Key words
ovarian cancer - low-grade serous - rare tumour
Schlüsselwörter
Ovarialkarzinom - Low-grade serös - seltener Tumor
Introduction
Ovarian cancer is the second most lethal gynaecological malignancy [1]. The World Health Organisation (WHO) classifies ovarian cancer as epithelial, non-epithelial
(germ cell and sex cord-stromal cell), and metastatic (from other primary cancers
such as gastric, colon, breast and other cancers) [2]. The most common histotype is serous ovarian carcinoma, which is subdivided into
high-grade serous (HGSOC) and low-grade serous ovarian carcinoma (LGSOC). For this
classification a two-tier system based on nuclear atypia was introduced in 2004, which
led to the recognition of two separate entities in term of their genetic landscape,
clinical behaviour, prognosis and management [3]. LGSOC accounts for 5 – 10% of patients diagnosed with serous carcinoma of the ovary,
Fallopian tube and peritoneum [4]. Similar to HGSOC, approximately 70% of LGSOC are diagnosed at an advanced stage
(FIGO III – IV) [5]. Interestingly, LGSOC seems to have a better prognosis, with a mean 5-year survival
for FIGO III – IV disease of 32.1% for HGSOC vs. 54.2% for LGSOC [6]. LGSOC also differs from HGSOC in having a lower age at presentation, with a median
age at diagnosis of 46.9 years compared to 63 years for HGSOC [7].
The clinical presentation of LGSOC is comparable to that of HGSOC and includes abdominal
or pelvic pain, bloating, or dysfunction of the bowel or bladder. Diagnostic workup
typically includes clinical examination including pelvic examination, CA125, ultrasound
or other imaging modalities such as computed tomography (CT) scan of the thorax, abdomen
and pelvis or whole body magnetic resonance imaging (MRI). LGSOC may develop de novo
or in the context of a borderline tumour (BOT, low malignant potential tumour). A
retrospective series from the MD Anderson Cancer Centre showed that about 60% of LGSOC
are found in the context of a serous borderline tumour at diagnosis (sBOT) [8]. Gene expression profiling supports the idea of a developmental relationship in
which sBOT can transform into LGSOC [9]. The current WHO classification considers sBOT with invasive implants as low-grade
carcinomas [10]. Malignant transformation from low-grade to high-grade serous ovarian cancer has
been described in the literature, although it is difficult to explain from a molecular
perspective [11]. LGSOC display a p53 wild-type phenotype (p53 is a typical marker of HGSOC which
is typically absent in LGSOC) with possible K-ras and BRAF mutations [12]. Additionally, DNA copy number changes have been reported as a key event in the
transition from BOT to carcinoma [13].
LGSOC has a significantly higher expression of ER and PR compared to HGSOC, which
makes LGSOC a possible target for endocrine therapy [14]. Mutations in the KRAS/BRAF/MAPK signalling pathway seem to have a favourable influence
on survival in LGSOC and could possibly be used as a target for systemic treatment
[4]. BRAF mutations are rare among LGSOC relative to sBOT and their presence usually
does not affect prognosis, in contrast to the presence of a K-ras mutation which has
been characterised as an adverse prognostic factor [15].
According to the guidelines on epithelial ovarian cancer, genetic testing should be
offered to all women diagnosed with LGSOC, even though germline BRCA mutations are
less common in LGSOC compared to HGSOC. The Gynaecologic Oncology Group (GOG) 218
study showed that among 1915 women with epithelial ovarian cancer, only 4 out of 70
women with low-grade serous carcinoma carried a pathogenic mutation in the BRCA1 or
BRCA2 gene [16].
Review
A key role for primary cytoreductive surgery in LGSOC
Surgery is the cornerstone of the treatment of LGSOC. We should therefore aim for
complete resection at primary cytoreductive surgery, even in advanced stage LGSOC.
If disease is unresectable or the patient is in a poor general health (including comorbidities,
age and nutritional status), neoadjuvant chemotherapy followed by interval debulking
surgery may be considered after histological confirmation of disease.
An exploratory case control study of the Arbeitsgemeinschaft Gynäkologische Onkologie
(AGO) meta-database confirmed that microscopic residual disease at primary cytoreductive
surgery results in a better overall survival (median: 97 vs. 35 months) compared with
women with residual disease > 1 cm [17]. When compared to the group with residual disease of between 1 and 10 mm, the group
with no residual disease had a markedly longer progression-free survival (median:
32 vs. 92 months). At upfront surgery, complete cytoreduction was achieved in 51.7%
of patients [17]. Other authors reported similar findings [18]. Since many patients are affected at a young age, fertility and sexuality should
be discussed [5]. Fertility-preserving options can be offered safely to women with FIGO IA disease
and IC1 LGSOC [5], [19]. Ovarian preservation should not be offered to women with invasive epithelial ovarian
cancer higher than FIGO I, even after complete staging. This discussion is currently
ongoing for patients with serous borderline tumour of the ovary with invasive implants
of BOT.
First-line treatment: should we use the same regimen as for HGSOC?
Adjuvant chemotherapy is recommended for all patients with LGSOC not limited to the
ovary. For FIGO IC–IIA LGSOC, carboplatin monotherapy should be considered; a combination
regimen containing carboplatin and paclitaxel is recommended for more advanced cases
[20]. However, it is commonly accepted that LGSOC is not as chemo-sensitive as HGSOC
[19], [21], [22]. The estimated response to paclitaxel-carboplatin in previously untreated LGSOC
is less than 25% [22]. The case control study of the AGO meta-database found a response rate of 23.1%
[17].
Bevacizumab is commonly used as an anti-angiogenic agent in combination with carboplatin-paclitaxel
in patients with previously untreated advanced ovarian cancer according to the data
of AGO-OVAR 11/ICON 7 [23]. Eighty patients with advanced LGSOC were included in this randomised study. The
addition of bevacizumab resulted in a non-significant HR of 0.78 (95% CI: 0.31 – 1.97;
p = 0.07) in this sub-analysis, favouring the addition of bevacizumab [23]. We do have to note that this study is too underpowered to detect any therapeutic
effect of bevacizumab in this subgroup, and studies on relapsed LGSOC show an advantage
for patients receiving bevacizumab as will be discussed in the section on recurrence
of LGSOC.
Gershenson et al. recently published a retrospective study of 203 patients with LGSOC
who received primary cytoreductive surgery followed by platinum-based chemotherapy
[24]. The authors compared 70 patients of this cohort who received hormonal maintenance
therapy after chemotherapy with 133 patients who received routine follow-up. Median
progression-free survival (PFS) of patients who received hormonal treatment was 64.9
months (95% CI: 43.5 – 86.3) vs. 26.4 months (95% CI: 21.8 – 31.0) in the observation
group (p < 0.001). Both patients with and without persistent disease at the end of
platinum-based chemotherapy had a better PFS in the hormonal maintenance therapy group
[24]. In this study, oestrogen receptor (ER) and progesterone receptor (PR) status was
known for less than half of patients who received hormonal maintenance therapy. Of
the tested patients, 96% were ER-positive and 58% were PR-positive. In a sub-analysis,
a PFS advantage was observed for patients who received hormonal maintenance therapy
irrespective of PR status. As only one patient who received hormonal maintenance therapy
was ER-negative, it is not possible to evaluate the treatment effect in an ER-negative
population [24]. Fader et al. published a series on 27 patients who were treated with anti-hormonal
treatment (tamoxifen, letrozole or anastrozole) after cytoreductive surgery instead
of platinum-based chemotherapy [18]. In this series, median PFS and overall survival (OS) had not yet been reached;
the authors reported a 3-year PFS of 79% and 3-year OS of 92.6% [18]. Notably, all patients who currently recurred had a PR status of 0 – 40%, suggesting
that hormonal treatment, as a monotherapy, might be less effective in this subgroup
[18], [25].
Management of recurrent or metastatic disease
Common options for the management of this subset of patients are:
Role of surgery for recurrent LGSOC
Despite radical first-line treatment, LGSOC may recur at some point [26]. Secondary cytoreductive surgery requires careful patient selection [27]. Defining precise criteria to select the appropriate surgical candidate is clearly
difficult, as is the case for every ovarian cancer histotype. Generally, time to recurrence,
localisation of disease and number of metastatic sites should be considered when attempting
secondary cytoreduction.
Due to the infiltrative nature of LGSOC, surgical expertise is necessary to achieve
macroscopic complete resection during secondary cytoreductive surgery (SCRS) for LGSOC.
A retrospective study at the MD Anderson Cancer Centre of 41 patients with recurrent
disease showed that cytoreduction without macroscopic residual disease could only
be achieved in 22% of patients. The median PFS for patients without residual disease
after SCRS was 60.3 months, compared to 10.7 months for patients with macroscopic
residual disease. Median survival after a diagnosis of LGSOC for patients with complete
resection during SCRS was 167.5 months vs. 88.9 months in patients with residual disease.
Median survival from the time of SCRS for patients with no gross residual disease
was 93.6 months compared to 45.8 months [28].
Complete resection during secondary cytoreductive surgery can improve PFS and possibly
also OS for patients with recurrent LGSOC. We should therefore discuss the option
of secondary cytoreductive surgery with maximal surgical resection in patients with
recurrent disease.
Systemic treatment for recurrent LGSOC
In recurrent platinum-resistant HGSOC, the objective response rates (ORR) for non-platinum
monotherapy vary between 17 and 19.7% [25]. In contrast, the ORR for LGSOC is approximately 4.9% for platinum-sensitive disease
and 2.1% for platinum-resistant patients [21]. Despite these poor ORR, 60% of patients achieved stable disease during chemotherapy
for recurrent LGSOC. Median time to progression was 34.7 weeks (range: 4.3 – 232.4
weeks) for platinum-sensitive patients and 26.4 (range: 8.4 – 149 weeks) for platinum-resistant
patients. Pegylated liposomal doxorubicin (PLD) seems to be the most active regimen
for LGSOC [29]. There is no data which compares the different regimens for platinum-based therapy
to treat LGSOC.
As PARP inhibitors are very efficient to treat high-grade ovarian cancer, LGSOC were
not included in the last phase III trials [30], [31], [32].
The addition of bevacizumab to standard chemotherapy for recurrent LGSOC can improve
response rates. Schmeler et al. were the first to publish a report on the possibly
beneficial effect of bevacizumab for LGSOC with a partial response in 5/13 patients
treated with chemotherapy in combination with bevacizumab for recurrent LGSOC [33]. This finding was confirmed by Dalton et al. in a series of 40 patients in which
they observed an ORR of 47.5% for bevacizumab-containing regimens, with a median PFS
of 10.2 months (95% CI: 7.9 – 14.4 months) [34]. Some reports even suggest that bevacizumab might be effective as monotherapy for
LGSOC [35], [36].
Hormonal treatment might be an alternative to chemotherapy for recurrent LGSOC. In
a series of 64 patients with recurrent LGSOC, an overall response rate of 9% was observed,
with stable disease achieved in 61.8% of cases [37].
Based on the known mutation in the KRAS/BRAF/MAPK and the PI3K/AKT/mTOR signalling
pathway, several clinical trials have been designed, using targeted agents to target
these pathways. In the GOG 0239 trial Farley et al. treated 52 patients with selumetinib,
a MEK1/2 inhibitor. They observed an objective response rate of 15%, with stable disease
in 65% of patients and an acceptable toxicity profile [38]. Based on this study, the AGO-OVAR 2.24/MILO trial was initiated, a randomised trial
in which patients received either physicianʼs choice of chemotherapy (PLD, paclitaxel
q1w or topotecan) vs. MEK162. The results of this study have not been published to
date but are expected in the near future. A second trial (NCT01936363) combined the
MEK inhibitor pimasertib with a PI3K/mTOR inhibitor (SAR245409) or placebo. There
is also a third trial which is still ongoing, in which patients are randomised between
trametinib (MEK inhibitor) and physicianʼs choice of therapy (letrozole, tamoxifen,
PLD, paclitaxel q1w or topotecan).
Conclusions
Low-grade serous carcinoma is relatively chemo-resistant. Surgery is therefore the
cornerstone of treatment for LGSOC, both as first-line therapy and to treat recurrence.
Standard of care in first-line therapy remains primary cytoreductive surgery followed
by platinum-based chemotherapy with or without bevacizumab. Hormonal therapy (e.g.,
aromatase inhibitors) could be considered as a maintenance therapy after end of chemotherapy
for LGSOC. If there is recurrence of disease, the feasibility of secondary cytoreductive
surgery should be evaluated and discussed with the patient. Chemotherapy could be
offered as a systemic treatment for recurrent LGSOC in accordance with treatment recommendations
for high-grade serous ovarian cancers. Endocrine treatment seems to show similar effects
as standard chemotherapy in this tumour entity.
