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Gynecological fertility-sparing surgery
Placenta 32 (2011) S224eS231
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Gynecological fertility-sparing surgery D. Vitobello*, G. Siesto, C. Bulletti, A. Accardi, P.E. Levi Setti Department of Gynecology, Cancer Center, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 23 June 2011
The implementation of early detection protocols and advanced treatment strategies has significantly improved survival outcomes for gynecologic cancer patients. The improvement of oncological outcomes has led to an increased attention toward Quality of Life issues, including the childbearing potential for young women. Traditionally the surgical treatment of cervical, endometrial and ovarian cancers involves the removal of the uterus and adnexa, irrespective of the impact on fertility and parenthood and regardless of patient desires. For young women affected by gynecological malignancies at an apparently early stage, fertility-sparing procedures could be offered. The aim of our review is to going through the available evidence in the Literature and to evaluate the current state of art regarding fertility-sparing procedures for women with gynecological malignancies in terms of oncological and fertility outcomes. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Cervical cancer Ovarian cancer Endometrial cancer Fertility-sparing surgery Fertility preservation
1. Introduction According to the American Cancer Society gynecologic tumors are among the 10 most common malignancies representing the 12e15% of all cancers suffered by women [1e3]. Although the majority of cases are diagnosed in postmenopausal females, a significant subset e approximately 20% e is represented by women in reproductive age who are yet to complete or commence a family planning [2e5]. In particular, 8% of endometrial, 12% of ovarian and 40% of cervical cancers occur in the childbearing years [2]. Historically, cancer treatment regimens focused primarily on eradicating disease, irrespective of the impact on fertility and parenthood, regardless of patient age and desires. However, the implementation of early detection protocols and advanced treatment strategies has significantly improved survival outcomes for gynecologic cancer patients so that a paradigm shift occurred, moving from a concept of “the maximum sustainable” to “the least effective” surgery. These improvements, which are principally based on our increased understanding of biologic behaviors, have also led to a greater attention toward Quality of Life (QoL) issues for cancer survivors, including the childbearing potential. Therefore, fertility preservation (FP) and parenthood after cancer are now integral
* Corresponding author. Tel.: þ39 02 82244601; fax: þ39 02 82244693. E-mail address: [email protected] (D. Vitobello). 0143-4004/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2011.06.017
components for the pre-treatment counseling, especially for those women who record low risk factors and for which a fertilitysparing approach seems to be reasonable without compromising long-term outcomes [3e5]. During the last years the number of paper reporting different fertility-sparing option together with survival outcomes has grown dramatically, moving the limit for a conservative treatment at ever more distant levels [2e5]. The aim of this paper is to go through the evidence available in the Literature and to assess the state of art about the fertilitysparing options for women affected by cervical, endometrial and ovarian cancer. 2. Methods e review criteria A comprehensive literature review of published clinical studies on gynecological fertility-sparing surgery was carried out at the Humanitas Clinical Institute with cross-search of seven different medical databases (AMED e Allied and Complementary Medicine Database, BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase and Medline on Web of Knowledge, OvidSP and PubMed). Search temporal limits included paper published between January 1990 and April 2011 with the purpose to provide the most recent evidence regarding this issue. Studies were queried using the following key-words in various combinations: “fertilitysparing/fertility preservation”, “cervical/endometrial/ovarian” and “cancer/carcinoma/tumour”. Among the hundreds of articles identified, we retrieved those manuscripts that were more relevant for the purpose of this review and provided results from case series and/or conceptual findings. If manuscripts were comparable for aim, their clinical relevance was scaled according to: originality, study design (meta-analyses vs. randomized vs. prospective vs. retrospective studies), the method used, the evidence level and the sample size. Case reports have been excluded from this analysis. The journal relevance based on the actual impact factor score was used as ultimate criterion of choice, if needed. A further manual cross-search of the
D. Vitobello et al. / Placenta 32 (2011) S224eS231 references of each selected article was finally performed in order to further identify studies not captured by the online search but potentially relevant for this review. Only articles published in English language were considered.
3. Results A total of 45 papers regarding fertility-sparing options for gynecological malignancies have been retrieved. In particular, 14 studies investigated the different treatment strategies for cervical cancer, 8 for endometrial cancer and 23 for ovarian cancer, respectively. In order to provide the most recent scenario regarding each gynecological malignancy of interest, the outcomes of more than 2250 patients included will be discussed separately, according to their primary cancer site. 4. Cervical cancer Data regarding the 14 studies about fertility-sparing procedures for cervical cancer have been summarized in Table 1 [6e19]. Cervical cancer represents the most common cause of death from gynecologic cancer worldwide. More than 40% of all cases are diagnosed in women younger than 45 years. For women with early stage disease the standard surgical treatment consists of a radical hysterectomy and pelvic lymph node dissection or concurrent pelvic chemo-radiation. In both cases fertility is lost [5,20,21]. Among patients with cervical cancer, women with favorable preoperative characteristics (including tumors of small volume (<2 cm), well differentiated, with a depth of stromal infiltration <10 mm and without evidence of lymphovascular space invasion) conservative treatment could be proposed, if requested. Smith et al. have recently performed an intriguing review regarding women with early stage cervical cancer to determine how many patients treated with radical hysterectomy may have been eligible for a fertility-sparing surgery consisting of cervical conization with pelvic nodal dissection [22]. During the study period 507 women have been identified. Of these 53 patients were 40 years of age with favorable pathologic characteristics and they could have been eligible for conservative, fertility-sparing surgery. Interestingly none of these 53 patients were found to have parametrial involvement or positive pelvic lymph nodes. These women have certainly benefited from a fertility-sparing treatment if only they had had the possibility [22]. Our literature review, however, leads to further considerations: among the 14 paper analyzed more than 550 patients have been collected: 12 studies evaluated the surgical, oncological and fertility outcomes of women who underwent radical trachelectomy with nodal dissection by laparoscopic, abdominal or vaginal approach [6e11,13,14,16e19], whereas the lasting 2 papers investigated the same outcomes of women undergoing cervical conization after neoadjuvant chemotherapy with TIP (paclitaxel 175 mg/ mq þ ifosphamide 5 g/mq þ cisplatin 75 mg/mq) or TEP (paclitaxel 175 mg/mq þ epirubicin 80 mg/mq þ cisplatin 75 mg/mq) for squamous cell carcinoma and adenocarcinoma, respectively [12,15]. Radical trachelectomy or cervical chemo-conization appeared to be feasible and oncologically safe in the long-term period also in case of locally advanced cervical cancer (FIGO stages Ib2eIIa) [6,7,9,16,17]. Indeed, in the overall population, only 18 (3.2%) recurrences were recorded with 8 (1.4%) patients who died for disease. On the other hand, concerning the fertility outcomes, among these young women (age range 17e45 years) just 116 pregnancies were obtained: in particular only 34 (29.3%) full term deliveries (most of which through cesarean section) were recorded. In 43 (34.5%) and 11 (9.5%) of cases preterm-deliveries and 2nd trimester pregnancy losses occurred, even if permanent abdominal cerclage was generally positioned at the end of the procedures. This
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risk seems to be reduced for patients who underwent chemoconization, but data are too small to draw definitive conclusion [6e19]. Therefore, despite the encouraging results given by the technical feasibility and the oncological safety of fertility-sparing procedures for cervical cancer, only a minority of patients definitely attempt to and achieve pregnancy and, paradoxically, those cases are also exposed to an increased risk of preterm delivery [21]. We feel that this is something that patients should be aware and that should be extensively explained during the preoperative counseling. 5. Endometrial cancer Data regarding the 8 studies about fertility-sparing procedures for cervical cancer have been summarized in Table 2 [23e30]. Endometrial carcinoma is the most common gynecological malignancy in western countries. This condition typically affects postmenopausal women. However, 20e25% of endometrial adenocarcinoma cases are diagnosed before menopause, but only and 2e14% of cases occur before the age of 40 years. These young women tend to have disease with favorable prognostic factors, such as low-grade endometrioid histology with oestrogen/progesterone receptor-positive disease and stage I disease with little or no myometrial invasion [20,28]. The standard treatment for patients with early stage endometrial cancer is the hysterectomy with bilateral salpingooophorectomy, with staging dependent upon risk factors [20,28]. To date only few reports of fertility-sparing procedures for endometrial cancer are available in the literature, as endometrial cancers are quite rare in this population subset and only well differentiated endometrioid adenocarcinoma without suspicious of myometrial involvement are considered as optimal candidates for conservative treatments. Lymph node status could be assessed with imaging studies as MRI in which a lymph node greater than 1 cm in short axis or with central necrosis is considered to be suspicious. Radiologic imaging, however, has its limitations and direct evaluation with laparoscopic pelvic lymphadenectomy is advocated by some authors [4]. Among the 8 papers retrieved about this issue a total of 165 women were included (age range 21e44 years). In particular 117 (70.9%) and 48 (29.1%) recorded the histological diagnosis of endometrial cancer and atypical endometrial hyperplasia, respectively. For these patients different treatments with progestins were proposed, with different doses, duration, mode of administration and timing of assessment of responses. Overall, 70 pregnancies have been obtained with 47 (40.2%) full term deliveries. Sixty-seven (57.6%) women were finally addressed to definitive treatment by total hysterectomy (bilateral salpingo-oophorectomy) [23e30]. More recently a progesterone releasing intrauterine device (IUD) has been successfully applied for the treatment of estrogendependent endometrial cancer with promising results [29,30]. The rationale for treating endometrial cancer with this device, instead of the oral administration, is that this IUD provides very high doses of the hormone at the specific site of the pathology. This avoids both the adverse effects produced by systemic administration and the suboptimal patient’s compliance [29,30]. Although these studies reported that treatment with progestin is effective and safe, there are several still unsolved issues for young patients with endometrial cancer that need to be specifically addressed, including: 1) what is the optimal progestin treatment regimen, particularly regarding dosage and duration? 2) Most of the younger women recognize the impaired ovulation as the underling pathologic condition which enhances the risk of endometrial cancer and long standing issues of infertility often complicates matters, so that, is the ovulation induction agent for
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Table 1 Studies about fertility-sparing options for women with cervical cancer. Author
N of patients,a age (range)
FIGO stages histologic types
Proposed treatment
Survival outcomes
Fertility outcomesb
Roy et al. 1998 [6]
30 patients 32 (22e42) years
Ia1eIIa SCC þ AdenoK
RVT þ laparoscopic PLN
F-U 25 (1e79) months Recurrence: 1 (3.3%) DOD: 1 (3.3%)
Burnett at al. 2002 [7]
19 patients 30 (23e41) years
Ia2eIIa SCC þ AdenoK
LARVT þ PLN
F-U 31.5 (22e44) months Recurrence: 0
Schlearth et al. 2003 [8]
10 patients 30.9 (22e44) years
Ia2eIb SCC þ AdenoK
LARVT (4/10; 40.0%) þ PLNRVT (6/10; 60.0%) þ PLN
F-U 47 (28e84) months Recurrence: 0
Ungar et al. 2005 [9]
30 patients 30.5 (23e37) years
Ia2eIb2 SCC þ AdenoK
ART þ PLN
F-U 47 (14e75) months Recurrence: 0
Hertel et al. 2006 [10]
100 patients 32 (21e41) years
Ia1eIb1 SCC þ AdenoK
LARVT þ PLN
F-U 29 (1e128) months Recurrence: 4/100 (4.0%) DOD: 2/100 (2.0%)
Shepherd et al. 2006 [11]
123 patients 30.6 (21e45) years
Ia2eIb1 SCC þ AdenoK
LARVT þ PLN
F-U 45 (1e120) months Recurrence: 5/123 (4.1%) DOD: 4/123 (3.3%)
Landoni et al. 2007 [12]
11 32 41 31
patients (24e41 years) patients (20e40) years
Ia2eIb1 SCC þ Adenok Ia1eIb1 SCC þ AdenoK
NACT þ conization
F-U 20 (7e29) months Recurence: 0 F-U 21 (3e60) months Recurrence: 1/41 (2.5%)
Rene Pareja et al. 2008 [14]
15 patients 30 (25e38) years
Ia2eIb1 SCC þ AdenoK
ART þ PLN
F-U 32 (5e32) months Recurrence: 0
Maneo et al. 2008 [15]
16 patients 30 (17e39) years
SCC þ AdenoK þ Indifferentiated
NACT þ conization
F-U 69 (10e214) months Recurrence: 0
Olawaiye et al. 2009 [16]
10 patients 31 (26e38) years
Ia1eIIa SCC þ AdenoK
ART þ PLN
F-U 28 (1e74) months Recurrence: 0
Kim et al. 2009 [17]
27 patients 29 (22e37) years
Ib1eIIa SCC þ AdenoK
LRT þ PLN PALN
F-U 31 (1e58) months Recurrence 1/27 (3.7%) DOD 1/27 (3.7%)
Nishio et al. 2009 [18]
61 patients 33 (26e44) years
Ia1eIb1 SCC þ AdenoK
ART þ PLN
F-U 27 (1e79) months Recurrence: 6/61 (9.8%)
Li et al. 2011 [19]
62 patients
Ia1eIb1SCC þ AdenoK(þ3 cases of Botryoid sarc)
ART þ PLN
F-U 22.8 (1e78) months Recurrence: 0
5 pregnancies achieved 1/5: 1st trimester loss 2/5: preterm delivery (<37weeks) 2/5: term delivery 3 pregnancies achieved 1/3: 2nd trimester loss 1/3: preterm delivery (<37weeks) 1/3: term delivery 4 pregnancies achieved 2/4: 2nd trimester loss 2/4: preterm delivery (<37weeks) 3 pregnancies achieved 1/3: 1st trimester loss 2/3: term delivery 15 pregnancies achieved 3/15: 1st trimester loss 8/15: preterm delivery (<37weeks) 4/15: term delivery 52 pregnancies achieved 17/52: 1st trimester loss 7/52: 2nd trimester loss 20/52: preterm delivery (<37weeks) 8/52: term delivery 3 pregnancies achieved 3/3: term delivery 7 pregnancies achieved 2/7: 1st trimester loss 1/7: 2nd trimester loss 3/7: preterm delivery (<37weeks) 1/7: term delivery 3 pregnancies achieved 1/3: preterm delivery (<37weeks) 2/3: term delivery 10 pregnancies achieved 1/10: 1st trimester loss 2/10: preterm delivery (<37weeks) 7/10: term delivery 3 pregnancies achieved 1/3: 1st trimester loss 1/3: preterm delivery (<37weeks) 1/3: term delivery 3 pregnancies achieved 2/3: 1st trimester loss 1/11: preterm delivery (<37weeks) 4 pregnancies achieved 2/4: preterm delivery (<37weeks) 2/4: term delivery 1 pregnancy achieved 1/1: term delivery
Sonoda et al. 2008 [13]
LARVT þ PLN PALN
Data are expressed as median (range); mean sd or absolute number (%). LARVT ¼ laparoscopic-assisted radical vaginal trachelectomy; LRT ¼ laparoscopic radical trachelectomy; RVT ¼ radical vaginal trachelectomy; ART ¼ abdominal radical trachelectomy; NACT ¼ neoadjuvant chemotherapy; PLN ¼ pelvic lymphadenectomy; PALN ¼ para-aortic lymphadenectomy. SCC ¼ Squamous cell carcinoma; AdenoK ¼ adenocarcinoma/Adenosquamous. a Number of successful fertility-sparing procedures. b Ongoing pregnancies have been excluded.
ART safe or helpful to young patients with endometrial cancer? 3) What is the chance of progression to advanced disease during or after medical treatment? 4) Is hysterectomy needed after completion of childbearing? [26e29].
6. Ovarian cancer Data regarding the 22 studies about fertility-sparing procedures for ovarian cancer have been summarized in Table 3.
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Table 2 Studies about fertility-sparing options for women with endometrial cancer. Author
N of patients, age (range)
FIGO stages included, grading and histological type
Proposed treatment
Results
Fertility outcomesb
Kaku et al. 2001 [23]
30 patients 29.3 (21e42) years
MPA 200e800 mg/d for 2e14 monthsD&C every 1e4 months
9 patients 32 (30e39) years
CR ¼ 21/30 (70%) PR ¼ 3/30 (10%) SD ¼ 6/30 (20%) Hysterectomy 11/30 (36.6%) CR ¼ 6/9 (66.7%) SD ¼ 3/9 (33.3%) Hysterectomy 3/9 (33.3%)
10 pregnancies achieved 5/10: 1st trimester loss 5/10: term delivery
Wang et al. 2002 [24]
AEH (18/30; 60%)þ EC Ia (M0)a (12/30; 40%) Grade 1 (12/12; 100%), Endometrioid. EC Ia (M0)a (9/9; 100%) Grade 1 (9/9; 100%), Endometrioid.
Gotlieb et al. 2003 [25]
13 patients 31 (23e40) years
Yamazawa et al. 2007 [26]
9 patients 36 (28e40) years
Signorelli et al. 2008 [27]
21 patients 32 (21e40) years
Hahn et al. 2009 [28]
35 patients 31 (21e43) years
Minig et al. 2011 [29]
Laurelli et al. 2011 [30]
MA 160 mg/d þ tamoxifen 30 mg/d for 6 months Hysteroscopy D&C/6 months
EC Ia (M0)a Grade 1 (11/13; 84.6%), Grade 2 (2/13; 15.4%) Endometrioid. EC Ia (M0)a (9/9; 100%) Grade 1 (9/9; 100%), Endometrioid.
MPA 200e600 mg/d vs. MA 160 mg/d for 2e3 months Serial D&C every 3e6 months
Hysterectomy 4/13 (30.8%)
MPA 400 mg/d for 6 months Transvaginal US þ biopsy monthlyD&C every 3 months
AEH (10/21; 47.6%) þ EC Ia (M0)a (11/21; 52.4%) Grade 1 (11/11; 100%), Endometrioid. Ia (M0),a Grade 1 (31/35; 88.6%), Grade 2 (4/35; 11.4%) Endometrioid.
NP 200 mg/d from 14th-25th day for 3e9 monthsSerial hysteroscopy þ endometrial biopsy every 3 months MPA 250e1500 mg/d and-or MA 160 mg/d for 3e20 months Serial D&C every 3 months
CR ¼ 3/9 (33.3%) PR ¼ 5/9 (53.6%)) SD ¼ 1/9 (11.1%) Hysterectomy 2/9 (22.2%) CR ¼ 3/21 (14%) PR ¼ 9/21 (43%) SD ¼ 9/11 (43%) Hysterectomy 15/21 (71.4%) CR ¼ 22/35 (62.9%) PR ¼ 1/35 (2.9%) SD ¼ 12/35 (34.3%) Hysterectomy 17/35 (48.6%)
34 patients 34 (22e40) years
AEH (20/34; 58.3%)þ EC Ia (M0)a (14/34; 41.7%) Grade 1 (14/14; 100%), Endometrioid.
LNG-IUD þ GnRH for 6 months; Transvaginal US/3 months Hysteroscopy þ biopsy/6 months
CR ¼ 27/34 (79.4%) SD ¼ 2/34 (5.9%) Progression ¼ 5/34 (14.7%) Hysterectomy 14/34 (41.2%)
14 patients 38 (26e40) years
EC Ia (M0)a Grade 1 (14/14; 100%), Endometrioid.
MA 160 mg/d for 6 months vs. LNG-IUD for 8 months
CR ¼ 12/14 (85.8%) PR ¼ 1/14 (7.1%) SD ¼ 1/14 (7.1%) Hysterectomy 1/14 (7.1%)
6 pregnancies achieved 3/6: 1st trimester loss 1/6: 2nd trimester loss 2/6: term delivery 10 pregnancies achieved 1/10: 1st trimester loss 9/10: term delivery 4 pregnancies achieved 1/4: 1st trimester loss 3/3: term delivery 16 pregnancies achieved 3/16: 1st trimester loss 1/16: 2nd trimester loss 12/16: term delivery 13 pregnancies achieved 5/13: 1st trimester loss 1/13: preterm delivery (<37weeks) 7/13: term delivery 10 pregnancies achieved 2/10: 1st trimester loss 1/10: preterm delivery (<37weeks) 7/10: term delivery 1 pregnancy achieved 1/1: term delivery
Data are expressed as median (range); mean sd or absolute number (%). AEH ¼ atypical endometrial hyperplasia; EC ¼ endometrial cancer; M0 ¼ no myometrial invasion. NP ¼ natural progesterone; MPA ¼ medroxyprogesterone acetate; MA ¼ Megestrol acetate; D&C ¼ dilation and curettage; LNG-IUD ¼ levonorgestrel-release intrauterine device. CR ¼ complete remission; PR ¼ partial remission; SD ¼ stable disease. a At imaging studies (MRI, CT scan and transvaginal US scan). b Ongoing pregnancies have been excluded.
Ovarian cancer represents a heterogeneous condition: up to 90% of ovarian tumors are epithelial and about 10% are germ cell tumors and sex-cord-stromal tumors, therefore these entities will be treated separately [3e5]. 7. Invasive epithelial ovarian cancer The diagnosis of epithelial ovarian cancer in the reproductive years has become more frequent with increasing gynecologic check-ups. In the US, 14e18% of all cases of ovarian cancer will occur in women 45 years of age or younger [2e5,31]. The traditional treatment for early ovarian cancer consists of a total abdominal hysterectomy, bilateral salpingo-oopherectomy (SO), and complete surgical staging with pelvic/para-aortic lymphadenectomy, but more conservative surgery with preservation of the uterus or ovary may be feasible in a properly selected patient population [2e5,31]. According to the last American College of Obstetrics and Gynecology (ACOG) and European Society for Medical Oncology (ESMO) guidelines, fertility-sparing surgery for young women with invasive EOC can be adopted for stage IA and non-clear cell histology Grade 1 or 2 [32]. In this review 9 studies, including 507 young women (age range 11e40), have investigated the oncological and fertility outcomes of patients addressed to surgery for an invasive epithelial ovarian
cancer at an apparently early stage who desired the fertility preservation [31e39]. The vast majority of surgical procedures have been performed by laparotomy and included unilateral SO with peritoneal and retroperitoneal staging. Adjuvant chemotherapy has been administered if appropriated. In the long-term period a total of 52 (10.3%) and 28 (5.5%) patients recorded a recurrence and died from disease, respectively. At the same time 186 full term deliveries have been recorded in the same population [31e39]. 8. Low malignant potential (borderline) tumors Low malignant potential (LMP) or borderline ovarian tumors account for 10e15% of epithelial ovarian malignancies and they usually occur in a subset of patients 15e20 years younger than those with invasive epithelial cancers. Most of these patients are of childbearing age. Given the less aggressive nature of these tumors, conservative surgery consisting of unilateral SO or ovarian cystectomy with surgical staging (omentectomy, staging biopsies) is appropriate in women interested in preserving fertility. In this review 9 studies, including 935 young women (age range 11e42 years), have investigated the oncological and fertility outcomes of patients addressed to surgery for LMP ovarian tumors who desired the fertility preservation [40e48,54].
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Table 3 Studies about fertility-sparing options for women with ovarian cancer. Author
N of patientsa
Ovarian tumor FIGO stages, histologic types
Zanetta et al. 1997 [33]
56 patients 29 (14e39) years
EOC Stages IAeIC No clear cells G1eG3
Raspagliesi et al. 1997 [34]
10 patients 22.7 (16e36) years
Brewer et al. 1999 [49]
16 patients 19.5 (7e32) years
Morris et al. 2000 [40]
43 patients 25 (15e39) years
Low et al. 2000 [50]
74 patients 20.9 (10e35) years
Zanetta et al. 2001 [51]
138 patients 21 (8e41) years
Zanetta et al. 2001 [41]
189 patients 28 (12e42) years
Morice et al. 2001 [35]
25 patients 24 (15e39) years
Morice et al. 2001 [42]
49 patients 32 11.4 years
Schilder et al. 2001 [36]
52 patients 26 (11e40) years
Tangir et al. 2003 [52]
64 patients
Boran et al. 2005 [43]
62 patients 27.5 (16e40) years
Fauvet et al. 2005 [44]
162 patients 35.5 13.1
Rao et al. 2005 [45]
38 patients 26 (15e39) years
Proposed treatment
Open: 56/56 (100%) Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy (sampling vs. radical) þ/-Adjuvant chemotherapy as appropriate EOC Open: 10/10 (100%) Stages IAeIIIC Adnexal surgery þ peritoneal cytology No clear cells þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy (sampling vs. radical)þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 16/16 (100%) Stages IBeIV Adnexal surgery þ peritoneal cytology Dysgerminomas and random biopsies.(þ/-lymphadenectomy , appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Open: 43/43 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology Serous/Mucinous and random biopsies. MOGCT Open: 74/74 (100%)Adnexal Stages IeIV surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 138/138 (100%) Stages IeIV Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Open: 189/189 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 31/31 (100%) EOC Adnexal surgery þ peritoneal cytology Stages IaeIIIc All types þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate LMP Open: 49/49 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate EOC Open: 52/52 (100%) IA or IC Adnexal surgery þ peritoneal cytology All types þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 64/64 (100%) IAeIIIC Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate LMP Open: 58/62 (93.5%); LPS: 4/62 (6.5%). Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Adnexal surgery Open and LPS Stages IeIII
LMP Stages IeIII Serous /Mucinous
Open: 38/38 (100%) Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate
Survival outcomes
Fertility outcomesb
F-U 94 (range 34e175) months Recurrence: 5/56 (9%) DOD: 2/56 (3.6%)
27 pregnancies achieved 10/27: 1st trimester loss 17/27: term delivery
F-U 70 (24e138) months Recurrence: 0
3 pregnancies achieved 1/3: 1st trimester loss 2/3: term delivery
F-U 89 (18e183) months Recurrence: 1/16 (6.3%)
3 pregnancies achieved 3/3: term delivery
F-U 68.4 (16.8e300) months Recurrence: 14/43 (9.5%) DOD: 1/43 (2.3%) F-U 52.1 months (overall) Recurrence: 7/74 (9.5%) DOD: 2/74 (2.7%)
23 pregnancies achieved 7/23: 1st trimester loss 16/23: term delivery 16 pregnancies achieved 16/16: term delivery
F-U 70 (13e180) months Recurrence: 16/138 (11.6%) DOD: 3/138 (2.2%)
55 pregnancies achieved 15/55: 1st trimester loss 40/55: term delivery
F-U 70 (13e180) months Recurrence: 28/184 (15.2%) DOD: 1/184 (0.5%)
44 pregnancies achieved 3/44: 1st trimester loss 41/44: term delivery
F-U 47 (6e201) months Recurrence: 7 (28%) DOD: 3 (12%)
4 pregnancies achieved 1/4: 1st trimester loss 3/4: term delivery
F-U 109 (24e300) months Recurrence: 9/49 (18.4%)
16 pregnancies achieved 6/16: 1st trimester loss 10/16: term delivery
F-U 78 (3e423) months Recurrence: 5/52 (9.6%) DOD: 2/52 (3.8%)
31 pregnancies achieved 5/31: 1st trimester loss 26/31:term delivery
F-U 122 (24e384) months DOD: 11/106 (10%) * (overall series)
47 pregnancies achieved 12/47: 1st trimester loss 35/47: term delivery
F-U 44.3 (3e128) months Recurrence: 4/62 (6.5%) DOD: 0
13 pregnancies achieved 3/13: 1st trimester loss 10/13: term delivery
F-U (13.4e136.9) months Recurrence: 27/162 (16.6%) DOD: 0
30 pregnancies achieved 13/30: 1st trimester loss 1/13: preterm delivery (<37weeks)17/30: term delivery 8 pregnancies achieved 3/8: 1st trimester loss 5/8: term delivery
F-U 26 months (median) Recurrence 6/38 (16%) DOD: 0
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Table 3 (continued ) Author
N of patientsa
Ovarian tumor FIGO stages, histologic types
Proposed treatment
Survival outcomes
Fertility outcomesb
Romagnolo et al. 2006 [46]
53 patients
LMP Stages IeIII
Open: 16/53 (30.2%); LPS: 37/53 (69.8%). Adnexal surgery
8 pregnancies achieved
Borgfeldt et al. 2003 [37]
11 patients
EOC Stages IAeIIIC All types G1eG3
14 pregnancies achieved 14/14: term delivery
Park et al. 2008 [38]
62 patients 26 (13e40) years
F-U 56 (6e205) months Recurrence 11/62 (17.7%) DOD 6/62 (9.7%)
24 pregnancies achieved 2/24: 1st trimester loss 22/24: term delivery
Park et al. 2009 [47]
184 patients 29.6 11.5 years
EOC IAeIIIC All types G1eG3 LMP IAeIIIC Serous, Mucinous
F-U 60 (3e216) months Recurrence 18/184 (9.8%) DOD 5/184 (2.7%)
34: term delivery
Schlaert et al. 2009 [31]
20 patients EOC Median age 27 years IAeIC All types G1eG3
F-U 122 (11e256) months Recurrence 3/20 (15%) DOD 3/20 (15%)
9 pregnancies achieved 9/9: term delivery
Satoh et al. 2010 [32]
211 patients 29 (14e40) years
EOC IA and IC All types G1eG3
F-U 122 (11e256) months Recurrence 18/211 (8.5%) DOD 5/211 (2.4%)
76 pregnancies achieved 53/76: term delivery
Kajiyama et al. 2010 [39] 60 patients 30 (12e40) years
EOC IAeIC All types G1eG3
F-U 54.7 (4.8e243.8) mo. Recurrence 8/60 (13.3%) DOD 7/60 (11.7%)
13 pregnancies achieved 3/13: 1st trimester loss 1/13: preterm delivery (<37weeks) 9/13: term delivery
Weinberg et al. 2011 [53] 22 patients 26.5 (10e48) years
MOGCT IeIII
F-U 54.7 (4.8e243.8) mo. Recurrence: 0
Song et al. 2011 [54]
LMP IeIII
Open: 11/11 (100%) Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate Open: 56/62 (90.3%); LPS: 6/62 (9.7%). Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) Open: 136/184 (73.9%); LPS: 48/184 (26.1%).Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 20/20 (100%). Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 211/211 (100%) Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 60/60 (100%). Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 22/22 (100%)Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 105/155 (67.8%); LPS: 50/155 (32.2%). Adnexal surgery þ peritoneal cytology (þ/-lymphadenectomy, appendectomy, omentectomy)þ/-Adjuvant chemotherapy as appropriate
F-U 44 (6e122) months Recurrence 11/53 (21%) DOD 1/53 (1.9%) F-U 8 (16e185) months Recurrence 0
13 pregnancies achieved 1/13: 1st trimester loss 2/13: preterm delivery (<37weeks) 10/13: term delivery 57 pregnancies achieved 3/57: 1st trimester loss 54/57: term delivery
155 patients 29 (10e48) years
F-U 56.0 (0.6e155.9) mo. Recurrence: 12 (7.7%)
Data are expressed as median (range); mean sd or absolute number (%). MOGCT ¼ Malignant Ovarian Germ Cell Tumors; LMP ¼ Low Malignant Potential; EOC ¼ epithelial ovarian cancer. LPS ¼ Laparoscopic approach; Open ¼ traditional abdominal approach. a Number of successful fertility-sparing procedures. b Ongoing pregnancies have been excluded.
Also in this case, most of the surgical procedure have been performed by laparotomy and included adnexal surgical procedure. Peritoneal and retroperitoneal staging procedure are also describes as well as the administration of adjuvant chemotherapy regimens, when needed. In the long-term period a total of 129 (13.8%) and 8 (0.9%) patients recorded a recurrence and died from disease, respectively. At the same time 141 full term deliveries have been assessed in the same population [40e48,54]. Across the last years a burgeoning literature is currently highlighting the advantages of minimally invasive surgery for the management of adnexal pathology including the treatment of LMP ovarian tumors especially in terms of reduced trauma to the ovarian tissue and the reduced risk of adhesions. Therefore the benefits of laparoscopic surgery may be also enhanced in the fertility-sparing setting. In addition minimally access surgery allows a faster recovery and it could be better tolerated especially when a secondlook or the treatment of a recurrence is needed. Indeed fertility-
sparing procedures in LMP ovarian tumors record higher recurrence rates than radical treatments, without affecting the overall survival. However, regarding the long-term oncologic outcomes, patients with advanced stage disease were included in most of the series analyzed. It is well known that the presence of invasive peritoneal implants in women with advanced stage tumors represents an independent prognostic factor which significantly affects survival in comparison to the counterpart with non-invasive implants [55]. This data should be taken into account especially in women addressed to fertility-sparing procedures. 9. Malignant germ cells ovarian tumors Malignant ovarian germ cell tumors (MOGCT) affect mainly children and young women. Preservation of fertility in this patient population is of particular interest. Malignant MOGCT can be divided into two groups: dysgerminomas and nondysgerminomas.
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Nondysgerminoma tumors include endodermal sinus tumors, immature teratomas, mixed germ cell tumors, choriocarcinomas, embryonal carcinomas, and polyembryomas, which are in most of cases unilateral. On the contrary dysgerminomas, in up to 15% of cases, are bilateral. Thus, conservative surgery with a unilateral SO surgical staging can be considered in this patient population. In cases of bilateral dysgerminomas, conservative surgery including bilateral ovarian cystectomies could be performed. In this review 5 studies, including 314 young women (age range 7e48), have investigated the oncological and fertility outcomes of patients addressed to surgery for MOGCT who desired the fertility preservation [49e53]. Also in this case, most of the surgical procedure have been performed by laparotomy and included mostly adnexal surgical procedure. Peritoneal and retroperitoneal staging procedure are also describes as well as the administration of adjuvant chemotherapy regimens, when needed. In the long-term period a total of 19 (6%) and 13 (4.1%) patients recorded a recurrence and died from disease, respectively. At the same time 124 full term deliveries have been assessed in the same population. For MOGCT fertility-sparing surgery represent a viable option also for advanced stages, since effective chemotherapy options are currently available, indeed several reports showed comparable outcomes between patients who underwent conservative treatments with those who were treated with more aggressive surgery. 10. Comment In gynecologic oncology, effective treatments to achieve cancer survival can compromise the ability to subsequently conceive and/or carry a child. Therefore, as the field of oncofertility continues to expand, a discussion regarding fertility preservation should be initiated when tailoring a cancer treatment protocol [2e6]. The necessary treatment for most of the gynecological malignancies involves either removal of the reproductive organ, or cytotoxic treatment that could partially or definitively affect reproductive function [20]. However, in carefully selected patients having a strong desire for future fertility staging and therapeutic surgical procedures can be tailored in order to preserve fertility. A detailed counseling session, even in a motivated patient, is crucial and mandatory to the success of these techniques [2e5]. Management of young women with early gynecologic cancer should therefore be individualized with the risk of conservative therapy balanced against the dangers and advantages of more radical therapy [2e5]. Ideally the increased know-how for gynecologic cancer treatment allows the performance of fertility-sparing procedures even in cases of locally advanced disease. However our treatment strategy should not be focused on the technical feasibility alone, but mainly on the patient’s desire to retain fertility and parenthood. Medicine is a dynamic process with a constant evolution in the ability to diagnose, treat, and cure diseases. In the field of gynecologic oncology, effective treatments can unfortunately come at the price of a woman’s ability to conceive and carry a child. Therefore, as we succeed in our fight against previously untreatable malignancies, the population of cancer survivors grows and the loss of fertility becomes a crucial component to a survivor’s QoL. The field of oncofertility requires therefore a multidisciplinary approach which should include the know-how of skilled surgeons, medical and radiation oncologists, reproductive endocrinologists, perinatologists, and psychosocial support professionals, to ensure that all patients are afforded the opportunity to maintain their reproductive potential and are given the chance to achieve their wishes of parenthood. However the oncological safety of fertility-preserving options needs to be proven through robust multicentre studies. Preliminary
findings suggest that fertility-sparing procedures in carefully selected patients provide promising results, which are comparable to dose achieved by more other radical treatments. Conflict of interest statement The authors declare that there are no conflicts of interest. References [1] American Cancer Society. Cancer Facts and Figures, (http://www.cancer.org/ acs/groups/content/@nho/documents/document/acspc-024113.pdf); 2010 [accessed 20 April, 2011]. [2] Noyes N, Knopman JM, Long K, Coletta JM, Abu-Rustum NR. Fertility considerations in the management of gynecologic malignancies. Gynecol Oncol 2011;120:326e33. [3] Makar AP, Tropé C. Fertility preservation in gynecologic cancer. Acta Obstet Gynecol Scand 2001;80:794e802. [4] Rasool N, Rose PG. Fertility-preserving surgical procedures for patients with gynaecologic malignancies. Clin Obstet Gynecol 2010;53:804e14. [5] Gershenson DM. Fertility-sparing surgery for malignancies in women. J Natl Cancer Inst Monogr 2005;34:43e7. [6] Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for earlystage cervical cancer. Am J Obstet Gynecol 1998;179:1491e6. [7] Burnett AF, Roman LD, O'Meara AT, Morrow CP. Radical vaginal trachelectomy and pelvic lymphadenectomy for preservation of fertility in early cervical carcinoma. Gynecol Oncol 2003;88:419e23. [8] Schlaerth JB, Spirtos NM, Schlaerth AC. Radical trachelectomy and pelvic lymphadenectomy with uterine preservation in the treatment of cervical cancer. Am J Obstet Gynecol 2003;188:29e34. [9] Ungár L, Pálfalvi L, Hogg R, Siklós P, Boyle DC, Del Priore G, et al. Abdominal radical trachelectomy: a fertility-preserving option for women with early cervical cancer. BJOG 2005;112:366e9. [10] Hertel H, Köhler C, Grund D, Hillemanns P, Possover M, Michels W, et al. Radical vaginal trachelectomy (RVT) combined with laparoscopic pelvic lymphadenectomy: prospective multicenter study of 100 patients with early cervical cancer. Gynecol Oncol 2006;103:506e11. [11] Shepherd JH, Spencer C, Herod J, Ind TE. Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancercumulative pregnancy rate in a series of 123 women. BJOG 2006;113:719e24. [12] Landoni F, Parma G, Peiretti M, Zanagnolo V, Sideri M, Colombo M, et al. Chemo-conization in early cervical cancer. Gynecol Oncol 2007;107:S125e6. [13] Sonoda Y, Chi DS, Carter J, Barakat RR, Abu-Rustum NR. Initial experience with Dargent's operation: the radical vaginal trachelectomy. Gynecol Oncol 2008; 108:214e9. [14] Pareja FR, Ramirez PT, Borrero FM, Angel CG. Abdominal radical trachelectomy for invasive cervical cancer: a case series and literature review. Gynecol Oncol 2008;111:555e60. [15] Maneo A, Chiari S, Bonazzi C, Mangioni C. Neoadjuvant chemotherapy and conservative surgery for stage IB1 cervical cancer. Gynecol Oncol 2008;111: 438e43. [16] Olawaiye A, Del Carmen M, Tambouret R, Goodman A, Fuller A, Duska LR. Abdominal radical trachelectomy: success and pitfalls in a general gynecologic oncology practice. Gynecol Oncol 2009;112:506e10. [17] Kim JH, Park JY, Kim DY, Kim YM, Kim YT, Nam JH. Fertility-sparing laparoscopic radical trachelectomy for young women with early stage cervical cancer. BJOG 2010;117:340e7. [18] Nishio H, Fujii T, Kameyama K, et al. Abdominal radical trachelectomy as a fertility-sparing procedure in women with early stage cervical cancer in a series of 61 women. Gynecol Oncol 2009;115:51e5. [19] Li J, Li Z, Wang H, Zang R, Zhou Y, Ju X, Ke G, Wu X. Radical abdominal trachelectomy for cervical malignancies: Surgical, oncological and fertility outcomes in 62 patients. Gynecol Oncol 2011;121:565e70. [20] Marhhom E, Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv 2007;62:58e72. [21] Rob L, Pluta M, Strnad P, Hrehorcak M, Chmel R, Skapa P, et al. A less radical treatment option to the fertility-sparing radical trachelectomy in patients with stage I cervical cancer. Gynecol Oncol 2008;111:S116e20. [22] Smith AL, Frumovitz M, Schmeler KM, Reis RD, Nick AM, Coleman RL, et al. Conservative surgery in early-stage cervical cancer: what percentage of patients may be eligible for conization and lymphadenectomy? Gynecol Oncol 2010;119:183e6. [23] Kaku T, Yoshikawab H, Tsudac H, Sakamoto A, Fukunaga M, Kuwabara Y, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167:39e48. [24] Wang CB, Wang CJ, Huang HJ, Hsueh S, Chou HH, Soong YK, et al. Fertilitypreserving treatment in young patients with endometrial adenocarcinoma. Cancer 2002;94:2192e8. [25] Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102:718e25.
D. Vitobello et al. / Placenta 32 (2011) S224eS231 [26] Yamazawa K, Hirai M, Fujito A, Nishi H, Terauchi F, Ishikura H, et al. Fertilitypreserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer. Hum Reprod 2007;22: 1953e8. [27] Signorelli M, Caspani G, Bonazzi C, Chiappa V, Perego P, Mangioni C. Fertilitysparing treatment in young women with endometrial cancer or atypical complex hyperplasia: a prospective single-institution experience of 21 cases. BJOG 2009;116:114e8. [28] Hahn HS, Yoon SG, Hong JS, Hong SR, Park SJ, Lim JY, et al. Conservative treatment with progestin and pregnancy outcomes in endometrial cancer. Int J Gynecol Cancer 2009;19:1068e73. [29] Minig L, Franchi D, Boveri S, Casadio C, Bocciolone L, Sideri M. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Ann Oncol 2011;22:643e9. [30] Laurelli G, Di Vagno G, Scaffa C, Losito S, Del Giudice M, Greggi S. Conservative treatment of early endometrial cancer: preliminary results of a pilot study. Gynecol Oncol 2011;120:43e6. [31] Schlaerth AC, Chi DS, Poynor EA, Barakat RR, Brown CL. Long-term survival after fertility-sparing surgery for epithelial ovarian cancer. Int J Gynecol Cancer 2009;19:1199e204. [32] Satoh T, Hatae M, Watanabe Y, Yaegashi N, Ishiko O, Kodama S, et al. Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection. J Clin Oncol 2010;28:1727e32. [33] Zanetta G, Chiari S, Rota S, Bratina G, Maneo A, Torri V, et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. BJOG 1997;104:1030e5. [34] Raspagliesi F, Fontanelli R, Paladini D, de Re EM. Conservative surgery in highrisk epithelial ovarian carcinoma. J Am Coll Surg 1997;185:457e60. [35] Morice P, Wicart-Poque F, Rey A, El-Hassan J, Pautier P, Lhommé C, et al. Results of conservative treatment in epithelial carcinoma. Cancer 2001;92:2412e8. [36] Schilder JM, Thompson AM, DePriest PD, Ueland FR, Cibull ML, Kryscio RJ, et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002;87:1e7. [37] Borgfeldt C, Iosif C, Masback A. Fertility-sparing surgery and outcome in fertile women with ovarian borderline tumors and epithelial invasive ovarian cancer. Eur J Obstet Gynecol Reprod Biol 2007;134:110e4. [38] Park JY, Kim DY, Suh DS, Kim JH, Kim YM, Kim YT, et al. Outcomes of fertilitysparing surgery for invasive epithelial ovarian cancer: oncologic safety and reproductive outcomes. Gynecol Oncol 2008;110:345e53. [39] Kajiyama H, Shibata K, Suzuki S, Ino K, Nawa A, Kawai M, et al. Fertilitysparing surgery in young women with invasive epithelial ovarian cancer. Eur J Surg Oncol 2010;36:404e8. [40] Morris R, Gershenson D, Silva EG, Follen M, Morris M, Wharton JT. Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol 2000;95:541e7.
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Gynecological fertility-sparing surgery D. Vitobello*, G. Siesto, C. Bulletti, A. Accardi, P.E. Levi Setti Department of Gynecology, Cancer Center, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 23 June 2011
The implementation of early detection protocols and advanced treatment strategies has significantly improved survival outcomes for gynecologic cancer patients. The improvement of oncological outcomes has led to an increased attention toward Quality of Life issues, including the childbearing potential for young women. Traditionally the surgical treatment of cervical, endometrial and ovarian cancers involves the removal of the uterus and adnexa, irrespective of the impact on fertility and parenthood and regardless of patient desires. For young women affected by gynecological malignancies at an apparently early stage, fertility-sparing procedures could be offered. The aim of our review is to going through the available evidence in the Literature and to evaluate the current state of art regarding fertility-sparing procedures for women with gynecological malignancies in terms of oncological and fertility outcomes. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Cervical cancer Ovarian cancer Endometrial cancer Fertility-sparing surgery Fertility preservation
1. Introduction According to the American Cancer Society gynecologic tumors are among the 10 most common malignancies representing the 12e15% of all cancers suffered by women [1e3]. Although the majority of cases are diagnosed in postmenopausal females, a significant subset e approximately 20% e is represented by women in reproductive age who are yet to complete or commence a family planning [2e5]. In particular, 8% of endometrial, 12% of ovarian and 40% of cervical cancers occur in the childbearing years [2]. Historically, cancer treatment regimens focused primarily on eradicating disease, irrespective of the impact on fertility and parenthood, regardless of patient age and desires. However, the implementation of early detection protocols and advanced treatment strategies has significantly improved survival outcomes for gynecologic cancer patients so that a paradigm shift occurred, moving from a concept of “the maximum sustainable” to “the least effective” surgery. These improvements, which are principally based on our increased understanding of biologic behaviors, have also led to a greater attention toward Quality of Life (QoL) issues for cancer survivors, including the childbearing potential. Therefore, fertility preservation (FP) and parenthood after cancer are now integral
* Corresponding author. Tel.: þ39 02 82244601; fax: þ39 02 82244693. E-mail address: [email protected] (D. Vitobello). 0143-4004/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2011.06.017
components for the pre-treatment counseling, especially for those women who record low risk factors and for which a fertilitysparing approach seems to be reasonable without compromising long-term outcomes [3e5]. During the last years the number of paper reporting different fertility-sparing option together with survival outcomes has grown dramatically, moving the limit for a conservative treatment at ever more distant levels [2e5]. The aim of this paper is to go through the evidence available in the Literature and to assess the state of art about the fertilitysparing options for women affected by cervical, endometrial and ovarian cancer. 2. Methods e review criteria A comprehensive literature review of published clinical studies on gynecological fertility-sparing surgery was carried out at the Humanitas Clinical Institute with cross-search of seven different medical databases (AMED e Allied and Complementary Medicine Database, BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase and Medline on Web of Knowledge, OvidSP and PubMed). Search temporal limits included paper published between January 1990 and April 2011 with the purpose to provide the most recent evidence regarding this issue. Studies were queried using the following key-words in various combinations: “fertilitysparing/fertility preservation”, “cervical/endometrial/ovarian” and “cancer/carcinoma/tumour”. Among the hundreds of articles identified, we retrieved those manuscripts that were more relevant for the purpose of this review and provided results from case series and/or conceptual findings. If manuscripts were comparable for aim, their clinical relevance was scaled according to: originality, study design (meta-analyses vs. randomized vs. prospective vs. retrospective studies), the method used, the evidence level and the sample size. Case reports have been excluded from this analysis. The journal relevance based on the actual impact factor score was used as ultimate criterion of choice, if needed. A further manual cross-search of the
D. Vitobello et al. / Placenta 32 (2011) S224eS231 references of each selected article was finally performed in order to further identify studies not captured by the online search but potentially relevant for this review. Only articles published in English language were considered.
3. Results A total of 45 papers regarding fertility-sparing options for gynecological malignancies have been retrieved. In particular, 14 studies investigated the different treatment strategies for cervical cancer, 8 for endometrial cancer and 23 for ovarian cancer, respectively. In order to provide the most recent scenario regarding each gynecological malignancy of interest, the outcomes of more than 2250 patients included will be discussed separately, according to their primary cancer site. 4. Cervical cancer Data regarding the 14 studies about fertility-sparing procedures for cervical cancer have been summarized in Table 1 [6e19]. Cervical cancer represents the most common cause of death from gynecologic cancer worldwide. More than 40% of all cases are diagnosed in women younger than 45 years. For women with early stage disease the standard surgical treatment consists of a radical hysterectomy and pelvic lymph node dissection or concurrent pelvic chemo-radiation. In both cases fertility is lost [5,20,21]. Among patients with cervical cancer, women with favorable preoperative characteristics (including tumors of small volume (<2 cm), well differentiated, with a depth of stromal infiltration <10 mm and without evidence of lymphovascular space invasion) conservative treatment could be proposed, if requested. Smith et al. have recently performed an intriguing review regarding women with early stage cervical cancer to determine how many patients treated with radical hysterectomy may have been eligible for a fertility-sparing surgery consisting of cervical conization with pelvic nodal dissection [22]. During the study period 507 women have been identified. Of these 53 patients were 40 years of age with favorable pathologic characteristics and they could have been eligible for conservative, fertility-sparing surgery. Interestingly none of these 53 patients were found to have parametrial involvement or positive pelvic lymph nodes. These women have certainly benefited from a fertility-sparing treatment if only they had had the possibility [22]. Our literature review, however, leads to further considerations: among the 14 paper analyzed more than 550 patients have been collected: 12 studies evaluated the surgical, oncological and fertility outcomes of women who underwent radical trachelectomy with nodal dissection by laparoscopic, abdominal or vaginal approach [6e11,13,14,16e19], whereas the lasting 2 papers investigated the same outcomes of women undergoing cervical conization after neoadjuvant chemotherapy with TIP (paclitaxel 175 mg/ mq þ ifosphamide 5 g/mq þ cisplatin 75 mg/mq) or TEP (paclitaxel 175 mg/mq þ epirubicin 80 mg/mq þ cisplatin 75 mg/mq) for squamous cell carcinoma and adenocarcinoma, respectively [12,15]. Radical trachelectomy or cervical chemo-conization appeared to be feasible and oncologically safe in the long-term period also in case of locally advanced cervical cancer (FIGO stages Ib2eIIa) [6,7,9,16,17]. Indeed, in the overall population, only 18 (3.2%) recurrences were recorded with 8 (1.4%) patients who died for disease. On the other hand, concerning the fertility outcomes, among these young women (age range 17e45 years) just 116 pregnancies were obtained: in particular only 34 (29.3%) full term deliveries (most of which through cesarean section) were recorded. In 43 (34.5%) and 11 (9.5%) of cases preterm-deliveries and 2nd trimester pregnancy losses occurred, even if permanent abdominal cerclage was generally positioned at the end of the procedures. This
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risk seems to be reduced for patients who underwent chemoconization, but data are too small to draw definitive conclusion [6e19]. Therefore, despite the encouraging results given by the technical feasibility and the oncological safety of fertility-sparing procedures for cervical cancer, only a minority of patients definitely attempt to and achieve pregnancy and, paradoxically, those cases are also exposed to an increased risk of preterm delivery [21]. We feel that this is something that patients should be aware and that should be extensively explained during the preoperative counseling. 5. Endometrial cancer Data regarding the 8 studies about fertility-sparing procedures for cervical cancer have been summarized in Table 2 [23e30]. Endometrial carcinoma is the most common gynecological malignancy in western countries. This condition typically affects postmenopausal women. However, 20e25% of endometrial adenocarcinoma cases are diagnosed before menopause, but only and 2e14% of cases occur before the age of 40 years. These young women tend to have disease with favorable prognostic factors, such as low-grade endometrioid histology with oestrogen/progesterone receptor-positive disease and stage I disease with little or no myometrial invasion [20,28]. The standard treatment for patients with early stage endometrial cancer is the hysterectomy with bilateral salpingooophorectomy, with staging dependent upon risk factors [20,28]. To date only few reports of fertility-sparing procedures for endometrial cancer are available in the literature, as endometrial cancers are quite rare in this population subset and only well differentiated endometrioid adenocarcinoma without suspicious of myometrial involvement are considered as optimal candidates for conservative treatments. Lymph node status could be assessed with imaging studies as MRI in which a lymph node greater than 1 cm in short axis or with central necrosis is considered to be suspicious. Radiologic imaging, however, has its limitations and direct evaluation with laparoscopic pelvic lymphadenectomy is advocated by some authors [4]. Among the 8 papers retrieved about this issue a total of 165 women were included (age range 21e44 years). In particular 117 (70.9%) and 48 (29.1%) recorded the histological diagnosis of endometrial cancer and atypical endometrial hyperplasia, respectively. For these patients different treatments with progestins were proposed, with different doses, duration, mode of administration and timing of assessment of responses. Overall, 70 pregnancies have been obtained with 47 (40.2%) full term deliveries. Sixty-seven (57.6%) women were finally addressed to definitive treatment by total hysterectomy (bilateral salpingo-oophorectomy) [23e30]. More recently a progesterone releasing intrauterine device (IUD) has been successfully applied for the treatment of estrogendependent endometrial cancer with promising results [29,30]. The rationale for treating endometrial cancer with this device, instead of the oral administration, is that this IUD provides very high doses of the hormone at the specific site of the pathology. This avoids both the adverse effects produced by systemic administration and the suboptimal patient’s compliance [29,30]. Although these studies reported that treatment with progestin is effective and safe, there are several still unsolved issues for young patients with endometrial cancer that need to be specifically addressed, including: 1) what is the optimal progestin treatment regimen, particularly regarding dosage and duration? 2) Most of the younger women recognize the impaired ovulation as the underling pathologic condition which enhances the risk of endometrial cancer and long standing issues of infertility often complicates matters, so that, is the ovulation induction agent for
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Table 1 Studies about fertility-sparing options for women with cervical cancer. Author
N of patients,a age (range)
FIGO stages histologic types
Proposed treatment
Survival outcomes
Fertility outcomesb
Roy et al. 1998 [6]
30 patients 32 (22e42) years
Ia1eIIa SCC þ AdenoK
RVT þ laparoscopic PLN
F-U 25 (1e79) months Recurrence: 1 (3.3%) DOD: 1 (3.3%)
Burnett at al. 2002 [7]
19 patients 30 (23e41) years
Ia2eIIa SCC þ AdenoK
LARVT þ PLN
F-U 31.5 (22e44) months Recurrence: 0
Schlearth et al. 2003 [8]
10 patients 30.9 (22e44) years
Ia2eIb SCC þ AdenoK
LARVT (4/10; 40.0%) þ PLNRVT (6/10; 60.0%) þ PLN
F-U 47 (28e84) months Recurrence: 0
Ungar et al. 2005 [9]
30 patients 30.5 (23e37) years
Ia2eIb2 SCC þ AdenoK
ART þ PLN
F-U 47 (14e75) months Recurrence: 0
Hertel et al. 2006 [10]
100 patients 32 (21e41) years
Ia1eIb1 SCC þ AdenoK
LARVT þ PLN
F-U 29 (1e128) months Recurrence: 4/100 (4.0%) DOD: 2/100 (2.0%)
Shepherd et al. 2006 [11]
123 patients 30.6 (21e45) years
Ia2eIb1 SCC þ AdenoK
LARVT þ PLN
F-U 45 (1e120) months Recurrence: 5/123 (4.1%) DOD: 4/123 (3.3%)
Landoni et al. 2007 [12]
11 32 41 31
patients (24e41 years) patients (20e40) years
Ia2eIb1 SCC þ Adenok Ia1eIb1 SCC þ AdenoK
NACT þ conization
F-U 20 (7e29) months Recurence: 0 F-U 21 (3e60) months Recurrence: 1/41 (2.5%)
Rene Pareja et al. 2008 [14]
15 patients 30 (25e38) years
Ia2eIb1 SCC þ AdenoK
ART þ PLN
F-U 32 (5e32) months Recurrence: 0
Maneo et al. 2008 [15]
16 patients 30 (17e39) years
SCC þ AdenoK þ Indifferentiated
NACT þ conization
F-U 69 (10e214) months Recurrence: 0
Olawaiye et al. 2009 [16]
10 patients 31 (26e38) years
Ia1eIIa SCC þ AdenoK
ART þ PLN
F-U 28 (1e74) months Recurrence: 0
Kim et al. 2009 [17]
27 patients 29 (22e37) years
Ib1eIIa SCC þ AdenoK
LRT þ PLN PALN
F-U 31 (1e58) months Recurrence 1/27 (3.7%) DOD 1/27 (3.7%)
Nishio et al. 2009 [18]
61 patients 33 (26e44) years
Ia1eIb1 SCC þ AdenoK
ART þ PLN
F-U 27 (1e79) months Recurrence: 6/61 (9.8%)
Li et al. 2011 [19]
62 patients
Ia1eIb1SCC þ AdenoK(þ3 cases of Botryoid sarc)
ART þ PLN
F-U 22.8 (1e78) months Recurrence: 0
5 pregnancies achieved 1/5: 1st trimester loss 2/5: preterm delivery (<37weeks) 2/5: term delivery 3 pregnancies achieved 1/3: 2nd trimester loss 1/3: preterm delivery (<37weeks) 1/3: term delivery 4 pregnancies achieved 2/4: 2nd trimester loss 2/4: preterm delivery (<37weeks) 3 pregnancies achieved 1/3: 1st trimester loss 2/3: term delivery 15 pregnancies achieved 3/15: 1st trimester loss 8/15: preterm delivery (<37weeks) 4/15: term delivery 52 pregnancies achieved 17/52: 1st trimester loss 7/52: 2nd trimester loss 20/52: preterm delivery (<37weeks) 8/52: term delivery 3 pregnancies achieved 3/3: term delivery 7 pregnancies achieved 2/7: 1st trimester loss 1/7: 2nd trimester loss 3/7: preterm delivery (<37weeks) 1/7: term delivery 3 pregnancies achieved 1/3: preterm delivery (<37weeks) 2/3: term delivery 10 pregnancies achieved 1/10: 1st trimester loss 2/10: preterm delivery (<37weeks) 7/10: term delivery 3 pregnancies achieved 1/3: 1st trimester loss 1/3: preterm delivery (<37weeks) 1/3: term delivery 3 pregnancies achieved 2/3: 1st trimester loss 1/11: preterm delivery (<37weeks) 4 pregnancies achieved 2/4: preterm delivery (<37weeks) 2/4: term delivery 1 pregnancy achieved 1/1: term delivery
Sonoda et al. 2008 [13]
LARVT þ PLN PALN
Data are expressed as median (range); mean sd or absolute number (%). LARVT ¼ laparoscopic-assisted radical vaginal trachelectomy; LRT ¼ laparoscopic radical trachelectomy; RVT ¼ radical vaginal trachelectomy; ART ¼ abdominal radical trachelectomy; NACT ¼ neoadjuvant chemotherapy; PLN ¼ pelvic lymphadenectomy; PALN ¼ para-aortic lymphadenectomy. SCC ¼ Squamous cell carcinoma; AdenoK ¼ adenocarcinoma/Adenosquamous. a Number of successful fertility-sparing procedures. b Ongoing pregnancies have been excluded.
ART safe or helpful to young patients with endometrial cancer? 3) What is the chance of progression to advanced disease during or after medical treatment? 4) Is hysterectomy needed after completion of childbearing? [26e29].
6. Ovarian cancer Data regarding the 22 studies about fertility-sparing procedures for ovarian cancer have been summarized in Table 3.
D. Vitobello et al. / Placenta 32 (2011) S224eS231
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Table 2 Studies about fertility-sparing options for women with endometrial cancer. Author
N of patients, age (range)
FIGO stages included, grading and histological type
Proposed treatment
Results
Fertility outcomesb
Kaku et al. 2001 [23]
30 patients 29.3 (21e42) years
MPA 200e800 mg/d for 2e14 monthsD&C every 1e4 months
9 patients 32 (30e39) years
CR ¼ 21/30 (70%) PR ¼ 3/30 (10%) SD ¼ 6/30 (20%) Hysterectomy 11/30 (36.6%) CR ¼ 6/9 (66.7%) SD ¼ 3/9 (33.3%) Hysterectomy 3/9 (33.3%)
10 pregnancies achieved 5/10: 1st trimester loss 5/10: term delivery
Wang et al. 2002 [24]
AEH (18/30; 60%)þ EC Ia (M0)a (12/30; 40%) Grade 1 (12/12; 100%), Endometrioid. EC Ia (M0)a (9/9; 100%) Grade 1 (9/9; 100%), Endometrioid.
Gotlieb et al. 2003 [25]
13 patients 31 (23e40) years
Yamazawa et al. 2007 [26]
9 patients 36 (28e40) years
Signorelli et al. 2008 [27]
21 patients 32 (21e40) years
Hahn et al. 2009 [28]
35 patients 31 (21e43) years
Minig et al. 2011 [29]
Laurelli et al. 2011 [30]
MA 160 mg/d þ tamoxifen 30 mg/d for 6 months Hysteroscopy D&C/6 months
EC Ia (M0)a Grade 1 (11/13; 84.6%), Grade 2 (2/13; 15.4%) Endometrioid. EC Ia (M0)a (9/9; 100%) Grade 1 (9/9; 100%), Endometrioid.
MPA 200e600 mg/d vs. MA 160 mg/d for 2e3 months Serial D&C every 3e6 months
Hysterectomy 4/13 (30.8%)
MPA 400 mg/d for 6 months Transvaginal US þ biopsy monthlyD&C every 3 months
AEH (10/21; 47.6%) þ EC Ia (M0)a (11/21; 52.4%) Grade 1 (11/11; 100%), Endometrioid. Ia (M0),a Grade 1 (31/35; 88.6%), Grade 2 (4/35; 11.4%) Endometrioid.
NP 200 mg/d from 14th-25th day for 3e9 monthsSerial hysteroscopy þ endometrial biopsy every 3 months MPA 250e1500 mg/d and-or MA 160 mg/d for 3e20 months Serial D&C every 3 months
CR ¼ 3/9 (33.3%) PR ¼ 5/9 (53.6%)) SD ¼ 1/9 (11.1%) Hysterectomy 2/9 (22.2%) CR ¼ 3/21 (14%) PR ¼ 9/21 (43%) SD ¼ 9/11 (43%) Hysterectomy 15/21 (71.4%) CR ¼ 22/35 (62.9%) PR ¼ 1/35 (2.9%) SD ¼ 12/35 (34.3%) Hysterectomy 17/35 (48.6%)
34 patients 34 (22e40) years
AEH (20/34; 58.3%)þ EC Ia (M0)a (14/34; 41.7%) Grade 1 (14/14; 100%), Endometrioid.
LNG-IUD þ GnRH for 6 months; Transvaginal US/3 months Hysteroscopy þ biopsy/6 months
CR ¼ 27/34 (79.4%) SD ¼ 2/34 (5.9%) Progression ¼ 5/34 (14.7%) Hysterectomy 14/34 (41.2%)
14 patients 38 (26e40) years
EC Ia (M0)a Grade 1 (14/14; 100%), Endometrioid.
MA 160 mg/d for 6 months vs. LNG-IUD for 8 months
CR ¼ 12/14 (85.8%) PR ¼ 1/14 (7.1%) SD ¼ 1/14 (7.1%) Hysterectomy 1/14 (7.1%)
6 pregnancies achieved 3/6: 1st trimester loss 1/6: 2nd trimester loss 2/6: term delivery 10 pregnancies achieved 1/10: 1st trimester loss 9/10: term delivery 4 pregnancies achieved 1/4: 1st trimester loss 3/3: term delivery 16 pregnancies achieved 3/16: 1st trimester loss 1/16: 2nd trimester loss 12/16: term delivery 13 pregnancies achieved 5/13: 1st trimester loss 1/13: preterm delivery (<37weeks) 7/13: term delivery 10 pregnancies achieved 2/10: 1st trimester loss 1/10: preterm delivery (<37weeks) 7/10: term delivery 1 pregnancy achieved 1/1: term delivery
Data are expressed as median (range); mean sd or absolute number (%). AEH ¼ atypical endometrial hyperplasia; EC ¼ endometrial cancer; M0 ¼ no myometrial invasion. NP ¼ natural progesterone; MPA ¼ medroxyprogesterone acetate; MA ¼ Megestrol acetate; D&C ¼ dilation and curettage; LNG-IUD ¼ levonorgestrel-release intrauterine device. CR ¼ complete remission; PR ¼ partial remission; SD ¼ stable disease. a At imaging studies (MRI, CT scan and transvaginal US scan). b Ongoing pregnancies have been excluded.
Ovarian cancer represents a heterogeneous condition: up to 90% of ovarian tumors are epithelial and about 10% are germ cell tumors and sex-cord-stromal tumors, therefore these entities will be treated separately [3e5]. 7. Invasive epithelial ovarian cancer The diagnosis of epithelial ovarian cancer in the reproductive years has become more frequent with increasing gynecologic check-ups. In the US, 14e18% of all cases of ovarian cancer will occur in women 45 years of age or younger [2e5,31]. The traditional treatment for early ovarian cancer consists of a total abdominal hysterectomy, bilateral salpingo-oopherectomy (SO), and complete surgical staging with pelvic/para-aortic lymphadenectomy, but more conservative surgery with preservation of the uterus or ovary may be feasible in a properly selected patient population [2e5,31]. According to the last American College of Obstetrics and Gynecology (ACOG) and European Society for Medical Oncology (ESMO) guidelines, fertility-sparing surgery for young women with invasive EOC can be adopted for stage IA and non-clear cell histology Grade 1 or 2 [32]. In this review 9 studies, including 507 young women (age range 11e40), have investigated the oncological and fertility outcomes of patients addressed to surgery for an invasive epithelial ovarian
cancer at an apparently early stage who desired the fertility preservation [31e39]. The vast majority of surgical procedures have been performed by laparotomy and included unilateral SO with peritoneal and retroperitoneal staging. Adjuvant chemotherapy has been administered if appropriated. In the long-term period a total of 52 (10.3%) and 28 (5.5%) patients recorded a recurrence and died from disease, respectively. At the same time 186 full term deliveries have been recorded in the same population [31e39]. 8. Low malignant potential (borderline) tumors Low malignant potential (LMP) or borderline ovarian tumors account for 10e15% of epithelial ovarian malignancies and they usually occur in a subset of patients 15e20 years younger than those with invasive epithelial cancers. Most of these patients are of childbearing age. Given the less aggressive nature of these tumors, conservative surgery consisting of unilateral SO or ovarian cystectomy with surgical staging (omentectomy, staging biopsies) is appropriate in women interested in preserving fertility. In this review 9 studies, including 935 young women (age range 11e42 years), have investigated the oncological and fertility outcomes of patients addressed to surgery for LMP ovarian tumors who desired the fertility preservation [40e48,54].
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Table 3 Studies about fertility-sparing options for women with ovarian cancer. Author
N of patientsa
Ovarian tumor FIGO stages, histologic types
Zanetta et al. 1997 [33]
56 patients 29 (14e39) years
EOC Stages IAeIC No clear cells G1eG3
Raspagliesi et al. 1997 [34]
10 patients 22.7 (16e36) years
Brewer et al. 1999 [49]
16 patients 19.5 (7e32) years
Morris et al. 2000 [40]
43 patients 25 (15e39) years
Low et al. 2000 [50]
74 patients 20.9 (10e35) years
Zanetta et al. 2001 [51]
138 patients 21 (8e41) years
Zanetta et al. 2001 [41]
189 patients 28 (12e42) years
Morice et al. 2001 [35]
25 patients 24 (15e39) years
Morice et al. 2001 [42]
49 patients 32 11.4 years
Schilder et al. 2001 [36]
52 patients 26 (11e40) years
Tangir et al. 2003 [52]
64 patients
Boran et al. 2005 [43]
62 patients 27.5 (16e40) years
Fauvet et al. 2005 [44]
162 patients 35.5 13.1
Rao et al. 2005 [45]
38 patients 26 (15e39) years
Proposed treatment
Open: 56/56 (100%) Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy (sampling vs. radical) þ/-Adjuvant chemotherapy as appropriate EOC Open: 10/10 (100%) Stages IAeIIIC Adnexal surgery þ peritoneal cytology No clear cells þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy (sampling vs. radical)þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 16/16 (100%) Stages IBeIV Adnexal surgery þ peritoneal cytology Dysgerminomas and random biopsies.(þ/-lymphadenectomy , appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Open: 43/43 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology Serous/Mucinous and random biopsies. MOGCT Open: 74/74 (100%)Adnexal Stages IeIV surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 138/138 (100%) Stages IeIV Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Open: 189/189 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 31/31 (100%) EOC Adnexal surgery þ peritoneal cytology Stages IaeIIIc All types þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate LMP Open: 49/49 (100%) Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate EOC Open: 52/52 (100%) IA or IC Adnexal surgery þ peritoneal cytology All types þ random biopsies þ omentectomy G1eG3 þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate MOGCT Open: 64/64 (100%) IAeIIIC Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate LMP Open: 58/62 (93.5%); LPS: 4/62 (6.5%). Stages IeIII Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate LMP Adnexal surgery Open and LPS Stages IeIII
LMP Stages IeIII Serous /Mucinous
Open: 38/38 (100%) Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate
Survival outcomes
Fertility outcomesb
F-U 94 (range 34e175) months Recurrence: 5/56 (9%) DOD: 2/56 (3.6%)
27 pregnancies achieved 10/27: 1st trimester loss 17/27: term delivery
F-U 70 (24e138) months Recurrence: 0
3 pregnancies achieved 1/3: 1st trimester loss 2/3: term delivery
F-U 89 (18e183) months Recurrence: 1/16 (6.3%)
3 pregnancies achieved 3/3: term delivery
F-U 68.4 (16.8e300) months Recurrence: 14/43 (9.5%) DOD: 1/43 (2.3%) F-U 52.1 months (overall) Recurrence: 7/74 (9.5%) DOD: 2/74 (2.7%)
23 pregnancies achieved 7/23: 1st trimester loss 16/23: term delivery 16 pregnancies achieved 16/16: term delivery
F-U 70 (13e180) months Recurrence: 16/138 (11.6%) DOD: 3/138 (2.2%)
55 pregnancies achieved 15/55: 1st trimester loss 40/55: term delivery
F-U 70 (13e180) months Recurrence: 28/184 (15.2%) DOD: 1/184 (0.5%)
44 pregnancies achieved 3/44: 1st trimester loss 41/44: term delivery
F-U 47 (6e201) months Recurrence: 7 (28%) DOD: 3 (12%)
4 pregnancies achieved 1/4: 1st trimester loss 3/4: term delivery
F-U 109 (24e300) months Recurrence: 9/49 (18.4%)
16 pregnancies achieved 6/16: 1st trimester loss 10/16: term delivery
F-U 78 (3e423) months Recurrence: 5/52 (9.6%) DOD: 2/52 (3.8%)
31 pregnancies achieved 5/31: 1st trimester loss 26/31:term delivery
F-U 122 (24e384) months DOD: 11/106 (10%) * (overall series)
47 pregnancies achieved 12/47: 1st trimester loss 35/47: term delivery
F-U 44.3 (3e128) months Recurrence: 4/62 (6.5%) DOD: 0
13 pregnancies achieved 3/13: 1st trimester loss 10/13: term delivery
F-U (13.4e136.9) months Recurrence: 27/162 (16.6%) DOD: 0
30 pregnancies achieved 13/30: 1st trimester loss 1/13: preterm delivery (<37weeks)17/30: term delivery 8 pregnancies achieved 3/8: 1st trimester loss 5/8: term delivery
F-U 26 months (median) Recurrence 6/38 (16%) DOD: 0
D. Vitobello et al. / Placenta 32 (2011) S224eS231
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Table 3 (continued ) Author
N of patientsa
Ovarian tumor FIGO stages, histologic types
Proposed treatment
Survival outcomes
Fertility outcomesb
Romagnolo et al. 2006 [46]
53 patients
LMP Stages IeIII
Open: 16/53 (30.2%); LPS: 37/53 (69.8%). Adnexal surgery
8 pregnancies achieved
Borgfeldt et al. 2003 [37]
11 patients
EOC Stages IAeIIIC All types G1eG3
14 pregnancies achieved 14/14: term delivery
Park et al. 2008 [38]
62 patients 26 (13e40) years
F-U 56 (6e205) months Recurrence 11/62 (17.7%) DOD 6/62 (9.7%)
24 pregnancies achieved 2/24: 1st trimester loss 22/24: term delivery
Park et al. 2009 [47]
184 patients 29.6 11.5 years
EOC IAeIIIC All types G1eG3 LMP IAeIIIC Serous, Mucinous
F-U 60 (3e216) months Recurrence 18/184 (9.8%) DOD 5/184 (2.7%)
34: term delivery
Schlaert et al. 2009 [31]
20 patients EOC Median age 27 years IAeIC All types G1eG3
F-U 122 (11e256) months Recurrence 3/20 (15%) DOD 3/20 (15%)
9 pregnancies achieved 9/9: term delivery
Satoh et al. 2010 [32]
211 patients 29 (14e40) years
EOC IA and IC All types G1eG3
F-U 122 (11e256) months Recurrence 18/211 (8.5%) DOD 5/211 (2.4%)
76 pregnancies achieved 53/76: term delivery
Kajiyama et al. 2010 [39] 60 patients 30 (12e40) years
EOC IAeIC All types G1eG3
F-U 54.7 (4.8e243.8) mo. Recurrence 8/60 (13.3%) DOD 7/60 (11.7%)
13 pregnancies achieved 3/13: 1st trimester loss 1/13: preterm delivery (<37weeks) 9/13: term delivery
Weinberg et al. 2011 [53] 22 patients 26.5 (10e48) years
MOGCT IeIII
F-U 54.7 (4.8e243.8) mo. Recurrence: 0
Song et al. 2011 [54]
LMP IeIII
Open: 11/11 (100%) Adnexal surgery þ peritoneal cytology þ random biopsies þ omentectomy þ appendectomy þ lymphadenectomy þ/-Adjuvant chemotherapy as appropriate Open: 56/62 (90.3%); LPS: 6/62 (9.7%). Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) Open: 136/184 (73.9%); LPS: 48/184 (26.1%).Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 20/20 (100%). Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 211/211 (100%) Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 60/60 (100%). Adnexal surgery þ peritoneal cytology and random biopsies. (þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 22/22 (100%)Adnexal surgery þ peritoneal cytology and random biopsies.(þ/-lymphadenectomy, appendectomy, omentectomy) þ/-Adjuvant chemotherapy as appropriate Open: 105/155 (67.8%); LPS: 50/155 (32.2%). Adnexal surgery þ peritoneal cytology (þ/-lymphadenectomy, appendectomy, omentectomy)þ/-Adjuvant chemotherapy as appropriate
F-U 44 (6e122) months Recurrence 11/53 (21%) DOD 1/53 (1.9%) F-U 8 (16e185) months Recurrence 0
13 pregnancies achieved 1/13: 1st trimester loss 2/13: preterm delivery (<37weeks) 10/13: term delivery 57 pregnancies achieved 3/57: 1st trimester loss 54/57: term delivery
155 patients 29 (10e48) years
F-U 56.0 (0.6e155.9) mo. Recurrence: 12 (7.7%)
Data are expressed as median (range); mean sd or absolute number (%). MOGCT ¼ Malignant Ovarian Germ Cell Tumors; LMP ¼ Low Malignant Potential; EOC ¼ epithelial ovarian cancer. LPS ¼ Laparoscopic approach; Open ¼ traditional abdominal approach. a Number of successful fertility-sparing procedures. b Ongoing pregnancies have been excluded.
Also in this case, most of the surgical procedure have been performed by laparotomy and included adnexal surgical procedure. Peritoneal and retroperitoneal staging procedure are also describes as well as the administration of adjuvant chemotherapy regimens, when needed. In the long-term period a total of 129 (13.8%) and 8 (0.9%) patients recorded a recurrence and died from disease, respectively. At the same time 141 full term deliveries have been assessed in the same population [40e48,54]. Across the last years a burgeoning literature is currently highlighting the advantages of minimally invasive surgery for the management of adnexal pathology including the treatment of LMP ovarian tumors especially in terms of reduced trauma to the ovarian tissue and the reduced risk of adhesions. Therefore the benefits of laparoscopic surgery may be also enhanced in the fertility-sparing setting. In addition minimally access surgery allows a faster recovery and it could be better tolerated especially when a secondlook or the treatment of a recurrence is needed. Indeed fertility-
sparing procedures in LMP ovarian tumors record higher recurrence rates than radical treatments, without affecting the overall survival. However, regarding the long-term oncologic outcomes, patients with advanced stage disease were included in most of the series analyzed. It is well known that the presence of invasive peritoneal implants in women with advanced stage tumors represents an independent prognostic factor which significantly affects survival in comparison to the counterpart with non-invasive implants [55]. This data should be taken into account especially in women addressed to fertility-sparing procedures. 9. Malignant germ cells ovarian tumors Malignant ovarian germ cell tumors (MOGCT) affect mainly children and young women. Preservation of fertility in this patient population is of particular interest. Malignant MOGCT can be divided into two groups: dysgerminomas and nondysgerminomas.
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Nondysgerminoma tumors include endodermal sinus tumors, immature teratomas, mixed germ cell tumors, choriocarcinomas, embryonal carcinomas, and polyembryomas, which are in most of cases unilateral. On the contrary dysgerminomas, in up to 15% of cases, are bilateral. Thus, conservative surgery with a unilateral SO surgical staging can be considered in this patient population. In cases of bilateral dysgerminomas, conservative surgery including bilateral ovarian cystectomies could be performed. In this review 5 studies, including 314 young women (age range 7e48), have investigated the oncological and fertility outcomes of patients addressed to surgery for MOGCT who desired the fertility preservation [49e53]. Also in this case, most of the surgical procedure have been performed by laparotomy and included mostly adnexal surgical procedure. Peritoneal and retroperitoneal staging procedure are also describes as well as the administration of adjuvant chemotherapy regimens, when needed. In the long-term period a total of 19 (6%) and 13 (4.1%) patients recorded a recurrence and died from disease, respectively. At the same time 124 full term deliveries have been assessed in the same population. For MOGCT fertility-sparing surgery represent a viable option also for advanced stages, since effective chemotherapy options are currently available, indeed several reports showed comparable outcomes between patients who underwent conservative treatments with those who were treated with more aggressive surgery. 10. Comment In gynecologic oncology, effective treatments to achieve cancer survival can compromise the ability to subsequently conceive and/or carry a child. Therefore, as the field of oncofertility continues to expand, a discussion regarding fertility preservation should be initiated when tailoring a cancer treatment protocol [2e6]. The necessary treatment for most of the gynecological malignancies involves either removal of the reproductive organ, or cytotoxic treatment that could partially or definitively affect reproductive function [20]. However, in carefully selected patients having a strong desire for future fertility staging and therapeutic surgical procedures can be tailored in order to preserve fertility. A detailed counseling session, even in a motivated patient, is crucial and mandatory to the success of these techniques [2e5]. Management of young women with early gynecologic cancer should therefore be individualized with the risk of conservative therapy balanced against the dangers and advantages of more radical therapy [2e5]. Ideally the increased know-how for gynecologic cancer treatment allows the performance of fertility-sparing procedures even in cases of locally advanced disease. However our treatment strategy should not be focused on the technical feasibility alone, but mainly on the patient’s desire to retain fertility and parenthood. Medicine is a dynamic process with a constant evolution in the ability to diagnose, treat, and cure diseases. In the field of gynecologic oncology, effective treatments can unfortunately come at the price of a woman’s ability to conceive and carry a child. Therefore, as we succeed in our fight against previously untreatable malignancies, the population of cancer survivors grows and the loss of fertility becomes a crucial component to a survivor’s QoL. The field of oncofertility requires therefore a multidisciplinary approach which should include the know-how of skilled surgeons, medical and radiation oncologists, reproductive endocrinologists, perinatologists, and psychosocial support professionals, to ensure that all patients are afforded the opportunity to maintain their reproductive potential and are given the chance to achieve their wishes of parenthood. However the oncological safety of fertility-preserving options needs to be proven through robust multicentre studies. Preliminary
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