Fertility-Sparing Options in Young Women with Cervical Cancer

Curr. Treat. Options in Oncol. (2016) 17: 5 DOI 10.1007/s11864-015-0386-9

Gynecologic Cancers (RJ Morgan, Section Editor)

Fertility-Sparing Options in Young Women with Cervical Cancer Federica Tomao, MD, PhD1,2,* Giacomo Corrado, MD, PhD3 Fedro Alessandro Peccatori, MD, PhD1 Sara Boveri, MD, PhD1 Eleonora Petra Preti, MD, PhD1 Nicoletta Colombo, MD, PhD1 Fabio Landoni, MD, PhD1 Address *,1 European Institute of Oncology BIEO,^, Via Giuseppe Ripamonti 435, 20141, Milan, Italy Email: [email protected] 2 University BSapienza^, Sapienza, Rome 3 National Cancer Institute BRegina Elena^, Regina Elena, Rome

Published online: 25 January 2016 * Springer Science+Business Media New York 2016

This article is part of the Topical Collection on Gynecologic CancersFederica Tomao and Giacomo Corrado contributed equally to this work. Keywords Fertility sparing I Cervical cancer I Conization I Trachelectomy I Neoadjuvant chemotherapy I Uterus transplantation

Opinion Statement Cervical cancer (CC) is the fourth most frequent tumor and the fourth most common cause of cancer death among women worldwide. Furthermore, more than 40 % of women with early CC are affected during reproductive age and wish to remain fertile. Thus, many patients demand a more conservative policy for managing these lesions in order to have an uneventful pregnancy in the near future. For this reason, interest in fertility preservation strategies has been increasing, and the number of published studies on this topic has grown significantly. Conization was the first fertility-sparing surgical procedure tested in stage IA1 CC. However, in recent decades, other strategies have been tested, particularly for more advanced tumors. The aim of this review is to analyze the main techniques performed in patients with CC who are eligible for fertilitysparing surgery, with particular attention paid to open questions and controversies.

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Curr. Treat. Options in Oncol. (2016) 17: 5

Introduction Cervical cancer (CC) accounts for 6.7 million new cancer cases and 3.5 million cancer deaths among the female population worldwide [1]. According to most international guidelines, standard treatment of CC consists of surgery for early tumors and concomitant chemoradiation for locally advanced disease. Because the risk of lymph node involvement is very low (G1 %) in patients with stage IA1 tumors in the absence of lymphovascular space invasion (LVSI), conization represents a reasonable option for preserving fertility [2]. On the contrary, the management of IA1 tumors with LVSI and early disease, defined by the International Federation of Gynecology and Obstetrics (FIGO) as stage IA2–IB1 CC, should be more aggressive, including radical hysterectomy with pelvic lymphadenectomy, thus significantly affecting reproductive capability. More than 42 % of patients affected by CC are younger than 45 years, and up to 40 % of early tumors are diagnosed in women of reproductive age [3]. For these reasons, conservative strategies have gained increasing interest in

the past decades, especially for patients affected by early disease. The most investigated surgical procedures aimed toward preserving fertility consist of organ-sparing surgery, such as conization or trachelectomy associated with laparoscopic pelvic lymphadenectomy. Other investigators proposed neoadjuvant chemotherapy (NACT) in patients with larger tumors to reduce tumor size so that fertility may be preserved. However, only a few centers perform these procedures; thus, such alternatives remain largely in the experimental stage. One of the most futuristic approaches for fertility preservation in women without a uterus consists of uterine transplantation. Recent studies analyzed this potential preservation option, which until now has been applied mainly for benign conditions [4, 5, 6••]. In this report, we provide a review of the existing literature data on the fertility-conserving strategies available for CC, analyzing the results from studies published in the past 10 years.

Standard Treatment by Disease Stage Stage IA1 According to most international guidelines, the first diagnostic and curative step for microscopic tumors is conization [4]. In the presence of negative margins and the absence of clinical contraindications to surgery, the cone biopsy may represent definitive treatment. However, for patients not interested in future pregnancy, the standard treatment is radical surgery consisting of extrafascial or radical hysterectomy with or without pelvic lymphadenectomy, depending on margin status. Thus, conization was the first fertility-sparing surgical method used in CC and has been a valid and safe procedure for patients with IA1 tumors without LVSI who want to preserve their fertility. For patients with LVSI, who have an increased risk of lymph node involvement, pelvic lymph node dissection or sentinel node biopsy should be considered [7]. Moreover, for these patients, some authors suggest trachelectomy, a surgical procedure in which the uterine cervix and adjacent tissues are removed.

Stage IA2 The standard treatment for IA2 tumors consists of radical hysterectomy with pelvic lymphadenectomy. However, for patients desiring to preserve fertility, cone biopsy or radical trachelectomy with pelvic lymph node dissection (or sentinel node biopsy) with or without para-aortic lymph node sampling also may be considered [8].


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Stage IB1 Radical surgery also is the first therapeutic choice for IB1 tumors. Scientific evidence shows that trachelectomy with pelvic lymphadenectomy is the most appropriate surgical treatment for fertility sparing in patients with these tumors. However, tumors larger than 2 cm clearly are associated with a higher risk of recurrence (3 % for lesions ≤2 cm vs 17 % for lesions 92 cm) [9••]; thus, international guidelines stress that this procedure is valid mostly for tumors measuring ≤2 cm in diameter [4]. Finally, some authors have suggested conization in this tumor setting as well [10••, 11–16].

More Advanced Tumors For higher-stage tumors, the standard treatment consists of pelvic radiotherapy with concurrent cisplatin-based chemotherapy with or without para-aortic lymph node radiotherapy followed by final brachytherapy. Some authors advocate NACT followed by radical surgery [17]. However, all these approaches lead to the loss of reproductive capability. Some authors propose a neoadjuvant approach followed by conservative surgery to avoid the destruction of genital organs.

Adenocarcinomas and Other Histotypes Adenocarcinomas of the uterine cervix account for approximately 25 % of all newly diagnosed CC cases [18]. Other histotypes represent a very small percentage, with the remaining 75 % consisting of the squamous variant. In general, adenocarcinomas are more likely to have lymph node involvement and hematogenous metastasis [18]. Eifel et al. [19, 20] reported significantly higher rates of distant metastasis for FIGO stage IB1-III adenocarcinomas than for squamous CC. Furthermore, numerous retrospective studies, including two large reviews by Chen et al. [21] and Hopkins and Morley [22], reported poorer overall survival (OS) in women with adenocarcinomas than in those with squamous tumors. Moreover, there still is no consensus regarding ovary preservation in young patients with early-stage CC. In general, the rate of ovarian metastasis in early-stage squamous CC is approximately 0 to 1.3 %. A recent meta-analysis found that adenocarcinoma is associated with a higher risk for ovarian metastasis compared with squamous CC [23]. Thus, some studies concluded that young women with squamous CC who are planning to undergo radical hysterectomy may opt to preserve their ovaries; whereas, simultaneous bilateral salpingo-oophorectomy is recommended for patients with adenocarcinoma, regardless of their age. However, a recent study by Lyu et al. [24] showed that ovarian preservation might be oncologically safe for young women with stage I cervical adenocarcinoma. This study included women aged 45 years and younger with stage I cervical adenocarcinoma and adenosquamous carcinoma. A total of 1062 women (64.8 %) underwent oophorectomy, and 577 (35.2 %) had their ovaries preserved during hysterectomy. The authors demonstrated that ovarian preservation had no effect on cancer-specific survival based on the Cox proportional hazards model. Although some evidence shows that IA1 adenocarcinomas with negative margins may be treated conservatively with no risk of recurrence [25], few data exist regarding the safety of fertilitysparing surgery in larger tumors of these histotypes. Mangler et al. [26] found

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Curr. Treat. Options in Oncol. (2016) 17: 5 that among tumors recurring after vaginal radical trachelectomy (VRT), adenocarcinomas were overrepresented, accounting for 40 % of cases, compared with 29 % at first diagnosis. Although it remains unclear whether adenocarcinomas are associated with a high incidence of recurrence, a study by Nishio et al. [27] suggests that patients treated by abdominal radical trachelectomy (ART) may have a higher risk of recurrence if they have a tumor ≥20 mm in diameter, severe LVSI, and adenocarcinoma, which exhibits skip lesions in some cases.

Fertility Strategies Nodal Staging CC usually spreads locally into the vagina, parametrium, and lymphatic system. Predictors of tumor dissemination include tumor size, LVSI, histopathologic grade of differentiation, and stromal invasion [28]. Furthermore, pelvic lymph node status is related strictly to parametrial involvement [29–31]. Based on these findings, it appears that pelvic lymphadenectomy and conization provide all the important prognostic factors for fertility-sparing surgery; thus, nodal status assessment is the first step in determining whether a conservative surgical approach for CC is warranted. This step can be skipped only in patients with IA1 tumors without LVSI, because in these cases, the risk of lymph node involvement is negligible (G1 %). However, in the presence of LVSI, most guidelines recommend performing a pelvic lymph node study [7], even though scientific evidence shows no correlation between LVSI and lymph node metastasis [32, 33]. In IA2 squamous CC, the risk of pelvic lymph node involvement is approximately 8 %. In more advanced stages, the incidence of nodal metastasis increases to 15 to 20 % for stage IB1 tumors and around 30 % for locally advanced neoplasia [34]. The standard approach for pelvic lymphadenectomy in fertility-sparing surgery usually is via laparoscopy, except for abdominal trachelectomy. However, some authors suggest the use of sentinel lymph node (SLN) biopsy, a technique generally associated with fewer complications and morbidities, such as lymphedema, lymphocele formation, or prolonged surgical time. A recent meta-analysis showed that SLN mapping is an accurate method for assessing lymph node involvement in uterine CC, with a detection rate of 89.2 % [35•]. However, in patients with tumors larger than 2 cm and with stage IB2 or more advanced disease, the detection rate and sensitivity are lower. Moreover, the diagnostic efficacy of this procedure varies depending on the mapping method (blue dye, radiotracer, or both) and whether the patient has a history of preoperative NACT. Thus, most international guidelines consider SLN mapping in fertility-sparing surgery to be a feasible procedure but stress that the best detection rates and mapping results are in tumors with a maximum diameter of less than 2 cm [7]. In general, SLN still is considered an experimental procedure.

Conization In a cone biopsy, a nonfragmented specimen is obtained with at least 3 mm of negative margins. Moreover, if the margins of resection are positive, a repeat cone biopsy and eventual trachelectomy will be necessary. As previously reported, simple conization, with or without lymphadenectomy, represents a reasonable treatment option for stage IA1–2 tumors in patients who wish to


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become pregnant [36]. For these lesions, the most debated question is which technique to use for excision. Several studies hypothesized that cold-knife conization (CKC) is more likely than the loop electrosurgical excision procedure (LEEP) to yield negative margins in precancerous lesions and in situ carcinomas [37, 38]. First, there is a perception that LEEP is associated with incomplete excision, because the depth of resected tissue and the overall dimensions of the specimen tend to be smaller compared with CKC. It also is argued that the tissue margins in a LEEP biopsy sample may show significant thermal artifact, which might interfere with the pathologic assessment of biopsy margins [39, 40]. However, recent evidence shows that no significant differences exist between the two procedures with regard to the incidence of persistent and/or recurrent endocervical neoplasia in patients with adenocarcinoma histotypes [41]. In terms of obstetric outcomes, a meta-analysis published in Lancet Oncology in 2006 showed that all the excisional procedures used to treat cervical intraepithelial neoplasia result in similar pregnancy-related morbidity, with no apparent neonatal morbidity [42]. Successively, another meta-analysis showed more preterm deliveries among patients treated with CKC (OR, 2.8) than those treated with with loop conization (1.7) [43]. However, insufficient data exist regarding the best option for excising intraepithelial and microscopic invasive cervical cancer; therefore, randomized clinical trials are needed to identify the most appropriate therapeutic procedure. The curative potential of conization has not been widely exploited in stage IB1 lesions. Recent studies suggest that in certain circumstances, patients with stage IB1 disease undergoing radical hysterectomy might have been safely cured by simple hysterectomy or even by cervical conization [44–49]. Covens et al. [44] suggested that the incidence of parametrial involvement is only 0.6 % in patients with tumors smaller than 2 cm, negative pelvic lymph nodes, and depth of invasion less than 10 mm. Similar data were reported by Steed et al. [45] and Wright et al. [46]. In particular, Wright et al. [46] retrospectively analyzed the pathologic characteristics of 594 specimens from patients who underwent radical hysterectomy for invasive cervical cancer and found that 64 cases, or 10.8 %, had parametrial involvement. Moreover, they showed that in women with negative lymph nodes, without LVSI, and with tumors smaller than 2 cm, the incidence of parametrial disease was only 0.4 %. In this perspective, an analysis of 28 recurrences reported among 548 patients (5 %) treated by radical trachelectomy confirmed that the risk factors for recurrence were lesions 92 cm, LVSI, and stromal invasion deeper than 10 mm [50]. These data suggest that a less radical surgical approach might be used in this patient setting. Therefore, some authors have proposed the use of conization, or eventually simple trachelectomy (ST), to preserve fertility in patients with IB1 cervical tumors. Thus, conization might represent a safe treatment option in select cases and may in turn improve the obstetric as well as the surgical outcome in terms of reduced risk of urologic morbidity. One of the many reports on the use of laparoscopic lymphadenectomy with conization in IB1 cervical cancers was published by Maneo et al. [11] This study included 36 patients from three different institutions. The authors reported only one pelvic lymph nodal relapse after a median follow-up of 66 months (range, 6–168). With regard to obstetric outcomes, 21 pregnancies occurred in 17 patients and 14 live babies were born (two preterm at 27 and 32 weeks), with one pregnancy ongoing at the time of manuscript preparation. Finally, three first-trimester

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Curr. Treat. Options in Oncol. (2016) 17: 5 miscarriages, one second-trimester fetal loss, an ectopic pregnancy, and a termination of pregnancy were recorded. Furthermore, a recent study by Ditto et al. [16] showed that this procedure is associated with a 53 % rate of spontaneous pregnancies. Thus, these data suggest that conization should be a valid therapeutic option for young patients who have IB1 tumors and want to preserve fertility. Table 1 lists most of the important studies regarding the use of conization in early CC, including FIGO stage IB1 tumors.

Radical Trachelectomy In 1957, Eugen Aburel was the first to report a new technique for fertilitysparing surgery in CC that consisted of pelvic lymphadenectomy with removal of the cervix and parametria (ART). However, none of the women he treated with this procedure achieved a successful pregnancy. The international group of Ungar et al. [51] later revived the use of this surgical approach, publishing their initial experience in 1997. The extent of radicality of ART is the nearest to our oncogynecologic representation of a radical surgical procedure in invasive CC that supposes extirpation of paracervical tissues to the extent of QuerleuMorrow types C1 and C2. At the annual meeting of the Society of Gynecologic Oncology in 1994, Daniel Dargent and his group presented their experience with laparoscopic pelvic lymphadenectomy and VRT as a fertility-sparing therapy for CC; subsequently, they published a study performed with 47 patients [52]. Shortly thereafter, several groups reported studies that raised as many questions as they answered [52–55]. Because the cervix is readily accessible through the vagina, VRT is the most Bnatural^ approach. With regard to the oncologic outcomes associated with VRT, the recurrence rate reported in most studies is less than 5 %, with a death rate around 2 % [9••, 50, 56–61, 62••, 63–66]. In particular, Plante et al. [62••] reported on 125 patients treated by VRT, showing that tumors 92 cm were statistically associated with a higher risk of recurrence (P = 0.001). Other authors, however, showed that the oncologic outcomes appear to be comparable between radical hysterectomy and radical trachelectomy for similarly sized lesions [50, 58]. In general, VRT requires specialized skills in the vaginal approach; therefore, some surgeons prefer an abdominal route. In 1997, Smith et al. [55] were the first to describe the ART procedure, which provides the advantage of a more radical resection of the parametria. Einstein et al. [54] compared a series of 28 VRTs and 15 ARTs, showing that the average parametrial length obtained abdominally was nearly twice as wide as that obtained vaginally (3.97 vs. 1.45 cm), suggesting that ART should be reserved for patients with larger lesions. However, it must be noted that approximately 65 % of patients do not show any residual cancer in the trachelectomy specimen after a diagnostic cone biopsy [56, 67]. This issue was raised previously in cases with stage IA2 tumors as well and highlights the question as to whether less aggressive surgery is as effective as radical trachelectomy [68]. Based on the studies of ART, the recurrence rate appears to be higher [27, 69]. However, the tumors reported in those studies were significantly larger, and 20 % of the patients showed nodal involvement. Moreover, several studies showed that ART is significantly associated with a higher rate of cervical stenosis and cerclage erosions.

32

31

33

30

31

28

31

11

36

17

23

21

10

22

Landoni et al. (2007) [10••] Maneo et al. (2011) [11] Fagotti et al. (2011) [12] Fanfani et al. (2014) [13] Choi et al. (2013) [14] Andikyan (2014) et al. [15] Ditto et al. (2015) [16] 12 SCC 4 AdenoCa 1 GC 11 SCC 11 AdenoCa 1 GC 17 SCC 2 AdenoCa 2 GC 8 SCC 1 AdenoCa 1 GC 10 SCC 11 AdenoCa 1 Adenosq

24 SCC 12 AdenoCa

5 SCC 6 AdenoCa

Histotype

100

100

100

100

95

100

LPS PLF + CON

11 CON + PDT; 5 LPS PLF + CON + PDT LPS SNB + CON 18 LPSb PLF + CON

10 IA1 1 IA2 9 IB1 1 IIA 7 IA1 3 IB1 6 IA2 16 IB1

86

94

100

7 IA1 16 IB1

100

LPS PLF + CON

4 IA2 13 IB1

97.2

PLF + CON

97.2

100

LPS PLF + CONa 100

Oncologic results DFS, OS, % %

Type of treatment

36 IB1

3 IA2 8 IB1

Stage

8

3

9

7

2

21

3

Obstetric results Pregnancies, n

3

3

5

6

2

14

3

Live births, n

Adenosq adenosquamous, AdenoCa adenocarcinoma, CON conization, DFS disease-free survival, GC glassy cell, LPS laparoscopic, OS overall survival, PDT photodynamic therapy, PLF pelvic lymphadenectomy, SCC squamous cell carcinoma, SNB sentinel node biopsy a Two patients underwent neoadjuvant chemotherapy; one patient received adjuvant chemotherapy b Three patients with metastatic lymph nodes and one who did not comply with follow-up underwent radical hysterectomy

Median age, y

Patients, n

Study

Table 1. Conization in early-stage CC (including FIGO stage IB1 tumors)

Curr. Treat. Options in Oncol. (2016) 17: 5 Page 7 of 18 5

5 Page 8 of 18

Curr. Treat. Options in Oncol. (2016) 17: 5 Recently, laparoscopic radical trachelectomy was introduced [70]. This procedure has the innate advantages of laparoscopic surgery over laparotomy, resulting in less blood loss and a shorter hospital stay. Vieira et al. [71] published a recent retrospective analysis of the use of radical trachelectomy, comparing open with minimally invasive surgery (MIS) for early-stage CC. A total of 100 patients from four different institutions were included in the analysis; 58 patients underwent open radical trachelectomy, whereas the other 42 underwent MIS. The pregnancy rate was higher in the open-surgery group (51 vs. 28 %, P = 0.018), although the median follow-up was shorter in the MIS group (25 vs. 66 months). Unfortunately, data regarding oncologic outcomes were not reported. Finally, some authors have suggested the use of robotics to obtain a radical trachelectomy such as that provided by ART but with the benefits of a minimally invasive approach [72–77]. However, the available data are too inconsistent to determine the obstetric and oncologic outcomes of this approach. With regard to the obstetric outcome from radical trachelectomy, abdominal or full laparoscopic radical procedures do not result in good pregnancy rates [51, 78••, 79–81]. Poor pregnancy results probably are a result of the complete discontinuation of important nerves from the pelvic plexus for tubal motility during an abdominal or full laparoscopic radical trachelectomy. The crucial factor in second-trimester abortion or premature labor is the amount of stromal tissue remaining; however, safe margins must be the same in abdominal and in vaginal procedures [51, 78••, 79–81]. Regarding complications related to the procedure, the most frequent are bladder dysfunction, vulvar edema/hematoma, and lymphocele. Other problems specifically related to trachelectomy are dyspareunia, dysmenorrhea, cervical stenosis, menstrual abnormalities, and chronic discharge. Moreover, after radical trachelectomy, most women need to undergo assistive reproductive procedures to conceive, because the cervix also is fundamental for conception.

Simple Trachelectomy Some studies have reported the absence of residual disease in trachelectomy specimens in the range of 60 to 65 %, questioning the necessity for radical surgery in patients with low-risk tumors [67]. Lanowska et al. [9••] performed step sectioning of all the parametrial tissues from 112 VRT cases and identified only one micrometastasis. Rob et al. [78••] conducted a pilot study testing the use of a largecone biopsy or ST in patients with node-negative disease who previously underwent lymphadenectomy [78••] and reported one isthmic recurrence and one carcinoma in situ. Other authors reported similar results with ST [67, 82, 83]. In particular, Raju et al. [83] compared 15 STs with 51 radical trachelectomies and reported no recurrences in the former group. Table 2 lists most of the important studies on ART, VRT, and ST.

Neoadjuvant Chemotherapy and Fertility-Sparing Surgery For tumors larger than 2 cm, NACT followed by conization or trachelectomy may be a valid choice. One of the most important studies on this topic was published by Maneo et al. [90••], who reported that 39 % of their study patients had either no residual disease or in situ disease only, and 39 % had microscopic residual disease (G3 mm) in the cone specimen. Subsequently, as

150: 40 FSS, 110 RH 16

61

Diaz et al. (2008) [60] Chen et al. (2008) [61]

Nishio et al. (2009) [27]

180

40

15

Pareja et al. (2008) [84] Beiner and Covens (2007) [50]

Rob et al. (2008) [78••]

257: 118 FSS, 139 RH

Marchiole et al. (2007) [58]

43

31

108

Hertel et al. (2006) [57]

Sonoda et al. (2008) [59]

30

123

Shepherd et al. (2006) [56]

33

28

32

NA

31

32 vs. 47

32

31

31

30

Ungar et al. (2005) [51]

Median age, y

Patients, n

Study

Table 2. Trachelectomy: ART, VRT, and ST

58 SCC 2 Adenok 1 Adenosq

11 SCC 4 Adk 39 SCC 44 Adk 6 Adenosq 1 GC 8 IA1 7 IA2 28 IB1 3 IA1 10 IA2 27 IB1 20 SCC 20 Other 14 SCC 2 Adk

90 SCC 25 Adk 3 Other

26 SCC 1 Adk 1 Adenosq 2 Other 83 SCC 33 Adk 3 Adenosq 4 Other 75 SCC 33 Adk

Histotype

3 IA1 7 IA2 6 IB1 4 IA1 8 IA2

24 SCC 16 Adk 3 Adenosq 32 SCC 7 Adk 1 Adenosq 40 IB1

NA

ART

NA

100

100

100

92

98

ST

100

96

98

VRT

99

NA

95

98

NA

28 VRT 12 ART LAVRT

95

90 VRT

96

118 LAVRT

NA

96

VRT

ART

NA

VRT

18 IA1 + LVSI 21 IA2 69 IB1 10 IA1 + LVSI 19 IA2 83 IB1 6 IIA 3 IA2 12 IB1 NA

NA

ART

10 IA2 15 IB1 5 IB2 2 IA2 121 IB1

NA


Type of treatment

Stage

4/29 (13.8 %) who were

5

9

23

11

NA

3

NA

16

88

3


NA

1

4

12

4

NA

3

NA

12

47

2

Live births, n


33 28

24 68

Cibula et al. (2009) [85] Du et al. (2011) [86]

31

101

105

30

14

Wethington et al. (2012) [87]

Kim et al. (2012) [63]

Saso et al. (2012) [69]

Palaia et al. (2012) [82]

32

32.5

32

29

37

Nick et al. (2011) [72]

31

125

Plante et al. (2011) [62••]

32

212

Lanowska et al. (2011) [9••]

Median age, y

Patients, n

Study

Table 2. (Continued)

45 SCC 50 Adk 8 Adenosq 2 Others 15 SCC 10 Adk 4 Adenosq 1 GC 11 SCC 3 Adk

12 SCC 22 Adk 3 Adenosq 40 SCC 6 Adk 6 Adenosq 1 Clear cell

69 SCC 48 Adk 8 Adenosq

2 IA2 25 IB1 2 IB2 1 IIA 5 IA2 9 IB1

49 IB1 (13 with tumors 92 cm) 34 IA1 + LVSI 47 IA2 131 IB1 2 IA2 22 IB1 3 IA1 28 IA2 37 IB1 7 IA1 + LVSI 29 IA2 85 IB1 2 IB2 2 IIA 5 IA1 11 IA2 21 IB1 3 IA1 8 IA2 88 IB1 1 IB2 1 IIA 14 IA1 12 IA2 79 IB1

21 Other

154 SCC 55 Adenok 3 Adenosq 14 SCC 10 Adk NA

Stage

Histotype

NA

NA

90

70 ART

51 VRT 49 ART 5 RT ART

100

NA

NA

ART

ST

NA

96

VRT

100

98

NA

98

100

97

ART + SLN

NA

98

NA

92


ART

VRT

Type of treatment

NA

3

27

16

4

106

8

6

NA

trying to conceive


NA

2

20

31

3

77

5

5

NA

Live births, n

5 Page 10 of 18 Curr. Treat. Options in Oncol. (2016) 17: 5

120

42

Hauerberg et al. (2015) [66]

Tokunaga et al. (2015) [89]

32

30

30

1 IA1 4 IA2 37 IB1


50 SCC 5 Adk 7 Adenosq 135 SCC 15 Adk

34 SCC 30 Adk 2 Adenosq 13 SCC 12 Adk 4 Adenosq 10 SCC 6 Adk

Histotype

18 IA1 + LVSI 19 IA2 113 IB1 2 CIS, persistent dysplasia 7 IA1 8 IA2 103 IB1 42 SCC

4 IA1 + LVSI 6 IA2 6 IB1 IB1

100

100

NA

NA

88

93

ART

77 VRT 73 ART VRT

ART

NA

95

NA

NA

100

97

22 ART 6 VRT 1 RT ST

IB1

100

51 VRT 15 ST

7 IA2 59 IB1

Oncologic results DFS, OS, % % 98

Type of treatment

Stage

5

77

24

3

8

0

21


3

NA

14

1

4

0

18

Live births, n

Adenosq adenosquamous, Adk, adenocarcinoma, ART abdominal radical trachelectomy, CIS carcinoma in situ, DFS disease-free survival, FSS fertility-sparing surgery, GC glassy cell, LAVRT laparoscopic-assisted vaginal radical trachelectomy, LVSI lymphovascular space invasion, NA not available, OS overall survival, RH radical hysterectomy, RT robotic trachelectomy, SCC squamous cell carcinoma, SLN sentinel lymph node mapping, ST simple trachelectomy, VRT vaginal radical trachelectomy

150

Cao et al. (2013) [65]

30

30

16

62

31

29

Wethington et al. (2013) [64] Plante et al. (2013) [67]

Li et al. (2013) [88]

28

66

Raju et al. (2012) [83]

Median age, y

Patients, n

Study

Table 2. (Continued)


5 Page 12 of 18

Curr. Treat. Options in Oncol. (2016) 17: 5 shown in Table 3, other authors investigated the use of the neoadjuvant approach. In particular, Robova et al. [91], in their study on the use of NACT followed by pelvic lymphadenectomy and ST, reported no residual disease in six women (21.4 %), microscopic disease in 11 women (39.3 %), and macroscopic tumor in 11 women (39.3 %). Finally, Lanowska et al. [92] performed lymphadenectomy before NACT to identify patients with nodal disease and offered this procedure to nodenegative patients only, showing a notably worse prognosis [92]. However, this interesting concept should be validated further. In conclusion, down-staging by NACT in IB1 and IB2 CC before fertility-sparing surgery is still an experimental procedure, although it shows some promise.

Future Developments As previously described, fertility-sparing surgery usually is indicated in patients with tumors smaller than 2 cm in diameter, whereas for patients with larger tumors who have a strong desire to preserve their fertility, NACT may offer the chance for conservative surgery. However, for more locally advanced stages, the need for radical hysterectomy, which may be followed by adjuvant chemoradiation or exclusive chemoradiation, does not allow for conservative management. Ovarian transposition outside the radiation field is a valid approach to preserve ovarian function both for endocrine reasons and for fertility functions, thus allowing embryo transfer to a surrogate mother. In fact, the available motherhood options for women without a uterus are adoption (to acquire legal motherhood) or pregnancy in a gestational surrogate carrier to acquire genetic motherhood, followed by adoption to achieve legal motherhood. Recently, Brännström et al. [4] reported the results of the first clinical trial on uterine transplantation, in nine patients, from live donors. Most of these patients had congenital absence of the uterus; only one had previously undergone radical hysterectomy for CC of an unspecified stage. All the women received immunosuppression to prevent rejection of the transplant. The authors subsequently reported the outcomes in the seven patients with a viable uterus after transplantation during a follow-up of 12 months [5]. All the patients had regular menses, and their uterine artery blood flow was unchanged. Four women showed mild inflammation on biopsy after mycophenolate mofetil withdrawal; all were treated with corticosteroids and azathioprine for the remainder of the 12 months. Subclinical rejection was observed on ectocervical biopsy in five recipients; however, all these rejection episodes were treated successfully with corticosteroids or dose increments of tacrolimus. Moreover, the same group reported the first live birth after uterus transplantation, in a patient with Rokitansky syndrome, after in vitro fertilization treatment of both the patient and her partner [6••]. Although these interesting results show that uterus transplantation is feasible, the use of high doses of immunosuppressive agents, the risk of cancer recurrence in immunocompromised patients, and the possible vascular abnormalities after pelvic radiation must be considered with caution before taking this approach in the vast majority of young women with a previous diagnosis of CC. Thus, only improvements in

Patients, n

28

32

29

20

28

15 SCC 13 Adk


4 SCC 3 Adk


32

7

9 SCC 12 Adk

Histotype

30

Median age, y

80

LPS PLF + ST IP (cisplatin– doxorubicin for Adk)

95

LPS PLF + VRT

TIP

100

100

100

90

100

100

100

100


LPS PLF + VRT

LPS PLF + CON

LPS PLF + CON

Type of treatment

5 TIP 2 TEP

2 TIP 9 TC

10 IB1 1 IB2

2 IB1 9 2 cm 3 IB2 2 IIA1 14 IB1 9 2 cm 5 IB2 1 IIA 21 IB1 7 IB2

9 TIP 12 TEP

CT regimen

21 IB1

Stage

13

7

1

6

10


11

4

0

7

9

Live births, n

Adenosq adenosquamous, Adk adenocarcinoma, CON conization, CT chemotherapy, DFS disease-free survival, IP ifosfamide, and cisplatin, LPS laparoscopic, NA not available, NACT neoadjuvant chemotherapy, OS overall survival, PLF pelvic lymphadenectomy, SCC squamous cell carcinoma, SLN sentinel lymph node mapping, ST simple trachelectomy, TC paclitaxel and carboplatin, TEP paclitaxel, epirubicin, and cisplatin, TIP paclitaxel, ifosfamide, and cisplatin, VRT vaginal radical trachelectomy

Lanowska et al. (2014) [92] Robova et al. (2014) [91]

NACT + Trachelectomy Marchiole et al. (2011) [94]

NACT + Conization 21 Maneo et al. (2008) [90••] Salihi et al. 11 (2015) [93]

Study

Table 3. Neoadjuvant chemotherapy and fertility-sparing surgery


5 Page 14 of 18

Curr. Treat. Options in Oncol. (2016) 17: 5 immunosuppressive therapy and very thorough patient selection will transform this futuristic procedure into a reproductive option for young cancer survivors without a uterus.

Conclusions Results from the studies reported in this review show that radical hysterectomy no longer is the standard treatment for small lesions in young women. For patients with IA1-2 tumors, conization with or without nodal staging is a valid option for fertility preservation. Currently, as documented by most international guidelines, trachelectomy is considered a standard fertility-sparing procedure in patients with early CC and tumors smaller than 2 cm. However, the low incidence of parametrial involvement reported in patients with tumors smaller than 2 cm and no nodal disease or LVSI suggest that conization and ST may be valid choices for fertility sparing in these lesions as well. Moreover, for women with tumors larger than 2 cm who seek parenthood, downsizing of the tumor to ≤2 cm by NACT, followed by uterus-sparing surgery, may be considered in order to avoid radical surgery. On the basis of its capability in terms of surgical radicality, ART might be effective in these cases. However, the high percentage of nodal disease in larger tumors has led to the use of adjuvant treatment in nearly half of patients, with the consequent damage of reproductive surgery. For this reason, consideration should be given to offering these patients NACT. In effect, interesting results have been obtained with the use of NACT approaches followed by conization or trachelectomy. However, these procedures are experimental and should be investigated further in future studies. For patients with more advanced disease, uterus transplantation may be a viable option, although it currently is regarded as a futuristic approach.

Compliance with Ethical Standards Conflict of Interest The authors declare that they have no competing interests. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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