1. health and fitness
2. disease
3. cancer

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
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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).
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Cancer Therapy Vol 1, page 375
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
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Gadducci et al: Treatment planning in endometrial cancer
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
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Cancer Therapy Vol 1, page 377
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).
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Gadducci et al: Treatment planning in endometrial cancer
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).
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Cancer Therapy Vol 1, page 379
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
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Gadducci et al: Treatment planning in endometrial cancer
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
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Cancer Therapy Vol 1, page 381
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
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Gadducci et al: Treatment planning in endometrial cancer
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.
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Cancer Therapy Vol 1, page 383
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
Gadducci et al: Treatment planning in endometrial cancer
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
Cancer Therapy Vol 1, page 385
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
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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
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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).
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