Transcription

Similar documents

folder...Endometrial Cryoablation

Robotic Approaches to Large Fibroids and Robotic Myomectomy

Endometrial Scratch

cervical spoon spray for citology fixation and slides hysterometer

Operative Reports Deciphering Appropriate Root Operations Part I

Endometrial ablation - Royal College of Obstetricians and

Adjuvant therapy for endometrial cancer Maria C. DeLeon , Natraj R. Ammakkanavar

Female Genital Pathology