Abstract

Since the last two decades, the feasibility of fertility-sparing surgery (FSS) in early-stage epithelial ovarian cancer (EOC) has been explored by several teams and is reconsidered in this systematic review undertaken using the PRISMA guidelines. Borderline ovarian tumours and non-EOCs were excluded. This review comprises 1150 patients and 139 relapsing patients reported by 21 teams. This conservative treatment can be safely carried out for stage IA and IC grade 1 and 2 disease and stage IC1 according to the new 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, 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 pathological analysis (or review) of the tumour by an expert pathologist.

introduction

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 five 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 finalised 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, we focused the analysis on most debatable and strategic (and finally philosophical) questions concern the oncological issues. We know that the outcomes (recurrence rate and survival) of patients 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 summarised in four main points: (i) the impact of the tumour grade on the risk of recurrence; (ii) 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 three different substages of IC disease [8]; (iii) the oncological results in stage I and (iv) the oncological results in ‘high risk’ histologic subtypes, particularly clear-cell ovarian tumours. The aim of this paper was to try to address these four questions by 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 1 April 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 five 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 and EOC or epithelial and non-epithelial cancers or three 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 supplementary Figure S1, available at Annals of Oncology online, shows the criteria used for including and excluding studies. Finally, 39 series were retained and analysed [9–47].

data extraction and analysis

The corresponding author and the first author extracted all the series on these topics. The analysis comprises patient characteristics (stage, tumour, histologic subtype) and oncological issues (characteristics of relapsing patients and post-recurrence 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 (Table 2). 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 factor. Nevertheless, all the series reporting pure laparoscopic surgery were included in the review [40–42].

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 n pts Stage (n pts) Pathology review Grade (n pts) Histologya (n pts) Staging nb 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 G1 (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 
Miyazaki 1988 [918 No NS S 4
M 12
E 1
CC 1 
NS 2 (1 IB, 1 IC, 1 S, 1 M) NS NS NS NS NS NS NS 2 DOD
NS 
Colombo 1994, 2005, Zanetta 1997, Fuscio 2013 [10–13237 IA 130
IB 2
IC 105 
Yes G1 141c
G2 70
G3 29 
S 62c
M 99
E 60
CC 17
Unk 2 
112 26 (14 IA, 12 IC, 10 S, 8 M, 6 E, 2 CC) 7/84 2/31 5/15 6/54 4/37 2/14 12/14 14 NED, 1 AWD, 11 DOD
FU 108 months 
Raspagliesi 1997, Ditto 2014, 2015 [14–1663 IA 46
IB 2
IC 15 
No G1 36c
G2 24
G3 9
Unk 1 
S 18c
M 36
E 8
CC at least 1
Other 7 
All At least 4d (3 IA, 1 IC, 1 M, 2 E, 1 CC) 2/? 0/? 1? 0/? 1/? 0/? 2/2 3 NED, 1 AWD
FU 76 months 
Gonzalez-Lira 1997 [1710 NS No NS S 6
M 2
E 1
Other 1 
NS NS NS NS NS NS NS NA NA 
Jobo 2000 [1811 IA 6
IC 5 
No NS S 2
M 8
E 1 
NS 3 (3 IC M) 2/1 3 DOD
FU 51 months 
Morice 2001, 2005
Marpeau 2008
Bentivegna 2015 [19–22
33 IA 30
IC 3 
Yes G1 15
G2 14
G3 4 
S 3
M 21
E 2
Other 3 
All 10d (7 IA, 3 IC
2 S, 5 M, 1 E,
1 CC, 1 Mixed) 
2/13 4/14 1/3 2/2 1/1 5/6 4 NED, 2 AWD, 3 DOD, 1 Unknown
FU 47 months 
Schilder 2002 [2352 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, 1 S, 2 M, 1 E, 1 Mixed) 2/33 2/6 0/3 0/5 1/3 0/2 3/2 3 NED, 2 DOD
FU 68 months 
Sardi 2005
Anchezar 2009 [24, 25
16 IA 11
IC 5 
Yes G1 14
G2 1
G3 1 
S 1
M 8
E 5
CC 2 
All 2 (2 IA, 1 S, 1 E) 2/11 0/0 0/0 0/3 0/1 0/1 0/2 1 NED, 1 DOD
FU 96 months 
Borgfeld 2007 [2611 IA 10
IC 1 
Yes G1 9
G2 1
G3 1 
S 2
M 8
E 1 
In 7 1 (IC M) 0/9 0/1 0/0 0/0 0/0 1/1 0/1 1 DOD
FU 92 months 
Park 2008 [2759 IA 36
IB 2
IC 21 
Yes G1 48c
G2 5
G3 9 
S 7c
M 41
E 8
CC 4
Other 2 
All 9 (5 IA, 4 IC, 5 M, 1 E, 2 CC, 1 mixed) 1/29 0/3 4/4 1/15 1/2 2/4 1/8 2 NED, 3 AWD, 4 DOD
FU 56 months 
Kwon 2009 [2821 IA 17
IC 4 
No G1 16
G2 3
G3 2 
S 1
M 16
E 2
CC 3 
In 14 1 (IC G1) NS NS NS NS NS NS NS NS
FU 43 months 
Muzii 2009 [29NS Yes NS S 4
M 3
E 2
CC 2 
All 1 (IC) NS NS NS NS NS NS NS 1 AWD
FU 20 months

 
Schlaerth 2009 [3020 IA 11d e
IC 9 
Yes G1 14
G2 5
G3 1 
S 1
M 11
E 6
CC 1
Unk 1 
In 18 3 (2 IC and 1 IA) and 1 uterine cancerd NS NS NS NS 2NS NS 3/0 3 DOD
FU 122 months 
Kajiyama 2010, 2011a, 2011b, 2014 [31–3494 IA 43
IC 51 
Yes G1 59
G2 14
G3 4 (CC 17) 
S 3
M 52
CC 17
E 21
Other 1 
In 14 14 (5 IA and 9 IC, 3 S, 4 M, 4 E, 3 CC) NS NS NS NS NS NS NS 11 DOD
FU 66 months 
Satoh 2010 [35211 IA 126
IC 85 
Yes G1 95
G2 13
G3 3 (CC 30) 
S 27
M 126
E 27
CC 30
Other 1 
In 86 18 (7 IA, 11 IC, 3 S, 6 M, 4 E, 5 CC)f 5/95 0/13 2/3f 5/65 0/2 1/3f 5/13 8 NED, 5 AWD, 5 DOD
 FU 78 months 
Hu 2011 [3682 IA 46
IB 8
IC 28 
Yes ? G1 57
G2 10
G3 1
Unk/CC 14 
S 31
M 32
E 5
CC 3
Other 11 
94 1 in stage I NS NS NS NS NS NS NS 0 in stage I
FU 132 months 
Cheng 2012 [3716 IA 10
IC 6 
Yes G1 4
G2 2 
S 1c
M 13
E 1
Other 2 
All 1 (IC mixed) 0/9 0/1 0/0 1/5 0/1 0/0 0/1 0
FU 61 months 
Kashima 2013 [3818 IC 18 No G1 14
CC 4 
S 2
M 9
E 3
CC 4 
In 15 5 (1 S, 3 M, 1 CC) 0/0 0/0 0/0 4/14 0/0 0/0f 1/4 1 NED, 4 DOD
FU 78 months 
Lee 2015 [3934 IA 21
IC 13 
No G1 27c
G2 5
G3 1
Unk. 2 
All M In 12 5 or 6 (1 stage II?) NS NS NS NS NS NS 1/ 4 or 5 NS
FU 104 months 
Cromi 2014, Ghezzi 2016 [40, 4161 IA 42
IB 1
IC 18 
No G1 38c
G3 19
G3 8 
S 15c
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 NS NS NS NS 1 DOD
FU 38 months 
Park 2016 [4216 IA 6
IC 12 (2 IIIA1) 
No G1 9
G2 4
G3 5 
S 3
M 7
E 5
CC 3 
11 0 in stage I 0/2 0/3 0/0 0/7 0/1 0/4 NS 0
FU 47 months 
Total 1092g      121 or 122 (11%)
(1st > I?) 
19/285 (7%) 8/72 (11%) 8/28 (29%) 18/170 (11%) 5/47 (11%) 7/30 (23%)   
Authors, years n pts Stage (n pts) Pathology review Grade (n pts) Histologya (n pts) Staging nb 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 G1 (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 
Miyazaki 1988 [918 No NS S 4
M 12
E 1
CC 1 
NS 2 (1 IB, 1 IC, 1 S, 1 M) NS NS NS NS NS NS NS 2 DOD
NS 
Colombo 1994, 2005, Zanetta 1997, Fuscio 2013 [10–13237 IA 130
IB 2
IC 105 
Yes G1 141c
G2 70
G3 29 
S 62c
M 99
E 60
CC 17
Unk 2 
112 26 (14 IA, 12 IC, 10 S, 8 M, 6 E, 2 CC) 7/84 2/31 5/15 6/54 4/37 2/14 12/14 14 NED, 1 AWD, 11 DOD
FU 108 months 
Raspagliesi 1997, Ditto 2014, 2015 [14–1663 IA 46
IB 2
IC 15 
No G1 36c
G2 24
G3 9
Unk 1 
S 18c
M 36
E 8
CC at least 1
Other 7 
All At least 4d (3 IA, 1 IC, 1 M, 2 E, 1 CC) 2/? 0/? 1? 0/? 1/? 0/? 2/2 3 NED, 1 AWD
FU 76 months 
Gonzalez-Lira 1997 [1710 NS No NS S 6
M 2
E 1
Other 1 
NS NS NS NS NS NS NS NA NA 
Jobo 2000 [1811 IA 6
IC 5 
No NS S 2
M 8
E 1 
NS 3 (3 IC M) 2/1 3 DOD
FU 51 months 
Morice 2001, 2005
Marpeau 2008
Bentivegna 2015 [19–22
33 IA 30
IC 3 
Yes G1 15
G2 14
G3 4 
S 3
M 21
E 2
Other 3 
All 10d (7 IA, 3 IC
2 S, 5 M, 1 E,
1 CC, 1 Mixed) 
2/13 4/14 1/3 2/2 1/1 5/6 4 NED, 2 AWD, 3 DOD, 1 Unknown
FU 47 months 
Schilder 2002 [2352 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, 1 S, 2 M, 1 E, 1 Mixed) 2/33 2/6 0/3 0/5 1/3 0/2 3/2 3 NED, 2 DOD
FU 68 months 
Sardi 2005
Anchezar 2009 [24, 25
16 IA 11
IC 5 
Yes G1 14
G2 1
G3 1 
S 1
M 8
E 5
CC 2 
All 2 (2 IA, 1 S, 1 E) 2/11 0/0 0/0 0/3 0/1 0/1 0/2 1 NED, 1 DOD
FU 96 months 
Borgfeld 2007 [2611 IA 10
IC 1 
Yes G1 9
G2 1
G3 1 
S 2
M 8
E 1 
In 7 1 (IC M) 0/9 0/1 0/0 0/0 0/0 1/1 0/1 1 DOD
FU 92 months 
Park 2008 [2759 IA 36
IB 2
IC 21 
Yes G1 48c
G2 5
G3 9 
S 7c
M 41
E 8
CC 4
Other 2 
All 9 (5 IA, 4 IC, 5 M, 1 E, 2 CC, 1 mixed) 1/29 0/3 4/4 1/15 1/2 2/4 1/8 2 NED, 3 AWD, 4 DOD
FU 56 months 
Kwon 2009 [2821 IA 17
IC 4 
No G1 16
G2 3
G3 2 
S 1
M 16
E 2
CC 3 
In 14 1 (IC G1) NS NS NS NS NS NS NS NS
FU 43 months 
Muzii 2009 [29NS Yes NS S 4
M 3
E 2
CC 2 
All 1 (IC) NS NS NS NS NS NS NS 1 AWD
FU 20 months

 
Schlaerth 2009 [3020 IA 11d e
IC 9 
Yes G1 14
G2 5
G3 1 
S 1
M 11
E 6
CC 1
Unk 1 
In 18 3 (2 IC and 1 IA) and 1 uterine cancerd NS NS NS NS 2NS NS 3/0 3 DOD
FU 122 months 
Kajiyama 2010, 2011a, 2011b, 2014 [31–3494 IA 43
IC 51 
Yes G1 59
G2 14
G3 4 (CC 17) 
S 3
M 52
CC 17
E 21
Other 1 
In 14 14 (5 IA and 9 IC, 3 S, 4 M, 4 E, 3 CC) NS NS NS NS NS NS NS 11 DOD
FU 66 months 
Satoh 2010 [35211 IA 126
IC 85 
Yes G1 95
G2 13
G3 3 (CC 30) 
S 27
M 126
E 27
CC 30
Other 1 
In 86 18 (7 IA, 11 IC, 3 S, 6 M, 4 E, 5 CC)f 5/95 0/13 2/3f 5/65 0/2 1/3f 5/13 8 NED, 5 AWD, 5 DOD
 FU 78 months 
Hu 2011 [3682 IA 46
IB 8
IC 28 
Yes ? G1 57
G2 10
G3 1
Unk/CC 14 
S 31
M 32
E 5
CC 3
Other 11 
94 1 in stage I NS NS NS NS NS NS NS 0 in stage I
FU 132 months 
Cheng 2012 [3716 IA 10
IC 6 
Yes G1 4
G2 2 
S 1c
M 13
E 1
Other 2 
All 1 (IC mixed) 0/9 0/1 0/0 1/5 0/1 0/0 0/1 0
FU 61 months 
Kashima 2013 [3818 IC 18 No G1 14
CC 4 
S 2
M 9
E 3
CC 4 
In 15 5 (1 S, 3 M, 1 CC) 0/0 0/0 0/0 4/14 0/0 0/0f 1/4 1 NED, 4 DOD
FU 78 months 
Lee 2015 [3934 IA 21
IC 13 
No G1 27c
G2 5
G3 1
Unk. 2 
All M In 12 5 or 6 (1 stage II?) NS NS NS NS NS NS 1/ 4 or 5 NS
FU 104 months 
Cromi 2014, Ghezzi 2016 [40, 4161 IA 42
IB 1
IC 18 
No G1 38c
G3 19
G3 8 
S 15c
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 NS NS NS NS 1 DOD
FU 38 months 
Park 2016 [4216 IA 6
IC 12 (2 IIIA1) 
No G1 9
G2 4
G3 5 
S 3
M 7
E 5
CC 3 
11 0 in stage I 0/2 0/3 0/0 0/7 0/1 0/4 NS 0
FU 47 months 
Total 1092g      121 or 122 (11%)
(1st > I?) 
19/285 (7%) 8/72 (11%) 8/28 (29%) 18/170 (11%) 5/47 (11%) 7/30 (23%)   

NS, not stated; NED, no evidence of disease; DOD, died of disease; AWD, alive with persistent disease; h, omentectomy.

aS, serous; M, mucinous; E, endometrioid; CC, clear cell; Unk, unknown.

bComplete staging definition varied in different series. In cases of incomplete data, patients having at least an omentectomy were considered as having ‘staging’ surgery.

cData incomplete stage >I disease.

dThe characteristics of relapsing patients were detailed in the second publication involving 18 conservative procedures; 1 patient had a recurrence in the form of borderline disease.

eOne patient had a recurrence in the form of a secondary uterine cancer. She is not included in the results.

fClear-cell recurrence(s) was/were not included because these lesions were not graded in this series.

gEighteen 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.

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 (nStage IC1 (n rec, n tot) Stage IC2 (n rec, n tot) Stage IC3 (n rec, n tot) Location recurrence DOD and AWD (n
Jobo 2000 [180/0 3/5 0/0 Two ovary, 1 lung Three DOD 
Schilder 2002 [2310 0/0 0/0 1/10 Ovary NED 
Borgfeld 2007 [260/0 0/0 1/1 Peritoneum DOD 
Kwon 2009 [28?/3 0/0 ?/1 NS NS 
Kajiyama 2010, 2014 [31, 3451 3/31 6/20 NS NS  
Satoh 2010 [3585 11 7/55 2/18 2/12 Three ovary, 8 peritoneum and/or nodes and/or liver Three NED, 4 AWD, 4 DOD 
Hu 2011 [3628 ?/9 ?/6 ?/13 NS NS 
Kashima 2013 [3818 3/11 1/3 1/4 One ovary, 2 nodes, 1 peritoneum, 1 brain Four DOD, 1 NED 
Park 2016 [4212 0/11 0/1 0/0 NA NA 
Total 214 31 (14%) 13/108 (12%) 6/27 (22%) 5/27 (19%)   
    IC2+3 = 17/74 (23%)   
Authors, years n pts Recurrence (nStage IC1 (n rec, n tot) Stage IC2 (n rec, n tot) Stage IC3 (n rec, n tot) Location recurrence DOD and AWD (n
Jobo 2000 [180/0 3/5 0/0 Two ovary, 1 lung Three DOD 
Schilder 2002 [2310 0/0 0/0 1/10 Ovary NED 
Borgfeld 2007 [260/0 0/0 1/1 Peritoneum DOD 
Kwon 2009 [28?/3 0/0 ?/1 NS NS 
Kajiyama 2010, 2014 [31, 3451 3/31 6/20 NS NS  
Satoh 2010 [3585 11 7/55 2/18 2/12 Three ovary, 8 peritoneum and/or nodes and/or liver Three NED, 4 AWD, 4 DOD 
Hu 2011 [3628 ?/9 ?/6 ?/13 NS NS 
Kashima 2013 [3818 3/11 1/3 1/4 One ovary, 2 nodes, 1 peritoneum, 1 brain Four DOD, 1 NED 
Park 2016 [4212 0/11 0/1 0/0 NA NA 
Total 214 31 (14%) 13/108 (12%) 6/27 (22%) 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.

findings

A total of 32 papers written by 21 teams and 7 multicentre studies were retained (39 articles) and analysed summarising 1150 patients who had undergone FSS (Table 1). One hundred and thirty-nine (12%) recurrences had occurred: 124 or 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

A total of 1110 stage I lesions were included in Tables 1 and 4. 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 = 0.002).

Among the series that reported details concerning the initial characteristics of patients and of relapsing patients (substage I and tumour grade), data were available 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 = 0.0004). 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 versus grade 3; P = 0.02). As mentioned above, several series published after 2010, involving 34 cases and 6 relapsing patients, considered clear-cell tumours as ungradable [35, 38]. Consequently, these six 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 and 4).

results according to the new FIGO staging system for stage IC disease

The 2014 FIGO staging system modified stage IC into three new clinically (and prognostically) more relevant subgroups in the stage I disease category [8] (Table 2). 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. Among these 31 recurrences, the substage of the disease was not reported in two series (comprising jointly 32 patients with stage IC disease) [28, 35]. In one of these two 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 (23%) patients with stage IC1 and IC2+3 disease (P = 0.02).

stage II and III disease: results

Forty cases of stage II or III disease were collected (Table 3). In a majority of these patients, the tumour was initially confined to the ovary but was finally modified to 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 five 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).

Table 3.

Literature review of patient characteristics and oncological outcomes after fertility-sparing surgery in stage II and III disease

Authors, years n pts Stage (FIGO 1987) Histology Grade Recurrence Time to recurrence (months) Location recurrence Outcomes 
Colombo 1994, 2005
Fuscio 2010 [10, 12, 13
I IIA, 2 IIB At least 1 serous At least 1 G1 151 Ovary NED 
Raspagliesi 1997, Ditto 2015 [14–161 IIA, 1 IIC, 5 IIIC At least 4 serous
2 mucinous 
At least 3 G1, 2 G2 0 6 patients NA NA NA 
Morice 2001 [191 IIA, I IIB At least 1 mixed At least 1 G 2 Ovary and peritoneum DOD 16 months 
Park 2008 [271 IIB, 1 IIIA, 1 IIIC At least 2 mucinous At least 1 G1, 1 G3 8, 10 1 ovary and peritoneum
1 nodes and lung 
2 DOD 10, 16 months 
Anchezar 2009 [252 IIIB 1 serous, 1 mucinous 1 G1, 1 G2 14 Ovary NED 38 months 
Muzii 2009 [291 IIB, I IIIA NS NS NA NA NA 
Hu 2011 [3612 1 II, 4 IIIA, 7 IIIC 3 serous, 2 mucinous, 4 endometrioid, 1 clear-cell, 1 mixed 7 G1, 3 G2, 2 unknown 7, 22, 24, 24, 26
Unknown for 3 
1 ovary, 4 peritoneum, 3 unknown 4 DOD, 3 AWD 
Cheng 2011 [37IIIA NS NS NA NA NA 
Petrillio 2014 [43IIC Endometrioid G2 NA NA NA 
Lee 2015 [391 IIC NS NS 1 ? NS NS NS 
Cromi 2014, Ghezzi 2015 [40, 411 IIB, 3 IIIC NA NA NA NA NA 
Park 2016 [422 IIIC 2 serous 1 G2, 1 G3 NA Peritoneum, liver and nodes AWD
44 months 
Total 40    15 (38%)    
Authors, years n pts Stage (FIGO 1987) Histology Grade Recurrence Time to recurrence (months) Location recurrence Outcomes 
Colombo 1994, 2005
Fuscio 2010 [10, 12, 13
I IIA, 2 IIB At least 1 serous At least 1 G1 151 Ovary NED 
Raspagliesi 1997, Ditto 2015 [14–161 IIA, 1 IIC, 5 IIIC At least 4 serous
2 mucinous 
At least 3 G1, 2 G2 0 6 patients NA NA NA 
Morice 2001 [191 IIA, I IIB At least 1 mixed At least 1 G 2 Ovary and peritoneum DOD 16 months 
Park 2008 [271 IIB, 1 IIIA, 1 IIIC At least 2 mucinous At least 1 G1, 1 G3 8, 10 1 ovary and peritoneum
1 nodes and lung 
2 DOD 10, 16 months 
Anchezar 2009 [252 IIIB 1 serous, 1 mucinous 1 G1, 1 G2 14 Ovary NED 38 months 
Muzii 2009 [291 IIB, I IIIA NS NS NA NA NA 
Hu 2011 [3612 1 II, 4 IIIA, 7 IIIC 3 serous, 2 mucinous, 4 endometrioid, 1 clear-cell, 1 mixed 7 G1, 3 G2, 2 unknown 7, 22, 24, 24, 26
Unknown for 3 
1 ovary, 4 peritoneum, 3 unknown 4 DOD, 3 AWD 
Cheng 2011 [37IIIA NS NS NA NA NA 
Petrillio 2014 [43IIC Endometrioid G2 NA NA NA 
Lee 2015 [391 IIC NS NS 1 ? NS NS NS 
Cromi 2014, Ghezzi 2015 [40, 411 IIB, 3 IIIC NA NA NA NA NA 
Park 2016 [422 IIIC 2 serous 1 G2, 1 G3 NA Peritoneum, liver and nodes AWD
44 months 
Total 40    15 (38%)    

A IIIC due to nodal spread.

NS, not stated; NA, not applicable; NED, no evidence of disease; AWD, alive with persistent disease; DOD, died of disease.

clear-cell tumours: results

The histologic subtypes of the tumours collected in Tables 1 and 4 (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 tumours (10%), 25 among 165 serous (15%), 23 among 174 endometrioid (13%) and 19 among 88 (22%) clear-cell tumours (P = 0.007).

Table 4.

Literature review of patients undergoing fertility-sparing surgery for clear-cell ovarian tumours

Authors, years n pts Stage (nPathology review Recurrence (nLocation recurrence Outcomes 
Miyazaki 1988 [9No NA NA 
Colombo 1994 Zanetta 1997, Fuscio 2010 [10, 11, 1317 All stage I? Yes 2 peritoneum 1 NED, 1 DOD 
Raspagliesi 1997, Ditto 2014 [14, 15IA No Ovary NED 
Morice 2001, 2005 [19, 20IA Yes Metastatic AWD 
Schilder 2002 [23NS Yes NA NA 
Sardi 2005 Anchezar 2009 [24, 25IA 1, IC 1 Yes NA NA 
Park 2008, Park 2016 [27, 4422 IA 12, IC 10 No 5 (3 IA and 2 IC) All metastatic +/− ovary 2 NED, 1 AWD, 2 DOD 
Kwon 2009 [28No NA NA 
Muzii 2009 [29NS Yes NA NA 
Schlaerth 2009 [30Yes NS NS NS 
Kajiyama 2010, 2011a, 2011b, 2011c, 2014a, 2014b [31, 32, 34, 45–4717 IA 7a
IC 9 
Yes NS NS 
Satoh 2010 [3530 Yes 5 (all stage IC) 1 ovary, 4 peritoneum, nodes or liver 1 NED, 3 AWD, 1 DOD 
Hu 2011 [363 I, 1 IIIA Yes? At least 1 NS At least 1 DOD 
Kashima 2013 [38All IC No Nodes DOD 
Ghezzi 2015 [41NS No NA NA 
Park 2016 [423 IC No NA NA 
Total 116   19/115 (17%)   
Authors, years n pts Stage (nPathology review Recurrence (nLocation recurrence Outcomes 
Miyazaki 1988 [9No NA NA 
Colombo 1994 Zanetta 1997, Fuscio 2010 [10, 11, 1317 All stage I? Yes 2 peritoneum 1 NED, 1 DOD 
Raspagliesi 1997, Ditto 2014 [14, 15IA No Ovary NED 
Morice 2001, 2005 [19, 20IA Yes Metastatic AWD 
Schilder 2002 [23NS Yes NA NA 
Sardi 2005 Anchezar 2009 [24, 25IA 1, IC 1 Yes NA NA 
Park 2008, Park 2016 [27, 4422 IA 12, IC 10 No 5 (3 IA and 2 IC) All metastatic +/− ovary 2 NED, 1 AWD, 2 DOD 
Kwon 2009 [28No NA NA 
Muzii 2009 [29NS Yes NA NA 
Schlaerth 2009 [30Yes NS NS NS 
Kajiyama 2010, 2011a, 2011b, 2011c, 2014a, 2014b [31, 32, 34, 45–4717 IA 7a
IC 9 
Yes NS NS 
Satoh 2010 [3530 Yes 5 (all stage IC) 1 ovary, 4 peritoneum, nodes or liver 1 NED, 3 AWD, 1 DOD 
Hu 2011 [363 I, 1 IIIA Yes? At least 1 NS At least 1 DOD 
Kashima 2013 [38All IC No Nodes DOD 
Ghezzi 2015 [41NS No NA NA 
Park 2016 [423 IC No NA NA 
Total 116   19/115 (17%)   

NS, not stated; NA, not applicable; NED, no evidence of disease; AWD, alive with persistent disease; DOD, died of disease.

aResults given in the series published in 2011 including 16 cases.

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 follow-up, 19 (17%) recurrences had occurred (Table 4). Among these 19 relapsing patients, the location of the recurrent disease was available in 15. Thirteen patients had metastatic (extra-ovarian disease) (87%) and 2 had an ovarian (13%) recurrence (this rate is statistically significant compared with 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 first related to the prognostic factors for recurrences in this context [a possible higher recurrence rate due to the use of a conservative treatment compared with conventional treatment (radical surgery)]. No phase II randomised 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 first, in series comparing conservative and conventional treatment, patients selected for FSS tend to have a better prognosis than those 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, Epidemiology and End Results) database reported that ovarian preservation in stage 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 1000 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 with 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 with 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. That is why, some teams consider that FSS is unsafe in stage I grade 3 disease and 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. Extra-ovarian 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 peroperatively ruptured stage IC1 tumours (half of these recurrences were isolated on the remaining ovary) (Table 2). 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 IC3 disease) or to the use of FSS itself. We cannot solve these endless and inextricable discussions in this paper.

In theory, a randomised trial should be carried out 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 order to observe a statistical difference in survival (even if a non-inferiority design is used in such a trial). Nevertheless, a prospective non-randomised trial (JCOG1203; UMIN00013380) is currently ongoing 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 [53]. 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 ovaries in place that could potentially be used later for in vitro fertilisation. 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 these 40 cases had stage IIA/B, IIIA2 or stage IIIA1 disease with a better prognosis 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 [50].

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 with other subtypes. Recently, mucinous tumours were divided into two 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 infiltrative mucinous tumours). Anyway, as the histologic subtype (and the tumour grade) is a key issue in the selection of patients for FSS, a pathological review of the slide by an expert pathologist should be done before validating this management. The centralisation and/or review of the pathological 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 two latter subgroups is better than that of epithelial cancer. Furthermore, in the same team in retrospective series dedicated to 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 pathological 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 summarises this pathological review (centralised or not in multicentre studies) and about 21 teams reported their results, 11 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 (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 clear-cell tumour in 16 cases and all but 3 received it. Even if, contrary to 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 first 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 of 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 two 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 ‘authorise’ the patient/couple to attempt a potential pregnancy before 2 years after FSS in clear-cell disease if we do not want to be 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. [51] 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. 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 [52]. Even if this rate depends on the local recruitment of cases and the criteria finally retained to select patients for 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 carried out 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 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).

funding

None declared.

disclosure

The authors have declared no conflicts of interest.

acknowledgements

The authors wish to thank Ms Lorna Saint Ange for editing.

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