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Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Fertility sparing surgery in epithelial ovarian
cancer in Italy: perceptions, practice, and main
issues
Alice Bergamini, Micaela Petrone, Emanuela Rabaiotti, Francesca Pella,
Raffaella Cioffi, Elena Giulia Rossi, Valentina Di Mattei, Massimo Candiani &
Giorgia Mangili
To cite this article: Alice Bergamini, Micaela Petrone, Emanuela Rabaiotti, Francesca Pella,
Raffaella Cioffi, Elena Giulia Rossi, Valentina Di Mattei, Massimo Candiani & Giorgia Mangili
(2017): Fertility sparing surgery in epithelial ovarian cancer in Italy: perceptions, practice, and main
issues, Gynecological Endocrinology, DOI: 10.1080/09513590.2017.1393508
To link to this article: http://dx.doi.org/10.1080/09513590.2017.1393508
Published online: 26 Oct 2017.
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http://www.tandfonline.com/action/journalInformation?journalCode=igye20
Download by: [Chalmers University of Technology]
Date: 29 October 2017, At: 01:18
GYNECOLOGICAL ENDOCRINOLOGY, 2017
https://doi.org/10.1080/09513590.2017.1393508
ORIGINAL ARTICLE
Fertility sparing surgery in epithelial ovarian cancer in Italy: perceptions, practice,
and main issues
Alice Bergaminia, Micaela Petronea, Emanuela Rabaiottia, Francesca Pellaa, Raffaella Cioffia, Elena Giulia Rossia,
Valentina Di Matteib,c, Massimo Candiania and Giorgia Mangilia
Downloaded by [Chalmers University of Technology] at 01:18 29 October 2017
a
Department of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Milan, Italy; bFaculty of Psychology, Vita-Salute San Raffaele University,
Milan, Italy; cClinical and Health Psychology Unit, Department of Clinical Neurosciences, IRCCS San Raffaele Hospital, Milan, Italy
ABSTRACT
ARTICLE HISTORY
About 2.7% of patients epithelial ovarian cancers (EOC) are younger than 40 and present with stage I disease. For this subset of women, the issue of fertility sparing surgery (FSS) has become critical. The aim of
this survey was to investigate the management of EOC patients desiring to preserve fertility in Italy. A
questionnaire consisting of 30 items was developed to evaluate: patient-selection criteria, rate of FSS,
patient’s counseling- and pregnancy-timing, fertility preservation, obstetrics, and oncologic outcomes. One
expert clinician for each of 50 major gynecologic oncology centers was invited to participate. Data were
entered into a database and statistically analyzed. 74% of questionnaires were complete. The proportion
of EOC patients treated with FSS was <10%, 10%–20% and >20% in 70.3%, 24.3% and 5.4% of cases,
respectively. Age, fertility preservation desire, histotype, and stage were considered relevant to select
patients for a conservative treatment for 64.8%, 72.9%, and 78.3% of responders, respectively. Only 17
centers (45.9%) resulted to have an assisted reproductive technique service and Obstetrics Department.
Our survey highlights discrepancies among oncologists in the management of patients with early EOC
undergoing FSS. More efforts should be made to define and broadcast the best management before and
after surgery.
Received 14 May 2017
Accepted 13 October 2017
Published online 25 October
2017
Introduction
Among all epithelial ovarian cancers (EOC), 3%–14% are diagnosed in fertile women. More than a half of these tumors are
detected at an early stage and delaying childbearing has become
nowadays increasingly more common, thus growing attention
has been focused in the last decades on conservative treatment
for EOC. In this particular setting, higher concerns and controversies exists as compared to the other gynecological malignancies, being EOC the most lethal.
According to the available guidelines, fertility sparing surgery
(FSS) approach is currently indicated in EOC at stage I A
grade1–2 [1,2]. For high-risk patients (clear cell histology,
stage IAG3) the indication to conservative surgery is still
debated [1–8]. Data from literature support the evidence that FSS
does not hamper the oncological outcome: recurrence rate
depends on grading and stage of disease while type of surgery
does not impact survival [4–8]. In the interesting study of
Fruscio et al., including 240 patients treated with FSS, after a
median follow-up of 9 years, 27 patients had relapsed (11%). Of
these, 11(5%) had died of disease for a distant recurrence.
Interestingly, in multivariate analysis only grade 3 was found to
affect prognosis. It is possible to speculate that overall prognosis
is unaffected by preservation of the contralateral ovary, rather
could it be related to the more aggressive biology of the tumor
[4]. If this is true, recurrence could not be prevented neither in
conservative nor in radical surgery.
Several studies have focused on the role of FSS in EOC to better select patients who can benefit from this therapeutic strategy.
CONTACT Alice Bergamini
[email protected]
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
KEYWORDS
Ovarian cancer; fertility;
pregnancy; conservative
surgery
However, there is still no consensus on the best management
and recommended timing of pregnancy after completion of treatment [9].
The aim of this survey was firstly to investigate the management of these patients in Italy by sending a properly developed
questionnaire to the major gynecologic oncology experts.
Secondly, based on the results of our survey, evidences from literature have been evaluated, critically reviewing all the potential
related issues.
Materials and methods
A questionnaire evaluating the approach to FSS in EOC was
properly developed by two experts in surgical and medical
oncology and one psycho-oncologist. The questionnaire consisted of 30 questions covering the following items: responder’s
professional characteristics, rate of FSS performed, patientsselection criteria, adjuvant therapy, patients counseling, pregnancy-timing related issues, fertility preservation, obstetric, and
oncologic outcomes. Item response options included yes/no,
multiple choice, comment boxes. Answer choices were categorized in order to facilitate the completion of questionnaire
forms.
50 major gynecologic oncology centers in north, central and
southern Italy have been considered eligible for the survey,
including University Medical Hospital and Clinical Centers. One
expert clinician for each center was invited to participate by
completing the questionnaire.
Department of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy
2
A. BERGAMINI ET AL.
Data obtained from the filled questionnaires were entered into
a database using Microsoft Access and analyzed. Statistical analyzes were performed using SPSS version 17.0(SPSS Inc.,
Chicago, IL, United States).
Results
At the end of the survey, 37 completed questionnaires were collected (74% of the target population). Respondents’ characteristics are summarized in Table 1 and answers to main questions
are reported in Table 2.
Table 1. Responders characteristics.
N ¼37 (%)
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Characteristic
Age
Mean ± SD (range)
Sex
M
F
Clinical activity
Surgeon
Medical Oncologist
Both
Years of experience
Mean
Center
Clinical center
University Medical Hospital
Scientific Research Institute
50.03 ± 8.51
26 (70.2)
11 (29.7)
22 (59.4)
11 (29.7)
4 (10.8)
18.43 ± 8.02
16 (43.3)
12 (32.4)
9 (24.3)
Discussion
Results from the current survey can be interpreted as a cross
section of the national perception regarding the optimal management for FSS in EOC, from selection of patients to optimal timing to conceive. Each of these issues will be herein discussed
considering the available evidence from literature and international consensus guidelines.
Criteria for selecting patients to a conservative approach have
been widely discussed. In the largest retrospective series available
[10] including 1189 patients with early EOC,432 of whom treated
conservatively, stage IC and grade 3 were the only independent
predictors of survival. Another important retrospective study by
Fruscio et al. [4] confirmed that G3 was the only independent
predictor for survival and was associated with a significant higher
rate of distant recurrence. Interestingly, among patients treated
conservatively, only one patient had a pelvic recurrence and was
treated with salvage surgery, while 83% had a distant recurrence
and died of disease. From these data, it seems that distant recurrences would not have been affected by conservative surgery,
being rather related to the aggressive biology of disease. Both
Fruscio and Ditto et al. conclude that type of surgical approach
does not influence survival, thus patients with high risk early
EOC should be offered conservative surgery with complete surgical staging [4,7]. Nevertheless, available guidelines are not always
concordant, in particular concerning high risk early stage EOC
(stage IC or IA,B G3), which is still considered by many Authors
questionable [3,9]. The most recent NCCN 2017 guidelines
Table 2. Results from survey questions evaluating practice in FSS for EOC.
Question/answer option
Criteria included to evaluate feasibility of fertility sparing surgery
Age
Fertility preservation desire
Histotype, stage
FSS/all surgical interventions for EOC (%)
<10
10–20
>20
Is Psycho-oncology evaluation performed?
Yes
No
Is fertility assessment perfumed before FSS?
Yes
No
Does fertility assessment affect choice of surgical approach?
Yes
No
Is fertility assessment performed during follow-up?
Yes
No
ART contraindicated after FSS
No
Yes
Minimum interval suggested before attempting pregnancy (months)
Median (range)
Responders
Not defined
Patients attempting a pregnancy after FSS (%)
Mean (±SD)
Is an ART service available within the center performing FSS?
Yes
No
Is there an Obstetrics Department within the center performing FSS?
Yes
No
Is completion of surgery suggested after treatment completion?
Yes
No
Unknown
N (%)
24 (64.8)
27 (72.9)
29 (78.3)
26 (70.3)
9 (24.3)
2 (5.4)
18 (48.6)
19 (51.4)
25(67.6)
12(32.4)
22 (88%)
3 (12%)
26 (70.3)
11 (29.7)
29 (78)
8 (22)
12 (6–12)
17
10
39.33 ± 5.21
17 (45.9)
20 (54.1)
16 (43.2)
21 (56.8)
26 (70.3)
9 (24.3)
2 (5.4%)
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GYNECOLOGICAL ENDOCRINOLOGY
suggest as primary treatment for all grades IA or IC EOC unilateral salpingo-oophorectomy along with comprehensive staging
for all patients who desires to preserve fertility [2]. In the most
recent ESMO and ESGO guidelines, a conservative approach is
limited to G1–2 IA and IC EOC with unilateral involvement, in
case of mucinous, serous, endometrioid, or mixed histotype [1].
Still there is no unanimous consensus concerning patients’
selection neither in our survey nor in literature; in some cases
FSS in EOC is even considered an experimental approach. This
highlights the ongoing efforts in updating clinical guidelines as
well as the necessity of further studies to better assess this issue.
In our survey, a median of 39% of patients undergoing FSS
eventually attempts to get pregnant. This results are in line with
other studies available on this topic, with an overall rate ranging
between 16% and 50% [11]. Several reasons could explain the discrepancy between patient selection and pregnancy-attempt outcome: first of all, the perception of the disease and their increased
consciousness in risk of recurrence, which could change during the
treatment plan. As reported by a recent literature review, cancer is
known to influence survivors’ motivation to childbearing, raising
concerns on conceiving, on the potential negative effects of both
cancer and treatments on a future child, as well as partner-related
fears [12]. It is clear how, in this setting, an adequate and multidisciplinary counseling should be mandatory. This should be structured considering all the potential confounding aspects including,
apart from the gynecological and oncological evaluation, a psychooncological, obstetric, and reproductive one. As reported in Table
2, less than half of the centers examined offer a proper psychooncological counseling to their patients. Counseling is a major field
of psychological science with knowledge and experience for dealing
with a variety of issues and has much to offer to medical settings.
Specifically, FSS psychological counseling is a communication process aimed at helping individuals in properly considering the different risks and opportunities associated with this surgical option.
The individual must be able to make informed choices particularly
regarding future risks. Psychological counseling should closely
examine and take into consideration the type of disease, the age of
the patient, the presence or not of a partner, the presence of children, and the psychological conditions of the patient (i.e. psychopathological symptoms).
Along with psychological and oncological issues, fertilityrelated ones should be discussed from the beginning. An interesting study by Peate et al. reports how, in breast cancer patients, a
low level of fertility-related knowledge was associated with higher
decisional difficulties regarding their fertility options [13]. One of
the possible problems of these patients is premature ovarian failure (POF), as adjuvant chemotherapy may affect the ovarian
reserve. The gonadotoxic risk is related to the type of chemotherapeutic agent, administration schedule, age, and previous ovarian
reserve [3]. Chemotherapeutic agents used in EOC, such carboplatin and paclitaxel, are considered less gonadotoxic as compared to other cytostatics; however, an accurate evaluation is
mandatory before starting FSS. Despite this, in our survey, such
evaluation is performed in only 67.6% of the centers before starting FSS and in 70.3% during follow-up. There is no consensus
on the optimal evaluation of ovarian reserve in these patients.
Several methods have been investigated, including ultrasonographic features (antral follicle count, AFC, and ovarian volume),
hormonal tests (AMH, FSH, E2), as well as clinical characteristics, like menses regularity. AMH, in particular, is considered by
several Authors as the most reliable marker even in patients
undergoing gonadotoxic treatments. A value of 1.2 ng/mL prior
to the beginning of chemotherapy has been set as a cutoff to
3
select those breast cancer patients with higher possibilities on
assisted reproductive technique (ART) at the end of treatment
[14]. In our survey, most centers rely on AMH evaluation, transvaginal ultrasound and hormonal assessment.
Another controversial issues emerging from our survey is
related to the role of ART for these patients. In 22% of our responders, EOC is a supposed contraindication for subsequent
ART. Literature evaluating these issue is limited by the heterogeneity of histological subtypes and, in some cases, by the inclusion of borderline tumors. In the few series including only EOC,
the conception rate of patients after FSS has been reported to be
higher than 60% in women with childbearing desire [3,15], no
relevant fertility impairment has been detected and only a minority of patients required ART. Experience on conservative surgery
in EOC is surely lower as compared to borderline ovarian
tumors, where the role of ART after FSS has been widely evaluated. Further studies are recommended in order to clarify the
feasibility, role, and timing of ART in this population.
Even if sufficient evidence is lacking, completion of surgery
after childbearing should be recommended in order to prevent
recurrence. The cases of late recurrences after conservative treatment described in literature support this indication [4]. Strict follow-up of patients is mandatory. A 3-month schedule including
clinical and ultrasound evaluation seems us reasonable with
major imaging evaluation every 6 months. Moreover, patients
should be tested for BRCA 1–2 genes mutations, the detection of
which might modify the follow-up program.
The final aim of FSS is pregnancy. The optimal time to conceive is still highly debated, as shown in the results of our survey,
with a suggested minimum interval of 6 months to a maximum
of 36 months from the end of chemotherapy, and a lack of indication given by 27% of the responders. No conclusive data in literature neither guidelines are available. ESMO guidelines
recommend at least a 6 months interval after completion of treatment, to reduce the possible teratogenic effect of chemotherapy
[1]. In the absence of a clear evidence from studies designed for
this specific subset of patients, each case should be managed separately and thoroughly discussed. As suggested in other settings
[16], the peak of relapse should be taken into consideration
before planning conception, in order to avoid disease recurrence
during pregnancy. Conception should be therefore suggested
after the estimated peak of recurrence, assessed according to low
and high-risk disease. Considering the largest series available in
literature [3–5,17], for low-risk disease (IAG1-G2) relapse is a
rare event and usually involves the contralateral ovary, allowing
clinicians to successfully rescue these patients. Relapses have
been reported even several years after diagnosis, but the recurrence rate decrease in most series after 2 years. Pregnancy with
careful ultrasound surveillance during pregnancy could therefore
be considered after this time span [7,8,15]. For high-risk disease,
recurrence rate is as high as 24% in the largest series available in
literature [4]. In this group, distant recurrence is frequent, and
these patients are difficulty rescued with chemotherapy or surgery. The peak of recurrence decrease between three to four
years, according to the different series reported in literature.
Careful evaluation of the risk profile should be observed before
suggesting conceiving. This choice could be obviously criticized
as delaying pregnancy could further reduce the ovarian reserve,
potentially harming the childbearing potential.
Our survey highlights discrepancies among oncologists in the
management of patients with early EOC undergoing FSS, from
counseling to selection of patients and follows up. More efforts
should be made in order to define the best management for this
4
A. BERGAMINI ET AL.
subset of patients and to give light on the abovementioned debated
issues, expected to become increasingly more common giving the
growing trend toward both FSS in EOC and late childbearing.
Disclosure statement
The authors report no conflicts of interest.
7.
8.
9.
10.
11.
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