fertility sparing

Annals of Oncology Advance Access published August 8, 2016
1
FERTILITY-SPARING SURGERY IN EPITHELIAL OVARIAN CANCER:
A SYSTEMATIC REVIEW OF ONCOLOGICAL ISSUES
E. Bentivegna1, S. Gouy1, A. Maulard1, P. Pautier2, A. Leary2,3, N. Colombo4, P.
Morice1,5,6
of Gynecologic Surgery, Gustave Roussy, Villejuif France
2Department
of Medical Oncology, Gustave Roussy, Villejuif France
3Unit
INSERM U981, Villejuif, France
4Department
of surgery and interdisciplinary Medicine, Milano,University Milano-
Bicocca Italy
5Unit
INSERM U10-30, Villejuif France
6University
Paris Sud, Le Kremlin Bicêtre France
Corresponding author: Prof. Philippe Morice, Gustave Roussy, 114 rue EdouardVaillant, 94805 Villejuif. France. E mail: [email protected], Phone: 33.1.42.11.44.39. Fax:
33.1.42.11.52.13.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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1Department
2
Abstract
Since the last two decades, the feasibility of fertility-sparing surgery (FSS) in
early-stage epithelial ovarian cancer has been explored by several teams and is
reconsidered in this systematic review undertaken using the PRISMA guidelines.
Borderline ovarian tumours and non-epithelial ovarian cancers were excluded. This
review comprises 1150 patients and 139 relapsing patients reported by 21 teams.
This conservative treatment can be safely performed for stage IA and IC grade 1 and
2 disease and stage IC1 according to the new FIGO staging system. Nevertheless
confirm whether FSS is safe in this subgroup. For patients with "less favourable"
prognostic factors (grade 3 or stage IC3 disease), the safety of FSS could not be
confirmed but patients should be informed that radical treatment probably may not
necessarily improve their oncological outcome, because the poorest survival
observed could be related to the natural history of the disease itself and not
specifically to the use of conservative therapy. FSS could probably be considered in
stage I clear-cell tumours but should remain contraindicated for stage II/III disease
(whatever the histologic subtype). As the disease stage and the histologic data
(tumour type and grade) are crucial to patient selection for this treatment, this implies
careful and mandatory complete surgical staging surgery in this context and a
pathologic analysis (or review) of the tumour by an expert pathologist.
Key words: Fertility-sparing surgery, conservative treatment, epithelial ovarian
cancer, early stage, recurrence, survival.
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the number of patients reported with grade 2 disease is too small to definitively
3
Key message: Conservative treatment to preserve fertility in ovarian cancer can be
safely performed for stage IA and IC grade 1 and 2 disease and stage IC1 according
to the new FIGO staging system. For patients with "less favourable" prognostic
factors (grade 3, stage IC3 disease, clear cell tumour), the safety of FSS could not be
confirmed but patients should be informed that radical treatment probably may not
necessarily improve their oncological outcome. FSS should remain contraindicated
for stage II/III disease (whatever the histologic subtype).
Fertility-sparing surgery (FSS) of epithelial ovarian cancer (EOC) is based on
unilateral (salpingo-)oophorectomy and complete surgical staging. This empirical
treatment option had initially been proposed to young women presenting with an
early-stage invasive tumour and a low risk of recurrence [1]. The first large series
specifically devoted to this management was published nearly 5 decades ago (mixing
different subtypes of ovarian tumours)[2]. Different publications, initially mixing
different subtypes (EOC and borderline tumours and/or epithelial and non-epithelial
cancers) and more recently specifically dedicated to EOC, have been reported [3-6].
Five years ago, international recommendations were finalized concerning the
indications and modalities for FSS in EOC [7].
Nevertheless, many questions continue to fuel debate and remain unclear
concerning this management. These questions concern oncological outcomes and
fertility issues. The fertility issues will not be covered in the present review most
debatable and strategic (and finally philosophical) questions concern the oncological
issues. We know that the outcomes (recurrence rate and survival) of patients
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Introduction
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undergoing FSS seem to be similar to those following conventional treatment, at least
in patients with stage IA (grade 1 and 2) and stage IC (grade 1) disease [3-6].
However, the current hot topics on oncological issues can be summarized in 4 main
points: 1. The impact of the tumour grade on the risk of recurrence; 2. The
oncological results in the most controversial subgroup of stage IC disease in the light
of the new FIGO staging system, modified in 2014 and now incorporating 3 different
substages of IC disease [8]; 3. The oncological results in stage > I and 4. The
oncological results in “high risk” histologic subtypes, particularly clear-cell ovarian
undertaking a systematic review of the literature and conducting an objective analysis
of our findings.
Data collection
Search Strategy and selection criteria
The design of this systematic review of the literature was in accordance with
the PRISMA guidelines. Data were identified from searches of MEDLINE, Current
Contents, PubMed and from references in relevant articles from 1988 to April 1,
2016, using the following search terms: “early-stage ovarian cancer”, “conservative
surgery”, “conservative treatment”, “fertility-sparing surgery”, “ovarian cancer” and
“ovary”. Only articles published in English were included. For repeated publications
by the same team on a similar topic, the series comprising the largest number of
patients (or the most complete data) was retained. Case reports reporting fewer than
5 cases were not retained (except if they reported stage > I and/or clear cell
tumours). In cases of series reporting mixed histologic subtypes (borderline tumours
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tumours. The aim of this paper was to try to address these 4 questions by
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and EOC or epithelial and non-epithelial cancers or 3 groups of tumours), we
retained papers that reported analysable results specifically in the subgroup of EOC.
Series reporting patients without oncological outcomes were not retained. The
flowchart in Figure I in the supplementary material shows the criteria used for
including and excluding studies. Finally, 39 series were retained and analysed [9-47].
Data extraction and analysis
topics. The analysis comprises patient characteristics (stage, tumour, histologic
subtype) and oncological issues (characteristics of relapsing patients and postrecurrence outcomes). In cases of stage IC disease, when the data were available,
the cases were reclassified according to the 2014 FIGO staging system (IC1, IC2 and
IC3) to determine the recurrence rate in each subgroup. The grading system (and
histologic subtypes) reported in Table 1 and in the paper were those reported at the
time of the publication and not reconverted in the light of the lastly updated
classification for histologic subtypes or of the recommendations for the grading
system [48]. Similarly, concerning clear-cell tumours, series published before 2010
included these lesions among grade 3 tumours (Table 1). In the different recent
series published later, as these tumours were not deemed histologically gradable
(even though clinicians considered them as “high-grade” lesions), they were not
included in the subcolumns, stage IA or IC/grade 3 disease, in Table 1, as in previous
series [35,38]. As the surgical approach (laparotomy or laparoscopy) had no impact
on the oncological issues, the results were not specifically studied according to this
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The corresponding author and the first author extracted all the series on these
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factor. Nevertheless, all the series reporting pure laparoscopic surgery were included
in the review [40,41,42].
Findings
A total of 32 papers written by 21 teams and 7 multicentre studies were
retained (39 articles) and analysed summarizing 1150 patients who had undergone
125 (because of 1 ambiguous stage) in stage I disease and 14 or 15 in stage II or III
disease (Tables 1-4).
The impact of stage IA/IC and the tumour grade on the recurrence rate in stage I
disease (Table 1)
A total of 1110 stage I lesions were included in Tables 1 and 3. The impact of
the histologic and clear-cell subtype will be examined specifically later. Among the
series detailing the clinical substage of the disease, 633 stage IA and 411 stage IC
cases were reported. More marginally, 15 stage IB disease cases were reported.
Among the series that provided details about the disease stage in relapsing patients,
55 (10%) recurrences had occurred among 560 patients with stage IA disease and
58 (16%) recurrences had occurred among 358 patients with stage IC disease (p=
.002).
Among the series that reported details concerning the initial characteristics of
patients and of relapsing patients (substage I and tumour grade), data were available
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FSS (Table 1). One hundred and thirty-nine (12%) recurrences had occurred: 124 or
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for 385 cases of stage IA disease (285 stage IA grade 1, 72 stage IA grade 2 and 28
stage IA grade 3). Among these lesions, 35 recurrences had occurred: 19 (7%) stage
IA grade 1, 8 (11%) stage IA grade 2 and 8 (29%) stage IA grade 3 (p=.0004).
Likewise, data were available for 247 cases of stage IC disease (170 stage IC grade
1, 47 stage IC grade 2 and 30 stage IC grade 3). Among these lesions, 30
recurrences had occurred: 18 (11%) stage IC grade 1, 5 (11%) stage IC grade 2 and
7 (23%) stage IC grade 3 disease (Grade 1+2 vs Grade 3; p= 0.02). As mentioned
above, several series published after 2010, involving 34 cases and 6 relapsing
relapsing patients were not included in the above calculation concerning stage IA or
IC grade 3 disease in Table 1. Among 91 relapsing patients with data concerning the
location of the recurrence, 34 (37%) were an isolated ovarian tumour and 57 (63%)
other sites of recurrence +/- involvement of the remaining ovary (Table 1). At the time
of the publication 72 patients had died of the disease or were alive with persistent
disease (Tables 1 & 3).
Results according to the new FIGO staging system (for stage IC disease)(Table 2)
The 2014 FIGO staging system modified stage IC into 3 new clinically (and
prognostically) more relevant subgroups in the stage I disease category [8]. We
collected 10 different papers, involving 214 patients with stage IC that provided
precise data on the initial subgroups of patients with stage IC (IC1, IC2 and IC3)
Thirty-one recurrences (14%) had occurred in this disease category (Table 2).
Among these 31 recurrences, the substage of the disease was not reported in 2
series (comprising jointly 32 patients with stage IC disease) [28,35]. In one of these 2
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patients considered clear-cell tumours as ungradable [35,38]. Consequently, these 6
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series, the team had mixed stage IC2+3 disease [31,34]. Finally, among the series
that had provided all the data required to perform the calculation, respectively 13 and
17 recurrences had occurred among 108 (12%) and 74 (19%) patients with stage IC1
and IC2+3 disease (p=0.02).
Stage II and III disease – Results (Table 3)
Forty cases of stage II or III disease were collected. In a majority of these
stage II or III disease after (re)staging surgery. Thirteen cases were stage IIA (3), IIB
(6), IIC (3) and undetermined stage II in 1. Twenty-seven cases of stage III disease
were reported: IIIA (7), IIIB (2) and IIIC (18). In this latter subgroup, at least 5 cases
were upstaged to IIIC due to nodal spread without peritoneal spread (stage IIIA1 of
the 2014 FIGO staging system). Among these 40 cases, 15 (38%) recurrences had
occurred. Eleven patients had died or were alive with persistent disease (Table 3).
Clear-cell tumours – Results (Table 4)
The histologic subtypes of the tumours collected in Table 1 (among 1116
cases with available data) were: mucinous n=588 (53%); serous n=203 (18%),
endometrioid n=190 (17%) and clear cell n=97 (9%). Thirty-eight
other/mixed/unknown subtypes (3%) should be added (Table 1). Among the series
which reported complete data on the histologic subtypes in initially treated patients
and in relapsing patients, 49 recurrences had occurred among 513 mucinous
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patients the tumour was initially confined to the ovary but was finally modified to
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tumours (10%), 25 among 165 serous (15%), 23 among 174 endometrioid (13%) and
19 among 88 (22%) clear-cell tumours (p=.007).
A total of 116 clear-cell tumours had been reported (98 are also presented in
Table 1, but 18 were added in the updated version of one previously published paper
[27,44])(Table 4). All but 1 of these tumours were stage I (but the stage is uncertain
for 27 clear-cell tumours). Among these 115 cases with specific data on the followup, 19 (17%) recurrences had occurred (Table 4). Among these 19 relapsing
had metastatic (extra-ovarian disease)(87%) and 2 had an ovarian (13%) recurrence
(this rate is statistically significant compared to the rate of ovarian/extra-ovarian
recurrences in the overall population; p< 0.0003). Eleven patients had died of the
disease or were alive with persistent disease.
Discussion
The results of this systematic review raised the main question of the selection
criteria for FSS in EOC. These criteria were strongly and firstly related to the
prognostic factors for recurrences in this context (a possible higher recurrence rate
due to the use of a conservative treatment compared to conventional treatment
[radical surgery]). No phase II randomized or phase III study comparing both
treatment modalities has been conducted to demonstrate that survival is totally
similar for early-stage EOC. Several of the previously published retrospective series
compared conservative and radical treatment but found no significant differences in
survival [16,32,33,39,44]. Yet such comparisons are sometimes unreliable from a
statistical and methodological point of view because firstly, in series comparing
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patients, the location of the recurrent disease was available in 15. Thirteen patients
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conservative and conventional treatment, patients selected for FSS tend to have a
better prognosis than patients treated according to the standard of care. Comparing
recurrence and survival rates between these two groups would therefore lead to a
potential bias. Secondly, the number of patients evaluated for FSS may be too small
to detect a difference in the prognosis of patients with similar oncological prognostic
factors (substage I, histologic type and tumour grade). If the two treatment modalities
are compared in a retrospective analysis, the number of patients required to confirm
the reliability of this calculation is critical. The analysis of the SEER (Surveillance,
IA or IC disease had no impact on survival [49]. But as stated by the authors, “to
detect a 20% difference in survival for patients with stage IC disease, a cohort of
1282 patients with 52 deaths is required”.
Nevertheless, even if this number of patients had never been reached in any
of the previous series, the current systematic review gathered more than 1,000 cases
of FSS published and thus seems to confirm the safety of this modality (meaning the
absence of an increased rate of recurrence specifically due to the use of a
conservative surgical procedure), at least in patients with stage I A/C and grade 1/2
disease. The recurrence rates reported in these subgroups were 7% in stage IA
grade 1 and 11% in stages IA grade 2 and IC grade 1/2 disease, so very close, or
similar, to the rates observed after radical surgery. This review confirms the safety
and the validity of FSS in young patients eligible for fertility-sparing management.
Nevertheless, the number of patients with IA and IC grade 2 disease (respectively 72
and 47) is too small to definitively confirm whether FSS is safe in this subgroup.
Can this management be safely extended to stage I (A or C) grade 3 disease?
Our review confirms that the risk of recurrence is increased in such cases compared
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Epidemiology and End Results) database reported that ovarian preservation in stage
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to patients with grade 1 or 2 disease. Nevertheless, in these patients, the risk of an
ovarian recurrence in currently “debatable” indications for FSS is lower compared to
extra-ovarian recurrences that occur more frequently and are less amenable to
surgical cure when they arise whereas in stage IA disease (a good indication for
FSS), isolated ovarian recurrences are more common and are also more curable
[21,22]. In the case of grade 3 tumours, 95% of the recurrences were extra-ovarian
(and only 22% of them were rendered disease free) [22]. If the potential recurrences
are less curable this could challenge the validity of these “debatable” indications.
is thus one of the limits of the oncological indication [4,5,20,22]. On the other hand, if
the recurrences are more frequently extra-ovarian, this could signify that the
preservation of one ovary is not necessarily the cause of the recurrence. Extraovarian relapses could then be related to the natural history of the disease and to the
presence of “intermediate” or the “poorest” prognostic factors (grade 3) or to ovarian
preservation itself. Thus, from this standpoint, some teams consider that the use of a
conservative approach would not be questioned even in these cases [12-15].
A similar attitude could be considered concerning the second question of the use
of FSS in patients with stage IC disease and the new FIGO staging system. Our
study confirms that the recurrence rate is acceptable (and seems to be similar to that
observed with conventional treatment) for preoperatively ruptured stage IC1 tumours
(half of these recurrences were isolated on the remaining ovary) (Table 3). However,
the recurrence rates are higher (23%) in stages IC2 + IC3 disease. As mentioned
above concerning grade 3 disease, it is unclear whether such recurrences are related
to the natural history of the disease (grade 3 and/or stage IC grade 2 and/or stage
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That is why, some teams consider that FSS is unsafe in stage I grade 3 disease and
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IC3 disease) or to the use of fertility-sparing surgery itself. We cannot solve these
endless and inextricable discussions in this paper.
In theory, a randomised trial should be performed to compare FSS and radical
surgery in patients with “high-risk” early-stage EOC in order to validate this practice.
However, it would not be ethical to propose radical treatment to young patients of
childbearing age because many studies have reported that FSS is safe in selected
cases. Furthermore, EOC is a rare disease and a randomised trial is technically
unachievable because it would be necessary to accrue a large number of patients in
used in such a trial). Nevertheless, a prospective non-randomized trial (JCOG1203;
UMIN00013380) is currently on-going in Japan in ”high risk” disease (stage IC and/or
stage IA clear-cell disease) and will probably provide us with more robust data in the
future [12-15]. While awaiting these results, we have two options: to use “the
precautionary principle” in these “uncertain” indications (stage IA grade 3 or stage
IC3 disease) and remove both ovaries (but leave the uterus in place for a subsequent
potential pregnancy using an ovum donation) or to “respond” to the enquiry of the
patient/couple and to use FSS with a “wait and see” policy. Nevertheless, in these
“debated oncological indications”, the age of the patient, and the ovarian reserve
(which should then be evaluated) need to be taken into account because
pragmatically, we do not need to take a “potential” risk of recurrence using FSS in
this context in a patient aged 37/38 or 39 years with a poor ovarian reserve (and thus
a very limited likelihood of spontaneous fertility).
As we know since a decade that the fallopian tubes are in fact the initial site of
“ovarian” tumours, particularly in high-grade serous carcinoma, another potential
theoretical option, akin to FSS, could be a bilateral salpingectomy but leaving both
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order to observe a statistical difference in survival (even if a non-inferiority design is
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ovaries in place that could potentially be used later for In Vitro Fertilization.
Nevertheless, this interesting concept could not be used in epithelial cancer because
ovarian hyperstimulation remains contraindicated in patients treated conservatively
for a previous malignant epithelial tumour.
Our review included the study of patients with stage II and III disease. Among
40 cases reported, the rate of recurrence was 38% (15/40). As mentioned earlier, we
contend that this recurrence rate seems to be close to that observed after
conventional management of stage II/III disease. Yet, a majority of patients among
than other stage III lesions. In our opinion, it is unsafe to use FSS in stage II and III
EOC. As the disease stage is critical for selecting patients for FSS, complete staging
surgery (including lymphadenectomy except for mucinous tumours) would be
imperatively included during the initial staging work-up or the restaging procedure
[51].
The last question raised is the impact of the histologic subtype on the
recurrence rate. The mucinous subtype was the most common (53%) reported. That
is logical because these tumours frequently arise in young patients and with a high
rate of disease confined to the ovary (stage I disease) explaining a higher rate of
such cases in patients eligible for FSS. This also explains a trend towards a lower
rate of recurrence in mucinous tumours compared to other subtypes. Recently,
mucinous tumours were divided into 2 separate subtypes: expansile (the most
common) and infiltrative (exhibiting a higher rate of nodal spread and the poorest
prognosis)[48]. This new classification should be used systematically in the case of
“mucinous carcinoma”. Nevertheless, we found no data in the current review (or other
series) on the results of conservative treatment in both subtypes (expansile and
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these 40 cases had stage IIA/B, IIIA2 or stage IIIA1 disease with a better prognosis
14
infiltrative mucinous tumours). Anyway, as the histologic subtype (and the tumour
grade) is a key issue in the selection of patients for FSS, a pathologic review of the
slide by an expert pathologist should be done before validating this management.
The centralization and/or review of the pathologic slides of the tumour is also a
quality assurance measure of the reliability of the interpretation of the series on the
conservative approach in epithelial tumours, in order to be certain that borderline
tumours or non-epithelial cancers will not be mixed in studies “officially” focused on
EOC, since the overall prognosis of these 2 latter subgroups is better than that of
FSS spanning a long time period, because such management is not so widespread,
the criteria for selecting patients distinguishing borderline tumours from true EOC
could have varied over time given the evolution of selection criteria and the
histological classifications of EOC. That is why, from our point of view, a pathologic
review of the slides (even in the case of patients treated in the same institution and
sometimes with the same pathologist) is a quality criterion. Table 1 summarizes this
pathologic review (centralized or not in multicentre studies) and about 21 teams
reported their results, eleven clearly stating this quality indicator (Table 1).
In fact, the hottest topic in terms of histologic subtypes for FSS is the case of
clear-cell tumours. Historically, these tumours had been considered as high-grade
lesions and thus ineligible for FSS. Yet, when we reviewed the different series
published, 116 FSS procedures for clear-cell tumours had been reported (in a
majority of cases for stage I disease). The recurrence rate was 17% (19 cases). This
rate seems as to be “oncologically” acceptable and so we can probably accept to
extend FSS even for stage I clear-cell tumours. Two series compared the survival of
patients with a clear-cell tumour according to the type of surgical treatment
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epithelial cancer. Furthermore, in the same team in retrospective series dedicated to
15
(conservative/radical) without demonstrating any difference in disease-free and
overall survival [44,46]. Nevertheless, as mentioned above, such analyses should be
interpreted with caution because the number of patients studied could be too small to
detect a possible statistically significant difference between the two treatments.
Anyway, more than 100 cases of conservative treatment had been reported in this
context with a “similar”, or very close recurrence rate to that observed after
conventional management. Among 19 relapsing patients, information was available
on the use (or not) of adjuvant chemotherapy during the initial management of the
recommendations initially made by several teams, FSS seems to be potentially
considered in patients with a stage I A/C clear-cell tumour, we should integrate two
key pieces of information about the time to recurrence. Among 19 relapsing patients,
the time to the 1st recurrence was reported in 16 cases: 2 patients had relapsed
within the 6 months after FSS, 6 between 6 and 12 months, 7 between 12 and 24
months and only 1 after 24 months. This means that relapsing patients in this
subgroup of clear-cell tumours had developed a recurrence very early, within the first
2 years after the initial treatment. The other key piece of information is the location
and prognosis of relapsing patients. This information was available for 15/19
relapsing patients. Among them, 13 had an extra-ovarian recurrence and 11 patients
had died or were alive with disease. This means that these patients have a high risk
of an extra-ovarian and lethal relapse. These 2 facts had a pragmatic impact on the
management of patients. Although this will not render doubtful the potential validity of
conservative management, as a recurrence may arise shortly and will then have a
poor prognosis, we should not “authorize” the patient/couple to attempt a potential
pregnancy before 2 years after FSS in clear-cell disease if we do not want to be
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clear-cell tumour in 16 cases and all but 3 received it. Even if, contrary to the
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faced with the diagnosis of a metastatic recurrence in a pregnant patient.
Finally, having discussed all these potential criteria for selecting patients with
EOC for FSS, how many patients could be involved ? Huber et al. focused recently
on this question and showed that in a local registry (Geneva) comprising 888 EOC,
only 1.2% would be potentially eligible for FSS [52]. A similar study had been
undertaken a decade ago by Sonoda et al. for cervical cancer. They estimated with
hindsight that nearly half of the patients below 40 years of age who had undergone a
radical hysterectomy would have been eligible for FSS [53]. Even if this rate depends
this conservative approach, these studies show that this discussion concerns a
minority of patients affected by EOC. This strategy is also an emblem of the progress
achieved in surgical treatment allowing this selected subgroup involving few patients
to have access to fertility preservation.
Conclusions
The management of patients with early EOC eligible for FSS should be
multidisciplinary. The histological review of the ovarian tumour and surgical staging
should be done by experienced teams. This conservative treatment can be safely
performed in stage IA and IC grade 1 and 2 disease and stage IC1 according to the
2014 FIGO staging system. Nevertheless the number of patients reported with grade
2 disease is too small to definitively confirm whether FSS is safe in this subgroup. For
patients with "less favourable" prognostic factors (grade 3 or stage IC3 disease), the
safety of FSS could not be confirmed. However, patients should be informed that
radical surgery may not necessarily improve their oncological outcome, because the
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on the local recruitment of cases and the criteria finally retained to select patients for
17
poorest survival observed is related to the natural history of the disease and not
specifically to the use of a conservative treatment. FSS could probably be considered
for stage I clear-cell tumours but should remain contraindicated in stage II/III disease
(whatever the histologic subtype).
Acknowledgments
The authors wish to thank Ms. Lorna Saint Ange for editing.
None declared.
Conflict of interest
The authors declare no conflict of interest related to this study.
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Funding
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44. Park JY, Suh DS, Kim JH et al. Outcomes of fertility-sparing surgery among
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Obstet. 2016 Mar 11. pii: S0020-7292(16)30006-6.
45. Kajiyama H, Shibata K, Suzuki S et al. Is there any possibility of fertility-sparing
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Fertility-sparing surgery in patients with clear-cell carcinoma of the ovary: Is it
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ovarian cancer patients are eligible for fertility-sparing surgery? Eur J Obstet Gynecol
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Table 1. Literature review of patient characteristics and oncological outcomes after Fertility-Sparing Surgery in stage I Epithelial
Ovarian Cancer (series including > 5 cases).
Authors-Years
9
Miyazaki 1988
n pts
Stage
n pts
Pathology
review
Grade
n pts
Histology*
n pts
Staging n**
Recurrence (n)
Stage,
histology in
relapsing pts
Stage IA G1
n rec, n tot
Stage IA G2
n rec, n tot
Stage IA G3
n rec, n tot
Stage IC Grade 1
n rec, n tot
Stage IC G2
n rec, n tot.
Stage IC
G3
n rec, n tot
Location
recurrence
Isolated
ovary/Other
Outcomes
Follow up
(months)
18
I
No
NS
S4
M 12
E1
CC 1
NS
2
(1 IB, 1 IC
NS
NS
NS
NS
NS
NS
NS
2 DOD
NS
G1
141***
G2 70
G3 29
S 62***
M 99
E 60
CC 17
Unk 2
112
7/84
2/31
5/15
6/54
4/37
2/14
12/14
14 NED, 1
AWD, 11 DOD
FU 108 mths
G1
36***
G2 24
G3 9
Unk 1
S 18***
M 36
E8
CC at least 1
Other 7
All
2/?
0/?
1?
0/?
1/?
0/?
2/2
3 NED, 1 AWD
FU 76 mths
NS
NS
NS
NA
NA
Colombo 1994, 2005
Zanetta 1997
10-13
Fuscio 2010
237
Raspagliesi 1997,
14-16
Ditto 2014, 2015
63
17
IA 130
IB 2
IC
105
Yes
IA 46
IB 2
IC 15
No
1 S, 1 M)
26
(14 IA, 12 IC
10 S, 8 M,
6 E, 2 CC)
At least 4****
(3 IA, 1 IC
1 M, 2 E, 1 CC)
10
NS
No
NS
S6
M2
E1
Other 1
NS
0
NS
NS
NS
18
11
IA 6
IC 5
No
NS
S2
M8
E1
NS
3 (3 IC M)
0
0
0
3
0
0
2/1
3 DOD
FU 51 mths
Morice 2001, 2005
Marpeau 2008
19-22
Bentivegna 2015
33
IA 30
IC 3
Yes
G1 15
G2 14
G3 4
S3
M 21
E2
Other 3
All
10****
(7 IA, 3 IC
2 S, 5 M, 1 E,
1 CC, 1 Mixed)
2/13
4/14
1/3
2/2
0
1/1
5/6
4 NED, 2 AWD,
3 DOD, 1
Unknown
FU 47 mths
52
IA 42
IC3
10
Yes
G1 38
G2 9
G3 5
S 10
M 25
E 10
CC 5
Other 2
All
5
(4 IA, 1 IC
2/33
2/6
0/3
0/5
1/3
0/2
3/2
3 NED, 2 DOD
FU 68 mths
S1
M8
E5
CC 2
All
2/11
0/0
0/0
0/3
0/1
0/1
0/2
1 NED, 1 DOD
FU 96 mths
Gonzalez-Lira 1997
Jobo 2000
Schilder 2002
23
Sardi 2005
24,25
Anchezar 2009
16
IA 11
IC 5
Yes
G1 14
G2 1
G3 1
1 S, 2 M, 1 E,
1 Mixed)
2
(2 IA,
1 S, 1 E)
Park 2008
27
11
IA 10
IC 1
Yes
G1 9
G2 1
G3 1
S2
M8
E1
In 7
1 (IC M)
0/9
0/1
0/0
59
IA 36
IB 2
IC 21
Yes
G1
48***
G2 5
G3 9
S 7***
M 41
E8
CC 4
Other 2
All
9
(5 IA, 4 IC
1/29
0/3
4/4
5 M, 1 E, 2 CC,
1 Mixed)
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26
Borgfeld 2007
0/0
0/0
1/1
0/1
1 DOD
FU 92 mths
1/15
1/2
2/4
1/8
2 NED, 3 AWD,
4 DOD
FU 56 mths
NS
NS
NS
NS
NS
FU 43 mths
NS
NS
NS
NS
1 AWD
FU 20 mths
NS
2NS
NS
3/0
3 DOD
FU 122 mths
NS
NS
NS
NS
11 DOD
FU 66 mths
28
Kwon 2009
21
IA 17
IC 4
No
G1 16
G2 3
G3 2
S1
M 16
E2
CC 3
In 14
1 (IC G1)
NS
NS
NS
29
Muzii 2009
9
NS
Yes
NS
S4
M3
E2
CC 2
All
1 (IC)
NS
NS
NS
20
IA 11
IC 9
Yes
G1 14
G2 5
G3 1
S1
M 11
E6
CC 1
Unk 1
In 18
3 (2 IC & 1 IA)
& 1 uterine
cancer****
NS
NS
NS
94
IA 43
IC 51
Yes
G1 59
G2 14
G3 4
(CC 17)
S3
M 52
CC 17
E 21
Other 1
In 14
14
(5 IA & 9 IC,
NS
NS
NS
G1 95
G2 13
G3 3
(CC 30)
S 27
M 126
E 27
CC 30
Other 1
In 86
(omentectomy)
5/95
0/13
2/3******
5/65
0/2
1/3******
5/13
8 NED, 5 AWD,
5 DOD
FU 78 mths
Schlaerth 2009
30
Kajiyama 2010, 2011a,
31-34
2011b, 2014
35
Satoh 2010
36
Hu 2011
Cheng 2011
37
38
Kashima 2013
211
IA 126
IC 85
Yes
3 S, 4 M, 4 E, 3
CC)
18
(7 IA, 11 IC
3 S, 6 M,
4 E, 5 CC)******
82
IA 46
IB 8
IC 28
Yes ?
G1 57
G2 10
G3 1
Unk/CC
14
S 31
M 32
E5
CC 3
Other 11
94
1 in stage I
NS
NS
NS
NS
NS
NS
NS
0 in stage I
FU 132 mths
16
IA 10
IC 6
Yes
G1 4
G2 2
S 1***
M 13
E1
Other 2
All
1 (IC Mixed)
0/9
0/1
0/0
1/5
0/1
0/0
0/1
0
FU 61 mths
18
IC 18
No
G1 14
CC 4
S2
M9
E3
CC 4
In 15
5
(1 S, 3 M, 1 CC)
0/0
0/0
0/0
4/14
0/0
0/0******
1/4
1 NED, 4 DOD
FU 78 mths
34
IA 21
IC 13
No
G1
27***
G2 5
G3 1
Unk. 2
All M
In 12
(omentectomy)
5 or 6
(1 stage II?)
NS
NS
NS
Cromi 2014,
61
IA 42
IB 1
IC 18
No
G1
38***
G3 19
G3 8
S 15 ***
M 25
E 21
CC 3
Other 1
All
10
(7 IA, 1 IB, 2 IC
3 S, 4 M, 3 E)
NS
NS
NS
16
IA 6
IC 12
(2
IIIA1)
No
G1 9
G2 4
G3 5
S3
M7
E5
CC 3
11
(omentectomy)
0 in stage I
0/2
0/3
0/0
40,41
Ghezzi 2015
Park 2016
Total
42
1092*******
121 or 122
(11%)
(1 st. > I?)
19/285 (7%)
*: S: Serous; M: Mucinous; E: Endometrioid; CC: Clear Cell; Unk: Unknown;
8/72 (11%)
8/28 (29%)
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39
Lee 2015
NS
NS
NS
1/ 4 or 5
NS
FU 104 mths
NS
NS
NS
NS
1 DOD
FU 38 mths
0/7
0/1
0/4
NS
0
FU 47 mths
18/170 (11%)
5/47 (11%)
**: Complete staging definition varied in different series. In cases of incomplete data, patients having at least an omentectomy were considered as having “staging” surgery
***: Data incomplete stage > I disease;
****: The characteristics of relapsing patients were detailed in the 2nd publication involving 18 conservative procedures; ****: 1 patient had a recurrence in the form of borderline disease
*****: 1 patient had a recurrence in the form of a secondary uterine cancer. She is not included in the results
******: Clear- cell recurrence(s) was/were not included because these lesions were not graded in this series
*******: 18 CC tumours reported by Park et al. separately in a specific updated paper and 40 stage II/ III , should be added to these 1092 stage I cases, resulting in a total of 1150 patients
NS: Not Stated; NED: No Evidence of Disease; DOD: Died of Disease; AWD: Alive with Persistent Disease; mths: months
7/30 (23%)
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Table 2. Literature review of oncological outcomes after Fertility-Sparing Surgery in stage IC Epithelial Ovarian Cancer according to
the FIGO 2014 staging system.
Authors-Years
n pts
Recurrence
(n)
Stage IC1
n rec, n tot
Stage IC2
n rec, n tot.
Stage IC3
n rec, n tot
Location recurrence
DOD & AWD (n)
5
3
0/0
3/5
0/0
2 ovary, 1 lung
3 DOD
23
10
1
0/0
0/0
1/10
ovary
26
Borgfeld 2007
1
1
0/0
0/0
1/1
Peritoneum
28
Kwon 2009
4
1
?/3
0/0
?/1
NS
51
9
3/31
35
Satoh 2010
85
11
7/55
2/18
2/12
3 ovary, 8 peritoneum
and/or nodes and/or liver
3 NED, 4 AWD, 4 DOD
36
Hu 2011
28
?
?/9
?/6
?/13
NS
NS
38
Kashima 2013
18
5
3/11
1/3
1/4
1 ovary, 2 nodes, 1
peritoneum, 1 brain
4 DOD, 1 NED
12
0
0/11
0/1
0/0
NA
NA
214
31 (14%)
13/108 (12%)
Jobo 2000
18
Schilder 2002
Kajiyama 2010, 2014
Park 2016
Total
42
31,34
6/20
6/27 (22%)
NS
NED
DOD
NS
NS
5/27 (19%)
IC2+3= 17/74 (23%)
NS: Not Stated; NA: Not Applicable; NED: No Evidence of Disease; AWD, Alive with Persistent Disease; DOD: Died of Disease; mths: months
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Table 3. Literature review of patient characteristics and oncological outcomes after Fertility-Sparing Surgery in stage II and II
disease.
Authors-Years
n pts
Stage
(FIGO 1987)
Histology
Grade
Recurrence
Time to
recurrence
months
Location
recurrence
Outcomes
Colombo 1994, 2005
10,12,13
Fuscio 2010
3
I IIA, 2 IIB
At least 1 serous
At least 1 G1
1 recurrence
151
Ovary
NED
Raspagliesi 1997,
14-16
Ditto 2015
7
1 IIA, 1 IIC, 5 IIIC
At least 4 serous
2 mucinous
At least 3 G1, 2
G2
No recurrence
for 6 pts
NA
NA
NA
19
Morice 2001
2
1 IIA, I IIB
At least 1 mixed in 1
At least 1 G 2
1 recurrence
5
Ovary &
peritoneum
DOD 16 mths
3
1 IIB, 1 IIIA, 1 IIIC
At least 2 mucinous
At least 1 G1, 1
G3
2
8, 10
1 ovary & perit.
1 nodes & lung
2 DOD 10, 16
mths
25
Anchezar 2009
2
2 IIIB
1 serous, 1
mucinous
1 G1, 1 G2
1
14
Ovary
NED 38 mths
29
Muzii 2009
2
1 IIB, I IIIA
NS
NS
No recurrence
NA
NA
NA
36
Hu 2011
12
1 II, 4 IIIA, 7 IIIC
3 serous, 2
mucinous, 4
endometrioid,
1 clear-cell, 1 mixed
7 G1, 3 G2,
2 unknown
8
7, 22, 24, 24, 26
Unknown for 3
1 ovary, 4
peritoneum, 3
unknown
4 DOD, 3 AWD
1
IIIA
NS
NS
No recurrence
NA
NA
NA
43
Petrillio 2013
1
IIC
Endometrioid
G2
No recurrence
NA
NA
NA
39
Lee 2015
1
1 IIC
NS
NS
1 Recurrence ?
NS
NS
NS
Cromi 2014,
4
1 IIB, 3 IIIC
(IIIC due to nodal spread)
NA
NA
No recurrence
NA
NA
NA
2
2 IIIC (due to nodal
spread)
2 serous
1 G2, 1 G3
1
NA
Peritoneum, liver
& nodes
AWD
44 mths
Park 2008
27
Cheng 2011
37
40,41
Ghezzi 2015
Park 2016
Total
42
40
15 (38%)
NS: Not Stated; NA: Not Applicable; NED: No Evidence of Disease; AWD: Alive with Persistent Disease; DOD: Died of Disease; mths: months
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Table 4. Literature review of patients undergoing Fertility-Sparing Surgery for Clear-Cell ovarian tumours.
Authors-Years
n pts
Stage (n)
Pathology
review
Recurrence (n)
Location recurrence
Outcomes
7
Miyazaki 1988
1
I
No
No recurrence
NA
NA
Colombo 1994 Zanetta 1997,
10,11,13
Fuscio 2010
17
All stage I?
Yes
2
2 Peritoneum
1 NED, 1 DOD
1
IA
No
1
Ovary
NED
1
IA
Yes
1
Metastatic
AWD
5
NS
Yes
No recurrence
NA
NA
2
IA 1, IC 1
Yes
No recurrence
NA
NA
22
IA 12, IC 10
No
5 (3 IA & 2 IC)
All metastatic +/- ovary
2 NED, 1 AWD,
2 DOD
28
Kwon 2009
3
I
No
No recurrence
NA
NA
29
Muzii 2009
2
NS
Yes
No recurrence
NA
NA
1
I
Yes
NS
NS
NS
17
IA 7*
IC 9
Yes
3
NS
NS
35
Satoh 2010
30
I
Yes
5 (all stage IC)
1 ovary, 4 peritoneum,
nodes or liver
1 NED, 3 AWD,
1 DOD
36
Hu 2011
4
3 I, 1 IIIA
Yes ?
At least 1
NS
At least 1 DOD
38
Kashima 2013
4
All IC
No
1
Nodes
DOD
41
Ghezzi 2015
3
NS
No
No recurrence
NA
NA
3
3 IC
No
No recurrence
NA
NA
Raspagliesi 1997, Ditto 2014
14,15
19,20
Morice 2001, 2005
Schilder 2002
23
24,25
Sardi 2005 Anchezar 2009
Park 2008, Park 2016
Schlaerth 2009
27,44
30
Kajiyama 2010, 2011a,
31,32,34,45-47
2011b, 2011 c, 2014a, 2014b
Park 2016
Total
42
116
19/115 (17%)
*: Results given in the series published in 2011 including 16 cases
NS: Not Stated; NA: Not Applicable; NED: No Evidence of Disease; AWD: Alive with Persistent Disease; DOD: Died of Disease; mths: months