Key words
uterine carcinoma - uterus - leiomyosarcoma
Schlüsselwörter
Uterussarkom - Uterus - Leiomyosarkom
Introduction
Uterine sarcomas are rare, particularly aggressive mesenchymal tumours that make up approx. 3 % of all
uterine malignancies [1]; its incidence is around 0.5–3.3 per 100 000 women
per year [2]. Various histological subtypes are included under the term
uterine sarcomas; the most frequent is leiomyosarcoma (LMS), followed by endometrial stromal sarcoma
(ESS), undifferentiated uterine sarcoma (UUS) and pure heterologous sarcomas. Mixed epithelial and
mesenchymal tumours include adenosarcomas and carcinosarcomas (mixed Mullerian tumours); as the latter
have an epithelial origin, they are not included under sarcomas.
This article focuses on uterine tumours of mesenchymal origin, i.e. LMS, ESS and UUS.
Leiomyosarcoma (LMS) of the Uterus
Leiomyosarcoma (LMS) of the Uterus
LMS makes up approx. 1 % of all uterine malignomas, with its incidence standing at 0.1–0.3 per 100 000
women per year [3], [4]. Apart from a rapidly
growing tumour in the pelvis, patients are typically asymptomatic and the diagnosis generally presents
itself intraoperatively or postoperatively.
Upon initial diagnosis, the LMS is limited to the uterus in the majority of cases and the cure rate –
between 20 and 60 % in total – ultimately depends on the tumour stage and the kind of primary operation
[5]. Other prognostic factors were discussed, but without a conclusive
result so far [6]. Due to the relatively high rate of recurrence and the
frequent distant metastasis, a comprehensive radiological staging with a CT or MRI of the thorax,
abdomen and pelvis is necessary [7].
Operative treatment
Surgical tumour removal is currently the central component of treatment for the LMS, and total
abdominal hysterectomy (TAH) with bilateral salpingo-oophorectomy (BSO), if necessary, is generally
the method of choice. Leaving the adnexa does not lead to a deterioration in the prognosis, meaning
that this can be left in pre-menopausal women if they do not appear remarkable intra-operatively.
Due to the low prevalence of lymph node metastases (3 % in early stages), the extensive removal of
pelvic and paraaortal lymph nodes is generally not indicated [6]. Lymph
node involvement increases in later stages, however. As the LMS is frequently first diagnosed during
or following an operation for another indication (e.g. apparent leiomyoma), the method of
laparoscopic uterus extraction via morcellation presents a potentially serious risk of an iatrogenic
stage progression. This approach, e.g. in the context of a laparoscopically assisted supracervical
hysterectomy, increases the risk of a dissemination of the tumour cells, which leads to a
significant deterioration in overall and recurrence-free survival time (5-year survival rate:
73 → 46 %!). Patients for whom such an intervention is planned due to a suspected diagnosis of a
leiomyoma should be fully and openly informed. [7].
Adjuvant treatment
Due to the LMSʼs high level of aggression with a correspondingly high risk of local and/or distant
recurrence even following the complete surgical removal of the primary tumour, additional
non-surgical treatment approaches are also of significant interest. As radiation therapy has not
proven to be effective in an investigation of stage I and II patients [8],
current investigations concentrate on an optimisation of systemic therapy.
A certain standard regime with a proven efficacy is not (yet) currently available, but there are
hints that chemotherapy (primarily doxorubicin ± ifosfamide) following complete surgical resection
could increase overall progression-free survival time [9]; in a small
randomised study, a combination of ifosfamide, doxorubicin and cisplatin with subsequent radiation
therapy displayed a significant advantage in progression-free survival in comparison with radiation
alone (3-year PFS 51 vs. 40 %), but cannot be recommended for daily clinical use due to its toxicity
[10].
In a single arm phase II study conducted by Hensley et al. [11], 47
patients received four cycles of gemcitabine in combination with docetaxel followed by four further
cycles of doxorubicin following an operation upon the initial diagnosis of a uterine LMS. The
progression-free 2 year and 3 year survival rates stood at 78 % and 57 % respectively. This schema
is currently being carried out in a randomised study vs. the observation for patients with an
initial diagnosis of an FIGO I LMS (GOG 277 protocol) ([Table 1]).
Table 1 Adjuvant chemotherapy in the event of leiomyosarcoma.
|
|
Entity
|
Stage
|
Design
|
Schedule
|
PFS
|
OS
|
|
Omura 1985
|
Uterine sarcomas
|
I, II
|
II (n = 156)
|
Adriamycin 60 mg/m2 q 21 vs. observation
|
No significant difference
|
73 months vs. 55 months; p = n. s.
|
|
Harter 2011
|
Uterine/ovarian sarcomas
|
I–IV and recurrence
|
II (n = 40)
|
Pegylated lip. doxorubicin 40 mg/m2 + carboplatin AUC 6 q28
|
8.6 months
|
29.5 months
|
|
Pautier 2012
|
Uterine sarcomas
|
I, II
|
II (n = 81)
|
Doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2/d d1–2 +
cisplatin 75 mg/m2 d3, q21 → RT vs. RT
|
3 year PFS: 51 vs. 40 %; p = 0.0048
|
3-year survival rate: 81 vs. 69 %; p = 0.41
|
|
Hensley 2009
|
Uterine leiomyosarcomas
|
I–IV (18 Patients stage I/II)
|
II (n = 25)
|
4 × gemcitabine 900 mg/m2 d1 and 8 + docetaxel 75 mg/m2
d8
|
Stage I/II: 2 year PFS: 59 %
|
Stage I/II: not reported
|
|
Hensley 2013
|
Uterine leiomyosarcomas
|
I, II
|
II (n = 47)
|
4 × gemcitabine 900 mg/m2 d1 and 8 + docetaxel 75 mg/m2 d8
→ 4 × doxorubicin 60 mg/m2 q21
|
2 year PFS: 78 %
|
Not reported
|
Treatment for recurrent LMS
Due to the relative rarity of LMS, there exist only a few systematic studies that investigated the
treatment and prognosis of the recurrent form alone in comparison with other subtypes of uterine
carcinoma or extra-pelvic forms of sarcoma, and it is currently unclear whether surgical tumour
reduction can improve the prognosis in these cases. As with other issues regarding the treatment and
management of the recurrent LMS, this must be decided on an individual basis.
In a randomised phase II study of patients with different soft tissue sarcomas [12], gemcitabine was compared with gemcitabine/docetaxel. The combination presented a
significant advantage over monotherapy with gemcitabine with regard to progression-free survival
(PFS) (6.2 vs. 3.0 months, p = 0.02) and overall survival (OS) (17.9 vs. 11.5 months, p = 0.03).
However, the toxicity was significantly higher in the combination arm, and over 40 % of patients
terminated the treatment before its scheduled end due to poor tolerance. A further phase II study
[13] comprised patients with advanced or recurrent liposarcoma or
leiomyosarcoma, in which treatment with anthracycline and ifosfamide remained unsuccessful. Two
different application schema of trabectedin monotherapy were compared in this study: a 24-hour
intravenous infusion of 1.5 mg/m2 every three weeks and a weekly infusion of
0.58 mg/m2 over three hours. Here, the 24-hour infusion displayed a better clinical
effect with a median PFS of 3.3 vs. 2.2 months (HR: 0.755; 95 % CI: 0.574–0.992; p = 0.0418) and a
median OS of 13.9 vs. 11.8 months (HR: 0.843; 95 % CI: 0.653–1.090; p = 0.1920).
In the hitherto only double blind randomised placebo-controlled phase III study into treatment of
metastatic and recurring soft tissue sarcoma, the application of pazopanib was investigated [14]. In comparison with the placebo, the oral treatment with 800 mg/day
extended PFS by a median of 3 months (4.6 vs. 1.6 months; HR: 0.31; 95 % CI: 0.24–0.40;
p < 0.0001), the difference in the OS was somewhat less pronounced and not statistically
significant (12.5 vs. 10.7 months; HR: 0.86; 95 % CI: 0.67–1.1; p = 0.25).
In a further phase III study, ridaforolimus was used in maintenance therapy following cytotoxic
chemotherapy induction. This displayed a significant advantage over the placebo regarding the
primary endpoint (PFS) (17.7 vs. 14.6 weeks; HR: 0.72; p < 0.0001), whereby stomatitis presented
as a side effect in the ridaforolimus arm in 52 % of patients [15]. The
full publication including OS data should enable a definitive evaluation of the potential role of
ridaforolimus in the treatment of sarcomas.
Schöffski et al. [16] also showed that recurrent or metastasised LMS
responded relatively well to chemotherapy in comparison with other forms of sarcomas. The
combination of carboplatin and pegylated liposomal doxorubicin also appears to display a positive
effectiveness safety profile in advanced or metastasised (epithelial) mesenchymal gynaecological
tumours. In a phase II study of the AGO study group [17], a median PFS of
8.6 months was found in this situation (95 % CI: 6.4–10.4 months) and an OS of 29.5 months, whereby
the 1-year survival rate was 77 %. Garcia-Del-Muro et al. [18] compared
the effectiveness of a combination of dacarbazine and gemcitabine with gemcitabine monotherapy in a
population of 113 patients with recurrent soft tissue sarcoma (32 of which had LMS). This study
found that the combination regime had a significant advantage with regard to PFS (4.2 vs. 2 months;
HR: 0.58; 95 % CI: 0.39–0.86; p = 0.005) as well as in terms of OS (16.8 vs. 8.2 months; HR: 0.56;
95 % CI: 0.36–0.90; p = 0.014). In a phase II study by Pautier et al., the combination of
trabectedin and doxorubicin was investigated. This study evinced a remission rate of 57 %, which was
significantly higher than the previously established pattern [19].
In Germany, the Pazo Doble study was started, in which gemcitabine in combination with pazopanib was
compared against pazopanib alone.
Endometrial Stromal Sarcoma (ESS)
Endometrial Stromal Sarcoma (ESS)
An ESS is a rare subtype, making up between 6 and 20 % of the already rare uterine carcinomas, or 0.2–1 %
of uterine malignomas, and primarily affects women in their fifties and sixties [2], [22]. The main symptoms of an ESS are abnormal ex utero
bleeding (approx. 90 %) and a palpable enlargement of the uterus (approx. 70 %); pain and dysmenorrhea
may be present, but not necessarily. Approximately 30–50 % of ESS have already metastasised once the
diagnosis has been reached [20]. However, local recurrences or distant
metastases can occur up to twenty years following the initial diagnosis [6].
The early common classification of the ESS in low and high grade categories is now obsolete;
differentiation must be made between endometrial stromal sarcomas and undifferentiated uterine sarcomas.
Although ESS are generally predominately intramyometral, the involvement of the endometrium is frequent,
and therefore curettage is often helpful in the preoperative diagnostic workup [21], [22]. In any case, the significance of the evaluation of
curettage fragments is limited, meaning that the definitive diagnosis can only be made based on the
hysterectomy preparation. Due to the low prevalence, there is only limited significant data on the
treatment and outcome, and the existing evidence has predominately been obtained from retrospective case
series with a low number of patients.
Operative treatment
The operative standard approach comprises an exploratory laparotomy, TAH/BSO, omental biopsy and
aspiration of peritoneal fluid for the cytological investigation [6]. ESS
frequently express oestrogen (ER) and progesterone receptors (PR), meaning that a hormone
substitution may be contraindicated following BSO [23]. It is disputed as
to whether the BSO in stage I of the ESS influences the PFS or OS, meaning that the theoretically
possible improvement in the prognosis is weighed up against the undesired effects of the early
surgical menopause [24].
The prevalence of lymph node involvement with ESS reported in the literature varies and amounts to a
maximum of 10 %, but most report considerably lower rates. While the resection of macroscopically
suspect or remarkable lymph nodes is part of standard surgical procedure, systematic pelvic and
paraaortal lymph nodectomies are regarded sceptically as routine surgical staging procedure, as the
propagation of the ESS is predominately haematogenous [25].
Adjuvant treatment
The evidence for adjuvant treatment methods for ESS is decidedly scarce, and the close-meshed
monitoring without specific intervention applies as standard in stages I and II; in further advanced
stages, endocrine treatment may be worth considering in the event of ER or PR positive ESS. There
are currently no indications of effectiveness for adjuvant radiation therapy for ESS (stages I and
II) [10].
There are no studies with regard to chemotherapy that decidedly focus on ESS, and ESS is merely
included as a subgroup in larger series, frequently without its own outcome analysis. In principle,
the decision regarding the systemic treatment of ESS must be made on an individual basis, and no
generally valid recommendations can be made. Should chemotherapy be contemplated, the results for
LMS presented above can serve as a guide.
In the case of the receptor-positive forms of advanced/metastasised ESS, endocrine treatment with
medroxyprogesterone (MPA) and aromatase inhibitors (AI) appears the most promising. In some cases,
endocrine treatment has led to the illness being monitored for a longer duration [26].
Treatment for recurrent ESS
ESS recurrences most frequently occur in the abdominal cavity and pelvis (40–50 %), followed by the
lung (approx. 25 %) [27], [28]. Late
recurrences are also frequent following treatment of the primary illness, and so the treatment for
the recurrence is of great importance in the context of the management of ESS. The treatment
strategy for the ESS recurrence primarily depends on the previous endocrine treatment: should this
not take place as part of the primary treatment, the administration of MPA and/or AI
should be the method of choice in any case in the event of a recurrence.
However, for patients who display a progressive development or a recurrence following antihormonal
treatment (in the adjuvant or first-line setting), cytotoxic therapy is the primary treatment
considered. Here, especially in the absence of illness-specific evidence, the approach corresponds
to that used in the event of recurrent or metastasised LMS, meaning that a gemcitabine/docetaxel and
doxorubicin-based schemata is the primary one considered.
Undifferentiated Uterine Sarcoma (UUS)
Undifferentiated Uterine Sarcoma (UUS)
This independent entity comprises high-grade epitheloids and spindle cell sarcomas and makes up less than
5 % of uterine sarcomas [6]. UUS grow quickly and display aggressive
dispersion behaviour with a correspondingly poor prognosis (25–55 % 5-year survival rate) [29], [30].
Operative treatment
In the absence of solid illness-specific evidence, TAH/BSO is recommended as the standard approach
for a UUS in accordance with the other forms of uterine sarcoma [6].
Similar to the case with ESS, the significance of the systematic lymph nodectomy in the case of USS
is not clear, but is disputed due to the primarily haematogenous propagation.
Adjuvant treatment
There is no conclusive clinical data on the adjuvant treatment of UUS. Due to the tumour-biological
characteristics of a UUS, cytotoxic chemotherapy may be considered. Analogously to other soft tissue
sarcomas, doxorubicin and/or ifosfamide are primarily discussed.
Treatment for recurrent UUS
No randomised controlled studies exist for the treatment of the recurrent UUS in which UUS is
differentiated from other tumour entities. Treatment is based on the same principles as other soft
tissue sarcomas.
Summary
To summarise, the treatment of gynaecological sarcomas is complex and each individual entity requires
specific treatment. At this stage, it is worth explicitly noting again that the risk factor of
morcellation reduces the probability of survival by approx. 40 %. Unfortunately, very few studies have
been conducted for these entities in the past decade. Study activity into the optimisation of
chemotherapeutic approaches as well as targeted treatments is now more active however, which is to be
warmly welcomed.
