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Gynaecologic cancer surgery and preservation of fertility
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Gynaecologic cancer surgery and preservation of fertility E. Bentivegna∗, A. Maulard , G. Miailhe , S. Gouy , P. Morice Département de chirurgie, Gustave-Roussy Cancer Campus, 114, rue Édouard-Vaillant, 94085 Villejuif cedex, France
KEYWORDS Gynaecological cancers; Fertility; Pregnancy; Recurrence; Fertility-sparing treatment
Summary For gynecological cancers, even at an early stage, the standard treatment is ‘‘radical excision’’ involving hysterectomy (radical or not) with bilateral salpingooophorectomy. But for young patients with early stage disease, many recent studies have focused on preservation of subsequent fertility by keeping at least one ovary and the uterus. The main objective of this fertility-sparing surgery is to preserve fertility, if this can be accomplished without increasing the oncological risks. Whether the initial site of the cancer is the cervix, uterine fundus or ovary, the oncologic validation of fertility-sparing treatment requires several evaluation criteria: a rigorous clinical, radiological and surgical staging to verify that the pathology is truly at an early initial stage; expert pathologic interpretation of biopsy specimens to validate the histological criteria of ‘‘good prognosis’’; provision of complete and understandable patient education verifying the true objectives for this fertility-sparing treatment (whose intent is to retain a potential for subsequent fertility without guaranteeing it) and provision of an explanation of the oncological constraints and implications of fertility-sparing surgery in the event of a possible pregnancy. As always in oncology, this strategy demands teamwork requiring successive discussions with the patient and spouse and thorough discussion of the oncological safety of this fertility-sparing strategy in multidisciplinary consultation meetings before ‘‘giving a green light’’. © 2018 Elsevier Masson SAS. All rights reserved.
The particularity of gynaecological cancers is that they involve organs directly involved in reproduction. The currently employed treatments (surgery, radiotherapy, chemotherapy) often impact negatively on subsequent fertility. With better screening and improved treatment, more and more young patients are being diagnosed at an earlier
∗
Corresponding author. E-mail address: [email protected] (E. Bentivegna).
stage and cured, but simultaneously deprived of their fertility. Fertility must be considered is an integral part of the quality of life after cancer treatment. When gynaecologic cancer develops in these young patients, it has major psychological implications, related not only to the announcement of a long and potentially fatal illness but also to necessary therapies that can result in definitive sterility. To preserve fertility while treating gynaecological cancers requires the use of techniques, proven to have carcinological efficacy by different studies, with evaluation
https://doi.org/10.1016/j.jviscsurg.2018.03.001 1878-7886/© 2018 Elsevier Masson SAS. All rights reserved.
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of remission, recurrence rate and overall survival rate. Several of these techniques [ovarian transposition, in vitro fertilization (IVF), oocyte freezing, cryopreservation of ovarian tissue than can be subsequently transplanted by ortho- or heterotopic autograft, and cryopreservation of ovarian tissue for in vitro maturation] have been evaluated and the patient and her partner can be informed of these options; these techniques are discussed in another chapter of this thematic issue. Organ-sparing surgical treatment aimed at preserving the uterus and at least one ovary is increasingly finding a role in the management of early-stage gynaecological cancers in patients of childbearing age. Its purpose is to preserve the functionality of the reproductive organs by reducing the radicality of the surgical procedure, thereby allowing the possibility of a future pregnancy. The option of fertilitysparing surgical treatment is reserved only for selected cases that are defined by the stage, histology, grade and prognostic factors of the disease. In this article, we will discuss the indications and modalities of fertility-sparing surgical treatment of the principal gynaecological cancers involving the uterine cervix, endometrium and ovaries. Pre-cancerous in situ or microinvasive lesions of the cervix will not be discussed here and borderline ovarian tumours are discussed in another chapter of this thematic issue.
Cancer of the uterine cervix Data in the literature concerning cervical cancer are numerous and rapidly evolving. More than 3000 cases of fertility-sparing treatment have now been published [1—21]. Selection of patients eligible for fertility preservation depends on precise staging of the lesion [clinical examination, lumbo-pelvic magnetic resonance imaging (MRI), expert pathology evaluation allowing definition of the histological type and the existence or absence of vascular emboli] and an evaluation of the patient’s potential fertility. Fertility-sparing treatment is oncologically acceptable only for cervical cancers smaller than 4 cm in size that do not require adjuvant treatment (no lymph node involvement). For some authors, the existence of vascular emboli is not an absolute contra-indication for uterine preservation, however their presence increases the risk of recurrence by about 10% [22]. A diagnostic cone biopsy has been proposed to improve the specific definition of tumour size and the existence or absence of vascular emboli [15]. All of the classical histological types (squamous, adenosquamous, and adenocarcinoma) can be managed with intent of fertility-sparing but the data on the mixed forms (poorly-differentiated adenosquamous glassy-cell carcinoma) are scant. However, neuroendocrine tumours are clearly associated with a greater risk of local recurrence and eventual metastasis, which absolutely contra-indicates fertility-sparing treatment. Five different technical procedures have been described whose indication depends on the size of the cervical lesion [22]: • vaginal radical trachelectomy (VRT) was described by Daniel Dargent who was the promoter of this very innovative surgery. The procedure consists of resection of the entire cervix along with a 1—2 cm vaginal cuff, parametrium and para-colpos (akin to vaginal radical hysterectomy), while preserving the uterine fundus and anastomosing the uterine isthmus to the vagina [1—5];
• RT by laparotomy [6] (LRT); • laparoscopic or robotically-assisted ‘‘minimally-invasive’’ RT (MIRT) [11—14]; • neo-adjuvant chemotherapy followed by fertility-sparing surgery (RT or cone resection depending on the surgical team [17—20]); • and finally, cone resection alone [7—10,16].
Whatever the choice of procedure, lymph node staging (full nodal dissection or sentinel lymph node biopsy) is performed laparoscopically at the outset since lymph node involvement makes fertility-sparing surgery less acceptable oncologically. The choice of one of these techniques does not always correspond to principles established by ‘‘evidencebased medicine’’ or on well-defined oncological strategic principles, but more often on very subjective elements such as the habits of the surgeons who specialize in these techniques and on their own beliefs about the advantages of one technique over the others. In order to better analyze the oncological results of these interventions in terms of fertility, we recently performed an exhaustive review of the different series in the literature [22,23]. Fig. 1 and Table 1 summarize these data. We reviewed nearly 160 articles, involving more than 3100 fertility-sparing surgeries. VRT is indicated only for cancers smaller than 2 cm because the 17% risk of recurrence for larger tumours is not carcinologically acceptable [22]. The oncological need for parametrial resection is debatable for cervical cancers smaller than 2 cm without vascular emboli. For such cases, a simple trachelectomy or conization could be envisaged as long as oncologic safety can be guaranteed by clear resection margins of at least 8 mm. The risk of recurrence in this context is < 0.5% (Fig. 1, Table 1) [22]. Nevertheless, since only a limited number of cases have been reported with this strategy, cohort studies or additional studies are essential before this gesture can be validated for routine use in tumors < 2 cm without vascular emboli. For tumors < 2 cm with some vascular emboli, VRT might also retain its potential indication (Table 1) [22]. In stage IB-1 cervical cancer > 2 cm where VRT is contraindicated, two strategies can be proposed: neo-adjuvant chemotherapy followed by organ-sparing surgery, or abdominal trachelectomy (LRT or MIRT) with a more extensive radical paracervical and paravaginal dissection than can be performed by the trans-vaginal route. Oncological outcomes are similar with a recurrence rate between 6% and 7% [22], but abdominal surgery has the disadvantage (especially when performed by laparotomy where the risk of adhesions is increased) of frequently requiring ligation of uterine artery branches that may potentially impair subsequent fertility [23]. Pregnancy rates are lower after LRT than after chemotherapy followed by fertility-sparing surgery (Table 1) [23]. The rate of premature delivery is also higher after laparotomy (Table 1) [23]. In addition, severe septic complications and two cases of uterine necrosis have been reported after abdominal LRT [22]. As a result, first-line chemotherapy followed by fertility-sparing treatment seems preferable to LRT for stage Ib-1 cervical cancer > 2 cm; the carcinological results are equivalent but the first option has improved fertility and fewer major complications. The use of a minimally-invasive abdominal approach (MIRT) seems to improve the pregnancy rate (Table 1) [23]. We do not yet have sufficient data to compare this neo-adjuvant chemotherapy strategy versus MIRT (whether purely laparoscopic or robot-assisted).
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Figure 1. Oncological outcomes after fertility-sparing surgery in node-negative IB1 cervical cancer (from Bentivegna et al. [22]). LVSI: lymphovascular space involvement; *: only one micro-invasive recurrence; **: proportion of patients with positive margins based on overall population undergoing this treatment.
Endometrial cancer There are two endometrial histological entities that can compromise the patient’s subsequent fertility: atypical endometrial hyperplasia and true endometrial cancer. Medical therapy is a feasible alternative option to conventional extirpative surgical for atypical endometrial hyperplasia or early endometrial cancer [24,25]. Progestin therapy can be considered if strict indications are observed and the patient and her partner are fully informed of risks and benefits. While the carcinological risk associated with this approach is not zero, it remains quite limited. A strict surveillance protocol is necessary to detect recurrence or non-response to treatment. Since the spontaneous fertility of these patients is rather low, the use of assisted reproductive techniques (ART) should be considered. There is no general agreement about the indication of hysterectomy after pregnancy, but it should be considered in view of the high recurrence rates
after conservative treatment (15—40% for atypical hyperplasia and 16—67% for endometrial cancer, according to various studies) [25]. Fertility-sparing treatment can be achieved in patients of childbearing age with atypical endometrial hyperplasia or stage 1A endometrial carcinoma (pure intramucosal, grade 1) who have a desire for pregnancy. These indications arise so rarely and the stakes are so high that systematic expert review of pathology slides should be performed. In addition, it is recommended that care be centralized to expert centers where hysteroscopy, medical treatment and ART are available and where these patients are entered into a national registry [26]. This treatment can only be applied only after a complete therapeutic assessment including: • hysteroscopy with biopsy and hormone receptor assay of tissue collected by cautery-loop resection or curettage of the endomerium and endocervix;
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Oncologic and fertility results after fertility-sparing surgery for cervical cancer (from Bentivegna et al. [23]).
Number
Simple Trachelec- VRT tomy/conization
LRT
MIRT
Neo-adjuvant chemotherapy
Total
Patients Recurrences Patients with infertility Pregnancies 1st trimester fetal death 2nd trimester fetal death 1st/2nd trimester (undetermined) fetal death Termination of pregnancy Ectopic pregnancy Ongoing pregnancy Premature delivery Between 24 & 30 weeks Between 31 & 35 weeks Between 36 & 38 weeks Term not specified Pregnancy rate Rate of live birth Rate of premature birth
212 4 4 103 9 5 0
1355 52 90 499 67 34 0
735 28 93 175 18 8 11
314 15 23 74 15 2 0
161 7 19 93 12 5 0
2777 106 229 944 121 54 11
2 1 14 8 1 3 0 4 22/39 = 56% 51/69 = 74% 8/51 = 15%
21 6 18 120 11 25 24 60 241/424 = 57% 308/460 = 67% 113/285 = 39%
1 0 17 59 8 15 26 10 135/310 = 44% 120/175 = 68% 59/104 = 57%
0 0 7 25 6 5 12 2 57/87 = 65% 50/64 = 78% 25/50 = 50%
0 1 4 11 2 5 2 2 60/78 = 77% 71/93 = 76% 11/71 = 15%
24 8 60 223 28 53 64 78 515/938 = 55% 600/861 = 70% 216/561 = 38%
RT: radical trachelectomy; VRT: vaginal RT; MIRT: mini-invasive RT; LRT: radical trachelectomy by laparotomy.
• laparoscopy for assessment of the pelvic cavity with peritoneal washings for cytology; • pelvic MRI, pelvic ultrasound; • assessment of potential for IVF (hormone balance on days 2 and 23 of the cycle, sperm analysis, ultrasound monitoring). Questions remain to be answered about the optimal type and duration of medical treatment, underlining the importance of collecting these patients for study to advance knowledge [26].
cytology > 0 [27,28]. Most teams feel that fertility-sparing treatment is strictly contra-indicated for stage > I and for grade 3 tumour, except for infiltrative mucinous tumours where fertility-sparing treatment may be possible despite their high grade (Table 2) [29—36]. After a pregnancy is successfully achieved, the need for secondary resection is a subject of debate but it is usually recommended since the prognosis for patients who have recurrence after fertilitysparing surgery remains poor, especially when the disease recurs outside the preserved ovary.
Non-epithelial type
Ovarian cancer Epithelial type Since the peak incidence of epithelial forms of ovarian cancer, the most common type, is age 60, the problem of fertility-sparing treatment rarely arises. The reported results reported are difficult to analyze because most series mix true ovarian cancers (epithelial and non-epithelial tumours) with borderline ovarian tumours when proposing organ-sparing treatment [26]. Complete staging including determination of lymph node status must be determined before proposing fertility-sparing treatment. This most often involves a secondary re-staging after ascertaining the diagnosis that includes omentectomy, pelvic and, lumbar-aortic nodal dissection, peritoneal cytology and systematic biopsies. Nodal dissections are not necessary for the expansile form of mucinous ovarian adenocarcinoma. Organ-sparing treatment may be proposed for serous, mucinous or endometrioid cancers of FIGO stage IA, grade 1 or grade 2 (lesion restricted to the ovary without peritoneal malignant cells) [27]. It can also be discussed for stage IC-1 (intraoperative tumour rupture) or stage IC-2 (preoperative tumour rupture), grade 1 or 2 with peritoneal
Non-epithelial ovarian cancers occur more frequently in young women and their prognosis is generally excellent, even in cases of extra-ovarian disease, due to high curability with chemotherapy. Surgery should be as fertility-sparing as possible for these lesions. Non-epithelial tumours can be classified into two main groups: germ cell tumours (GCT) and stromal sex cord tumours (SSCT). Preoperative measurement of tumour markers helps to define the diagnosis (alpha-feto protein,HCG, inhibin B, anti-müllerian hormone) and must be systematically ordered in young woman with ovarian tumours.
Germ cell tumors (GCT) The most common tumours in this group are dysgerminomas, vitelline duct tumours (endodermal sinus or yolk-sac tumours), and mixed subtypes. BEP chemotherapy (bleomycin, etoposide, cisplatin) is the typical regimen for these tumours. In young patients, fertility-sparing surgery is standard management. For non-dysgerminoma tumours, biopsies of the contralateral ovary are not recommended as long as it is macroscopically normal. For dysgerminoma, contralateral ovarian biopsy may be indicated because there is a potential risk of occult disease in 10% of cases.
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Recurrence Stage IA n (%)
Stage IC
Histologic type
Grade 1
Grade 2
Grade 3
Grade 1
Grade 2
Grade 3
Serous
Mucinous
Endometrioid
Clear Cell
56
5 (9%)
1/24
2/8
1/4
0/10
1/6
0/3
2/18
1/23
2/13
nr
52 34 62 18 211 240 673
5 (10%) 10 (29%) 11 (18%) 3 (17%) 18 (8%) 27 (11%) 79/673 12%
2/33 1/13 1/29 1/10 5/95 7/84 18/288 6%
2/6 4/14 0/3 nr 0/13 2/31 10/75 13%
0/3 1/3 4/4 1/1 2/3 5/15 14/33 42%
0/5 2/2 1/15 0/3 5/65 6/54 14/154 9%
1/3 nr 1/2 0/1 0/2 4/37 7/51 14%
0/2 1/1 2/2 0/1 1/3 2/14 6/26 23%
2/10 2/3 0/7 0/2 3/27 11/62 20/128 16%
2/25 5/21 7/41 1/9 6/126 8/99 30/344 9%
1/10 1/5 1/8 1/5 4/27 6/60 16/128 12%
0/5 1/2 2/4 0/2 5/30 2/17 10/60 17%
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Results of fertility-sparing treatment for epithelial ovarian cancers according to stage, grade and histology of disease (from Bentivegna et al. [37])
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Table 2
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Preservation of part of an ovary could be considered in patients with bilateral involvement or in patients with peritoneal disease treated with adjuvant chemotherapy (particularly in dysgerminoma or malignant teratoma). Since these patients have a high rate of permanent cure, there is no need to consider radical resection after a successful pregnancy.
Stromal sex cord tumours (SSCT) The most common subtypes of SSCT are granulosa cell, Sertoli-Leydig cell and thecal cell tumours. Granulosa tumours are rarely bilateral but are often associated with endometrial hyperplasia or even cancer. Therefore, while systematic biopsies of a macroscopically normal contralateral ovary are not necessary, uterine curettage should be routinely performed. Early-stage granulosa tumours (stage IA) have a good overall prognosis, which allows consideration of fertility-sparing treatment in young women. However, fertility-sparing treatment should not be offered for the more advanced stages or in the case of rupture of the ovarian capsule during the initial surgery, because their prognosis is less certain. Whether radical resection is indicated after pregnancy continues to be debated for SSCT.
Conclusion For women of procreative age, the problem of preserving fertility must be considered from the very outset of gynaecologic cancer management. As long as rigorous oncologic oversight is observed, fertility-sparing treatment may be proposed in selected patients with early stage tumours, excellent prognosis, and without need for adjuvant treatment (at least for uterine cancers). In other cases, the data in the literature are more uncertain (e.g., stage IC-2 ovarian epithelial tumours, or stage IB-1 cervical cancers larger than 2 cm); specialized multidisciplinary management (including oncologist, surgeon, gynaecologist, specialized pathologist, radiologist, ART specialist, psychologist) is absolutely necessary in such cases. To allow the patient to weigh the cancer risk in relation to her hopes for future pregnancy requires careful explanation that fertility-sparing treatment is not necessarily the patient’s right even if she so wishes and that fertility-sparing management is formally contra-indicated if it threatens the vital prognosis in cases where carcinological management should be the primary concern.
• Conservative organ-sparing treatment is possible for cervical cancer stage IB-1 squamous or adenosquamous without nodal involvement and ideally without vascular invasion. • Fertility can be preserved in young patients with endometrial cancer stage IA (limited to the mucosa), grade 1 but may require active management of subsequent infertility, which commonly occurs. Completion radical hysterectomy is recommended after successful pregnancy. • Fertility-sparing treatment is possible for early-stage low-grade epithelial ovarian cancers (stage IA, grade 1 or 2). For stage IC, this strategy may sometimes be proposed for low-grade (grades 1 or 2). Stage IC-1 or IC-2 tumours.
Disclosure of interest The authors declare that they have no competing interest.
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7 [27] Bentivegna E, Gouy S, Maulard A, et al. Fertility sparing surgery in epithelial ovarian cancer: a systematic review of oncological issues. Ann Oncol 2016;27:1994—2004. [28] Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014;124:1—5. [29] Zanetta G, Chiari S, Rota S, et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 1997;104:1030—5. [30] Colombo N, Chiari S, Maggioni A, Bocciolone L, Torri V, Mangioni C. Controversial issues in the management of early epithelial ovarian cancer: conservative surgery and role of adjuvant therapy. Gynecol Oncol 1994;5:S47—51. [31] Schilder JM, Thompson AM, DePriest PD, et al. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol Oncol 2002;87:1—7. [32] Morice P, Leblanc E, Rey A, et al. Conservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC (Groupe des chirurgiens de Centre de lutte contre le cancer) and SFOG (Société francaise d’oncologie gynécologique). Hum Reprod 2005;20:1379—85. [33] Park JY, Kim DY, Suh DS, et al. Outcomes of fertility-sparing surgery for invasive epithelial ovarian cancer: oncologic safety and reproductive outcomes. Gynecol Oncol 2008;110:345—53. [34] Anchezar JP, Sardi J, Soderini A. Long-term follow-up results of fertility sparing surgery in patients with epithelial ovarian cancer. J Surg Oncol 2009;100:55—8. [35] Satoh T, Hatae M, Watanabe Y, et al. Outcomes of fertilitysparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection. J Clin Oncol 2010;28:1727—32. [36] Fruscio R, Corso S, Ceppi L, et al. Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series. Ann Oncol 2013;24:138—44. [37] Bentivegna E, Morice P, Uzan C, et al. Fertility-sparing surgery in epithelial ovarian cancer. Future Oncol 2016;12:389—98.
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Gynaecologic cancer surgery and preservation of fertility E. Bentivegna∗, A. Maulard , G. Miailhe , S. Gouy , P. Morice Département de chirurgie, Gustave-Roussy Cancer Campus, 114, rue Édouard-Vaillant, 94085 Villejuif cedex, France
KEYWORDS Gynaecological cancers; Fertility; Pregnancy; Recurrence; Fertility-sparing treatment
Summary For gynecological cancers, even at an early stage, the standard treatment is ‘‘radical excision’’ involving hysterectomy (radical or not) with bilateral salpingooophorectomy. But for young patients with early stage disease, many recent studies have focused on preservation of subsequent fertility by keeping at least one ovary and the uterus. The main objective of this fertility-sparing surgery is to preserve fertility, if this can be accomplished without increasing the oncological risks. Whether the initial site of the cancer is the cervix, uterine fundus or ovary, the oncologic validation of fertility-sparing treatment requires several evaluation criteria: a rigorous clinical, radiological and surgical staging to verify that the pathology is truly at an early initial stage; expert pathologic interpretation of biopsy specimens to validate the histological criteria of ‘‘good prognosis’’; provision of complete and understandable patient education verifying the true objectives for this fertility-sparing treatment (whose intent is to retain a potential for subsequent fertility without guaranteeing it) and provision of an explanation of the oncological constraints and implications of fertility-sparing surgery in the event of a possible pregnancy. As always in oncology, this strategy demands teamwork requiring successive discussions with the patient and spouse and thorough discussion of the oncological safety of this fertility-sparing strategy in multidisciplinary consultation meetings before ‘‘giving a green light’’. © 2018 Elsevier Masson SAS. All rights reserved.
The particularity of gynaecological cancers is that they involve organs directly involved in reproduction. The currently employed treatments (surgery, radiotherapy, chemotherapy) often impact negatively on subsequent fertility. With better screening and improved treatment, more and more young patients are being diagnosed at an earlier
∗
Corresponding author. E-mail address: [email protected] (E. Bentivegna).
stage and cured, but simultaneously deprived of their fertility. Fertility must be considered is an integral part of the quality of life after cancer treatment. When gynaecologic cancer develops in these young patients, it has major psychological implications, related not only to the announcement of a long and potentially fatal illness but also to necessary therapies that can result in definitive sterility. To preserve fertility while treating gynaecological cancers requires the use of techniques, proven to have carcinological efficacy by different studies, with evaluation
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of remission, recurrence rate and overall survival rate. Several of these techniques [ovarian transposition, in vitro fertilization (IVF), oocyte freezing, cryopreservation of ovarian tissue than can be subsequently transplanted by ortho- or heterotopic autograft, and cryopreservation of ovarian tissue for in vitro maturation] have been evaluated and the patient and her partner can be informed of these options; these techniques are discussed in another chapter of this thematic issue. Organ-sparing surgical treatment aimed at preserving the uterus and at least one ovary is increasingly finding a role in the management of early-stage gynaecological cancers in patients of childbearing age. Its purpose is to preserve the functionality of the reproductive organs by reducing the radicality of the surgical procedure, thereby allowing the possibility of a future pregnancy. The option of fertilitysparing surgical treatment is reserved only for selected cases that are defined by the stage, histology, grade and prognostic factors of the disease. In this article, we will discuss the indications and modalities of fertility-sparing surgical treatment of the principal gynaecological cancers involving the uterine cervix, endometrium and ovaries. Pre-cancerous in situ or microinvasive lesions of the cervix will not be discussed here and borderline ovarian tumours are discussed in another chapter of this thematic issue.
Cancer of the uterine cervix Data in the literature concerning cervical cancer are numerous and rapidly evolving. More than 3000 cases of fertility-sparing treatment have now been published [1—21]. Selection of patients eligible for fertility preservation depends on precise staging of the lesion [clinical examination, lumbo-pelvic magnetic resonance imaging (MRI), expert pathology evaluation allowing definition of the histological type and the existence or absence of vascular emboli] and an evaluation of the patient’s potential fertility. Fertility-sparing treatment is oncologically acceptable only for cervical cancers smaller than 4 cm in size that do not require adjuvant treatment (no lymph node involvement). For some authors, the existence of vascular emboli is not an absolute contra-indication for uterine preservation, however their presence increases the risk of recurrence by about 10% [22]. A diagnostic cone biopsy has been proposed to improve the specific definition of tumour size and the existence or absence of vascular emboli [15]. All of the classical histological types (squamous, adenosquamous, and adenocarcinoma) can be managed with intent of fertility-sparing but the data on the mixed forms (poorly-differentiated adenosquamous glassy-cell carcinoma) are scant. However, neuroendocrine tumours are clearly associated with a greater risk of local recurrence and eventual metastasis, which absolutely contra-indicates fertility-sparing treatment. Five different technical procedures have been described whose indication depends on the size of the cervical lesion [22]: • vaginal radical trachelectomy (VRT) was described by Daniel Dargent who was the promoter of this very innovative surgery. The procedure consists of resection of the entire cervix along with a 1—2 cm vaginal cuff, parametrium and para-colpos (akin to vaginal radical hysterectomy), while preserving the uterine fundus and anastomosing the uterine isthmus to the vagina [1—5];
• RT by laparotomy [6] (LRT); • laparoscopic or robotically-assisted ‘‘minimally-invasive’’ RT (MIRT) [11—14]; • neo-adjuvant chemotherapy followed by fertility-sparing surgery (RT or cone resection depending on the surgical team [17—20]); • and finally, cone resection alone [7—10,16].
Whatever the choice of procedure, lymph node staging (full nodal dissection or sentinel lymph node biopsy) is performed laparoscopically at the outset since lymph node involvement makes fertility-sparing surgery less acceptable oncologically. The choice of one of these techniques does not always correspond to principles established by ‘‘evidencebased medicine’’ or on well-defined oncological strategic principles, but more often on very subjective elements such as the habits of the surgeons who specialize in these techniques and on their own beliefs about the advantages of one technique over the others. In order to better analyze the oncological results of these interventions in terms of fertility, we recently performed an exhaustive review of the different series in the literature [22,23]. Fig. 1 and Table 1 summarize these data. We reviewed nearly 160 articles, involving more than 3100 fertility-sparing surgeries. VRT is indicated only for cancers smaller than 2 cm because the 17% risk of recurrence for larger tumours is not carcinologically acceptable [22]. The oncological need for parametrial resection is debatable for cervical cancers smaller than 2 cm without vascular emboli. For such cases, a simple trachelectomy or conization could be envisaged as long as oncologic safety can be guaranteed by clear resection margins of at least 8 mm. The risk of recurrence in this context is < 0.5% (Fig. 1, Table 1) [22]. Nevertheless, since only a limited number of cases have been reported with this strategy, cohort studies or additional studies are essential before this gesture can be validated for routine use in tumors < 2 cm without vascular emboli. For tumors < 2 cm with some vascular emboli, VRT might also retain its potential indication (Table 1) [22]. In stage IB-1 cervical cancer > 2 cm where VRT is contraindicated, two strategies can be proposed: neo-adjuvant chemotherapy followed by organ-sparing surgery, or abdominal trachelectomy (LRT or MIRT) with a more extensive radical paracervical and paravaginal dissection than can be performed by the trans-vaginal route. Oncological outcomes are similar with a recurrence rate between 6% and 7% [22], but abdominal surgery has the disadvantage (especially when performed by laparotomy where the risk of adhesions is increased) of frequently requiring ligation of uterine artery branches that may potentially impair subsequent fertility [23]. Pregnancy rates are lower after LRT than after chemotherapy followed by fertility-sparing surgery (Table 1) [23]. The rate of premature delivery is also higher after laparotomy (Table 1) [23]. In addition, severe septic complications and two cases of uterine necrosis have been reported after abdominal LRT [22]. As a result, first-line chemotherapy followed by fertility-sparing treatment seems preferable to LRT for stage Ib-1 cervical cancer > 2 cm; the carcinological results are equivalent but the first option has improved fertility and fewer major complications. The use of a minimally-invasive abdominal approach (MIRT) seems to improve the pregnancy rate (Table 1) [23]. We do not yet have sufficient data to compare this neo-adjuvant chemotherapy strategy versus MIRT (whether purely laparoscopic or robot-assisted).
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Figure 1. Oncological outcomes after fertility-sparing surgery in node-negative IB1 cervical cancer (from Bentivegna et al. [22]). LVSI: lymphovascular space involvement; *: only one micro-invasive recurrence; **: proportion of patients with positive margins based on overall population undergoing this treatment.
Endometrial cancer There are two endometrial histological entities that can compromise the patient’s subsequent fertility: atypical endometrial hyperplasia and true endometrial cancer. Medical therapy is a feasible alternative option to conventional extirpative surgical for atypical endometrial hyperplasia or early endometrial cancer [24,25]. Progestin therapy can be considered if strict indications are observed and the patient and her partner are fully informed of risks and benefits. While the carcinological risk associated with this approach is not zero, it remains quite limited. A strict surveillance protocol is necessary to detect recurrence or non-response to treatment. Since the spontaneous fertility of these patients is rather low, the use of assisted reproductive techniques (ART) should be considered. There is no general agreement about the indication of hysterectomy after pregnancy, but it should be considered in view of the high recurrence rates
after conservative treatment (15—40% for atypical hyperplasia and 16—67% for endometrial cancer, according to various studies) [25]. Fertility-sparing treatment can be achieved in patients of childbearing age with atypical endometrial hyperplasia or stage 1A endometrial carcinoma (pure intramucosal, grade 1) who have a desire for pregnancy. These indications arise so rarely and the stakes are so high that systematic expert review of pathology slides should be performed. In addition, it is recommended that care be centralized to expert centers where hysteroscopy, medical treatment and ART are available and where these patients are entered into a national registry [26]. This treatment can only be applied only after a complete therapeutic assessment including: • hysteroscopy with biopsy and hormone receptor assay of tissue collected by cautery-loop resection or curettage of the endomerium and endocervix;
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Oncologic and fertility results after fertility-sparing surgery for cervical cancer (from Bentivegna et al. [23]).
Number
Simple Trachelec- VRT tomy/conization
LRT
MIRT
Neo-adjuvant chemotherapy
Total
Patients Recurrences Patients with infertility Pregnancies 1st trimester fetal death 2nd trimester fetal death 1st/2nd trimester (undetermined) fetal death Termination of pregnancy Ectopic pregnancy Ongoing pregnancy Premature delivery Between 24 & 30 weeks Between 31 & 35 weeks Between 36 & 38 weeks Term not specified Pregnancy rate Rate of live birth Rate of premature birth
212 4 4 103 9 5 0
1355 52 90 499 67 34 0
735 28 93 175 18 8 11
314 15 23 74 15 2 0
161 7 19 93 12 5 0
2777 106 229 944 121 54 11
2 1 14 8 1 3 0 4 22/39 = 56% 51/69 = 74% 8/51 = 15%
21 6 18 120 11 25 24 60 241/424 = 57% 308/460 = 67% 113/285 = 39%
1 0 17 59 8 15 26 10 135/310 = 44% 120/175 = 68% 59/104 = 57%
0 0 7 25 6 5 12 2 57/87 = 65% 50/64 = 78% 25/50 = 50%
0 1 4 11 2 5 2 2 60/78 = 77% 71/93 = 76% 11/71 = 15%
24 8 60 223 28 53 64 78 515/938 = 55% 600/861 = 70% 216/561 = 38%
RT: radical trachelectomy; VRT: vaginal RT; MIRT: mini-invasive RT; LRT: radical trachelectomy by laparotomy.
• laparoscopy for assessment of the pelvic cavity with peritoneal washings for cytology; • pelvic MRI, pelvic ultrasound; • assessment of potential for IVF (hormone balance on days 2 and 23 of the cycle, sperm analysis, ultrasound monitoring). Questions remain to be answered about the optimal type and duration of medical treatment, underlining the importance of collecting these patients for study to advance knowledge [26].
cytology > 0 [27,28]. Most teams feel that fertility-sparing treatment is strictly contra-indicated for stage > I and for grade 3 tumour, except for infiltrative mucinous tumours where fertility-sparing treatment may be possible despite their high grade (Table 2) [29—36]. After a pregnancy is successfully achieved, the need for secondary resection is a subject of debate but it is usually recommended since the prognosis for patients who have recurrence after fertilitysparing surgery remains poor, especially when the disease recurs outside the preserved ovary.
Non-epithelial type
Ovarian cancer Epithelial type Since the peak incidence of epithelial forms of ovarian cancer, the most common type, is age 60, the problem of fertility-sparing treatment rarely arises. The reported results reported are difficult to analyze because most series mix true ovarian cancers (epithelial and non-epithelial tumours) with borderline ovarian tumours when proposing organ-sparing treatment [26]. Complete staging including determination of lymph node status must be determined before proposing fertility-sparing treatment. This most often involves a secondary re-staging after ascertaining the diagnosis that includes omentectomy, pelvic and, lumbar-aortic nodal dissection, peritoneal cytology and systematic biopsies. Nodal dissections are not necessary for the expansile form of mucinous ovarian adenocarcinoma. Organ-sparing treatment may be proposed for serous, mucinous or endometrioid cancers of FIGO stage IA, grade 1 or grade 2 (lesion restricted to the ovary without peritoneal malignant cells) [27]. It can also be discussed for stage IC-1 (intraoperative tumour rupture) or stage IC-2 (preoperative tumour rupture), grade 1 or 2 with peritoneal
Non-epithelial ovarian cancers occur more frequently in young women and their prognosis is generally excellent, even in cases of extra-ovarian disease, due to high curability with chemotherapy. Surgery should be as fertility-sparing as possible for these lesions. Non-epithelial tumours can be classified into two main groups: germ cell tumours (GCT) and stromal sex cord tumours (SSCT). Preoperative measurement of tumour markers helps to define the diagnosis (alpha-feto protein,HCG, inhibin B, anti-müllerian hormone) and must be systematically ordered in young woman with ovarian tumours.
Germ cell tumors (GCT) The most common tumours in this group are dysgerminomas, vitelline duct tumours (endodermal sinus or yolk-sac tumours), and mixed subtypes. BEP chemotherapy (bleomycin, etoposide, cisplatin) is the typical regimen for these tumours. In young patients, fertility-sparing surgery is standard management. For non-dysgerminoma tumours, biopsies of the contralateral ovary are not recommended as long as it is macroscopically normal. For dysgerminoma, contralateral ovarian biopsy may be indicated because there is a potential risk of occult disease in 10% of cases.
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Recurrence Stage IA n (%)
Stage IC
Histologic type
Grade 1
Grade 2
Grade 3
Grade 1
Grade 2
Grade 3
Serous
Mucinous
Endometrioid
Clear Cell
56
5 (9%)
1/24
2/8
1/4
0/10
1/6
0/3
2/18
1/23
2/13
nr
52 34 62 18 211 240 673
5 (10%) 10 (29%) 11 (18%) 3 (17%) 18 (8%) 27 (11%) 79/673 12%
2/33 1/13 1/29 1/10 5/95 7/84 18/288 6%
2/6 4/14 0/3 nr 0/13 2/31 10/75 13%
0/3 1/3 4/4 1/1 2/3 5/15 14/33 42%
0/5 2/2 1/15 0/3 5/65 6/54 14/154 9%
1/3 nr 1/2 0/1 0/2 4/37 7/51 14%
0/2 1/1 2/2 0/1 1/3 2/14 6/26 23%
2/10 2/3 0/7 0/2 3/27 11/62 20/128 16%
2/25 5/21 7/41 1/9 6/126 8/99 30/344 9%
1/10 1/5 1/8 1/5 4/27 6/60 16/128 12%
0/5 1/2 2/4 0/2 5/30 2/17 10/60 17%
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Zanetta et al., Colombo et al. [29,30] Schilder et al. [31] Morice et al. [32] Park et al. [33] Anchezar et al. [34] Satoh et al. [35] Fruscio et al. [36] Total
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Results of fertility-sparing treatment for epithelial ovarian cancers according to stage, grade and histology of disease (from Bentivegna et al. [37])
Gynaecologic cancer surgery and preservation of fertility
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Table 2
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Preservation of part of an ovary could be considered in patients with bilateral involvement or in patients with peritoneal disease treated with adjuvant chemotherapy (particularly in dysgerminoma or malignant teratoma). Since these patients have a high rate of permanent cure, there is no need to consider radical resection after a successful pregnancy.
Stromal sex cord tumours (SSCT) The most common subtypes of SSCT are granulosa cell, Sertoli-Leydig cell and thecal cell tumours. Granulosa tumours are rarely bilateral but are often associated with endometrial hyperplasia or even cancer. Therefore, while systematic biopsies of a macroscopically normal contralateral ovary are not necessary, uterine curettage should be routinely performed. Early-stage granulosa tumours (stage IA) have a good overall prognosis, which allows consideration of fertility-sparing treatment in young women. However, fertility-sparing treatment should not be offered for the more advanced stages or in the case of rupture of the ovarian capsule during the initial surgery, because their prognosis is less certain. Whether radical resection is indicated after pregnancy continues to be debated for SSCT.
Conclusion For women of procreative age, the problem of preserving fertility must be considered from the very outset of gynaecologic cancer management. As long as rigorous oncologic oversight is observed, fertility-sparing treatment may be proposed in selected patients with early stage tumours, excellent prognosis, and without need for adjuvant treatment (at least for uterine cancers). In other cases, the data in the literature are more uncertain (e.g., stage IC-2 ovarian epithelial tumours, or stage IB-1 cervical cancers larger than 2 cm); specialized multidisciplinary management (including oncologist, surgeon, gynaecologist, specialized pathologist, radiologist, ART specialist, psychologist) is absolutely necessary in such cases. To allow the patient to weigh the cancer risk in relation to her hopes for future pregnancy requires careful explanation that fertility-sparing treatment is not necessarily the patient’s right even if she so wishes and that fertility-sparing management is formally contra-indicated if it threatens the vital prognosis in cases where carcinological management should be the primary concern.
• Conservative organ-sparing treatment is possible for cervical cancer stage IB-1 squamous or adenosquamous without nodal involvement and ideally without vascular invasion. • Fertility can be preserved in young patients with endometrial cancer stage IA (limited to the mucosa), grade 1 but may require active management of subsequent infertility, which commonly occurs. Completion radical hysterectomy is recommended after successful pregnancy. • Fertility-sparing treatment is possible for early-stage low-grade epithelial ovarian cancers (stage IA, grade 1 or 2). For stage IC, this strategy may sometimes be proposed for low-grade (grades 1 or 2). Stage IC-1 or IC-2 tumours.
Disclosure of interest The authors declare that they have no competing interest.
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