Available online at www.sciencedirect.

com

Gynecologic Oncology 110 (2008) S29 S32 www.elsevier.com/locate/ygyno

Vaginal approaches to fertility-sparing surgery in invasive cervical cancer

Jaume Pahisa, Inmaculada Alonso , Aureli Torn
Department of Obstetrics and Gynaecology, Hospital Clinic, Barcelona, Spain Received 8 May 2008 Available online 27 June 2008

Abstract There is an important proportion of reproductive-age patients with early stage cervical cancer, low risk of parametrial or lymph node invasion and 95% overall survival rate at 5 years. Actually, there are two conservative techniques for fertility preservation for which long-term follow-up data consistently show acceptable overall and recurrence-free survival rates: conization and vaginal radical trachelectomy (VRT) (Dargent' s operation). Conization is optimal for women with stage IA1 disease without lymphvascular space invasion, and Dargent' s operation is optimal for women with stage IA2 and IB1 disease who have tumors 2 cm in diameter. Other criteria are age 40 years, a desire to preserve fertility, and negative lymph nodes. In other techniques like conization or simple trachelectomy with lymphadenectomy selection of patients with low -risk factors is essential; no vascular space invasion and stromal invasion 1 cm are required. Sentinel node mapping and biopsy are good predictors of node metastasis and could be a good method to select patients for conservative parametrial and cervical surgery. Neoadjuvant chemotherapy could be useful in women with stage IB1 tumors 2 4 cm in diameter with 50% stromal invasion with or without lymphovascular invasion. 2008 Elsevier Inc. All rights reserved.
Keywords: Fertility-sparing surgery; Vaginal radical trachelectomy; Dargent's operation

Introduction The main objective of fertility-sparing surgery in patients with invasive cervical cancer is to maintain reproductive capacity without decreasing overall and recurrence-free survival. Before available selecting patients to receive conservative treatment, surgeons must be knowledgeable about the dissemination pathways of cervical cancer. Cervical cancer spreads locally into the vagina, parametrium, uterosacral ligaments, and occasionally the corpus uteri. Another route of dissemination is through the lymphatic system: lateral (parametrial, external iliac, and obturator lymph nodes); anterior (interiliac nodes); and posterior (uterosacral, presacral, and lateral aortic nodes). Predictors of dissemination include tumor size, lymphovascular space invasion, tumor

Corresponding author. Villarroel Street, 170, 08036 Barcelona, Spain. Fax: +34 93 2279325. E-mail address: ialonsov@yahoo.es (I. Alonso). 0090-8258/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.05.005

grade, and stromal invasion. Some of these factors are included in the International Federation of Gynecology and Obstetrics (FIGO) staging system, except for grade and vascular space invasion. Lymph node metastasis and parametrial invasion are directly related [1,2]. In a series reported by Benedetti-Panici et al., parametrial invasion occurred in 100% of patients with positive pelvic nodes and only 2% of patients with negative nodes. In stage IB1, 16%20% of cases had positive lymph nodes; in stage IA1, less than 1% of cases had positive nodes, and in stage IA2, 5%8% of cases had positive nodes [2]. Benedetti-Panici et al. reported 31% of stage IB1 cases had parametrial invasion [2] but only 2% of cases with negative nodes had parametrial invasion. Based on these findings, it is clear that lymph node status plays an important role in surgical planning. According to the 26th Annual Report of the FIGO, of the 15,081 cases of cervical cancer treated between 1999 to 2001 in 108 centers in the world, 10% were stage IAIB1 in women younger than 40 years [3]. In the Department of Obstetrics and Gynaecology of the Hospital Clinic of Barcelona from 1996 to 2007, 20% of 635

S30

J. Pahisa et al. / Gynecologic Oncology 110 (2008) S29S32

cases were women younger than 40, and of these, 42% had early stage cervical cancer (9% of the overall group). These findings suggest that there is an important proportion of reproductive-age patients with early stage cervical cancer, low risk of parametrial or lymph node invasion and 95% overall survival rate at 5 years [1]. The standard surgical treatment for invasive cervical cancer is radical hysterectomy, which does not preserve fertility. In 1994, Dargent et al. first presented their method of conservative surgical treatment for selected cases of early stage cervical cancer. With this method, patients were capable of becoming pregnant later in life. Actually, there are two conservative techniques for fertility preservation for which long-term follow-up data consistently show acceptable overall and recurrence-free survival rates: conization and vaginal radical trachelectomy (VRT) (Dargent's operation). Conization The efficacies of laser conization, loop electrosurgical excision procedure (LEEP), and cold-knife conization are similar [3]. Several authors have reported a 0% rate of node metastasis when stromal invasion is less than 4 mm [1,4,5]. Tseng et al. reported on 12 cases of stage IA1 cervical cancer treated with conization with an overall survival rate of 100% at 6.7 years [5]. So, conization is an acceptable treatment in stage IA1 cervical cancer. Bisseling et al. [6] studied 29 patients with stage IA1 and 9 patients with stage IA2 adenocarcinoma and performed 16 conizations in stage IA1 and 2 in stage IA2 disease without recurrences at 72 months of follow-up. We performed 4 conizations in patients with adenocarcinoma stage IA1 with 1672 months of follow-up and saw only one case of microinvasive recurrence 5 years after conization. Vaginal radical trachelectomy At the 1994 Annual Congress of the Society of Gynecologic Oncologists, Dargent et al. reported on their results of a series of 28 patients treated by VRT . The technique consisted of removing two thirds of the cervix with the parametrium and the upper 2 cm of the vagina (Figs. 1, 2, 3).

Fig. 2. Cervix and parametria.

Interest in VRT has increased since that presentation. Covens et al. in their review of published data reported on a total of 548 cases with an overall survival rate of 96.9% and disease-free survival rate of 94.9% in a follow-up of 2976 months [7]. The selection criteria for VRT have varied between reported studies. Several authors apply this technique only for tumors 2 cm in diameter, and others used it for tumors up to 4 cm in diameter [7,8,9]. In their review of literature, Dursun et al. reported on a total of 520 patients who underwent VRT; 88% of patients had tumors 4 cm in diameter and 24% had lymphovascular space invasion [8]. In our series, we performed 15 radical trachelectomies from 2000 to 2007 with a follow-up of 295 months; 12 patients had stage 1B1 tumors 2 cm in diameter and the other 3 patients had stage IB1 tumors N 2 cm in diameter (one with vascular space invasion). There have been two recurrences: one 67 months after surgery (primary tumor 23 mm) as a presacral mass of 130 mm and the other one 7 months after surgery (primary tumor 11 7 mm) in the residual cervix. The first patient died 4 months after the diagnosis of presacral recurrence. In 2 other cases a hysterectomy was performed because of endocervical disease in residual cervix found intraoperatively (Table 1).

Fig. 1. Cervix and parametria.

Fig. 3. View of exocervix and the 2 cm of vagina.

J. Pahisa et al. / Gynecologic Oncology 110 (2008) S29S32 Table 1 Patients with cervical cancer treated with Dargent's surgery at the Hospital Clinic of Barcelona Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Stage IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 IB1 Size (mm) 23 11 9 9 15 13 16 8 8 11 14 35 11 20 35 Stromal invasion (mm) 15 7 4 3 4 6 6 5 4 7 8 7 7 10 6 LVI No No No No No No No No No No No Yes No No No Histology Sq Ad Ad Sq Sq Sq Ad Sq Sq Ad Sq Sq Sq Ad Ad Recurrence Yes No No No No No No No No Yes No No No No No Disease-free (months) 67 31 35 29 25 24 22 21 16 7 9 5 2 12 4 Pregnancy No Yes No No No No Yes No Yes No No No No

S31

Complications No No No No Anemia Port-site hernia No No No No No Bladder injury No Hysterectomy Hysterectomy

LVI, lymphovascular invasion; Sq, squamous; Ad, adenocarcinoma.

Covens et al. [7] compared radical hysterectomy versus radical trachelectomy. They performed VRT and lymph node dissection in 32 patients and compared results with patients treated with radical hysterectomy. There were no significant differences in the 2-year actuarial overall survival (95% vs 100%). Marchiole et al. compared Dargent's operation with laparoscopic-assisted vaginal radical hysterectomy. They compared results of patients with tumors b2 cm in diameter and patients with tumors 24 cm. Although VRT is a possible option in patients stage IB1 24 cm they obtained 28.6% of recurrences in this group [9]. Related to fertility results, in the review of Beiner et al., among the 548 patients included, there were 208 reported pregnancies which resulted in 134 third trimester live births (64%). The rate of first trimester miscarriage was 18% (similar to that in the general population). The rate of second trimester miscarriage was 10% and preterm delivery (b 37 weeks) occurred in 20% of the pregnancies [10]. In our series, 4 patients tried to become pregnant, 3 became pregnant, 1 delivered at term by cesarean section, and 2 patients are currently pregnant. One patient had 2 failed attempts at in vitro fertilization. The surgical complication rate of VRT is 4%, bladder injury is the most frequent complication [10]. Morbidity after VRT includes dysmenorrhea (24%), atypical cytology (24%), discharge (10%), cervical channel stenosis (10%), and irregular menstruation (17%) [11]. In a comparison of long-term morbidity with VRT versus radical hysterectomy, increased pain and discharge rates were found in the first [10]. In conclusion, Dargent's technique is associated with overall and recurrence-free survival rates similar to those with radical hysterectomy, and the rate of surgical complications is also similar. Fertility results are promising. Indications for this technique are stage IA1 disease with vascular space invasion and stage IA2 and IB1 disease with negative nodes. To minimize the risk of recurrence, we should restrict VRT in patients with stage IB1 disease to those with tumors 2 cm in diameter, negative nodes, and low-risk histological tumor types. Vascular space invasion and adenocarcinoma are not contraindications to VRT [7,8]. However, 60% of trachelectomies performed after conization show no evidence of residual cancer. In our series of 15

trachelectomies, 75% of patients had no residual disease. So, it is possible that we are using VRT in cases with a favorable prognosis that can benefit from a more conservative treatment. Radical surgery with parametrium and vagina removal may be replaced by these less invasive methods. Neoadjuvant chemotherapy may be useful for downstaging locally advanced cases to permit less radical surgery without increasing morbidity and mortality. Conization or simple trachelectomy with lymphadenectomy There are three studies in the literature describing this treatment: Rob et al. [12], Landoni et al. [13], and Bisseling et al. [6]. Rob described a series of 26 patients: 7 had conization and 15 had a trachelectomy, and all patients had a lymphadenectomy. Selection criteria were stage IA2 or IB1 disease with tumors 2 cm in diameter and 50% stromal invasion. No patient had recurrence at 14 months of follow-up after surgery, and 11 of 15 women became pregnant during a follow-up of 1884 months. Landoni et al. reported on a total of 11 patients treated by neoadjuvant chemotherapy followed by conization or conization alone with pelvic lymphadenectomy. Eight cases were stage IB1 and 3 were IA2. The selection criterion was tumor size 3 cm. There were 3 pregnancies and no recurrences [13]. Adjuvant chemotherapy was applied if there was lymphovascular invasion, if there were clear surgical margins b3 mm, and stromal invasion N 10 mm and positive nodes [13]. Bisseling et al. described and reported on a total of 38 patients with stage IA1 or IA2 adenocarcinomas of which 11 underwent a conization with lymphadenectomy, and there were no recurrences at 72 months of follow-up. Among the 11 patients, there were 18 pregnancies with 11 live births [6]. These studies indicate that a more conservative surgery is possible. Chemotherapy and fertility-preserving surgery Few studies of chemotherapy and fertility-preserving surgery have been reported. At the 2004 meeting of the Society for Gynecologic Oncologists, Maneo et al. reported on a series of 16 patients with tumors b 3 cm in diameter who received neoadjuvant

S32

J. Pahisa et al. / Gynecologic Oncology 110 (2008) S29S32

chemotherapy, followed by conization and lymphadenectomy. Four patients completely responded to treatment and were free of recurrences at 30 months of follow-up. Landoni et al. [13] reported on 11 patients with tumors 3 cm in diameter; neoadjuvant chemotherapy was used in 2 cases, and adjuvant chemotherapy was used in 1 patient. The patients were free of recurrence at 729 months of follow-up. Plante et al. reported on 3 patients with tumors 34 cm in diameter who were treated with neoadjuvant chemotherapy and posterior Dargent's surgery; all 3 completely responded to the treatment and had no disease recurrences [14]. Robova et al. reported a series of 5 patients with stage IB1 tumors N 2 cm in diameter and N50% stromal invasion; treatment included neoadjuvant chemotherapy, followed by lymphadenectomy and simple trachelectomy [15]. Two patients responded completely, and two patients became pregnant. Conclusions In conclusion, the use of fertility-preserving surgery in women with initial cervical cancer is feasible. Two possible techniques exist: conization and Dargent's operation. Conization is optimal for women with stage IA1 disease, and Dargent's operation is optimal for women with stage IA2 and IB1 disease who have tumors b2 cm in diameter. Other criteria are age 40 years, a desire to preserve fertility, and negative lymph nodes. Selection of patients with low-risk factors is essential; no vascular space invasion and stromal invasion 1 cm are required for conization or simple trachelectomy with lymphadenectomy. Current diagnostic methods to evaluate patients for possible conservative treatment are conization and magnetic resonance imagery to determine tumor size and cervical length, and positron emission tomography to evaluate node disease. However, node invasion frequently is microscopic and cannot be detected with these techniques. Sentinel node mapping and biopsy are good predictors of node metastasis and could be a good method to select patients for conservative parametrial and cervical surgery. Neoadjuvant chemotherapy could be useful in women with stage IB1 tumors 24 cm in diameter with 50% stromal invasion with or without lymphovascular invasion.
Conflict of interest statement The authors have no conflicts of interest to declare.

References
[1] Benedetti-Panici P, Palaia I, Basile S, Perinola G, Sansone M, Gradinaru N, Zullo MA, Angioli R. Conservative approaches in early stages of cervical cancer. Gynecol Oncol 2007;107:S1315. [2] Benedetti Panici P, Maneschi F, D'Andrea G, Cutillo G, Rabitti C, Congiu M, Coronetta F, Capelli A. Early cervical carcinoma: the natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer 2000;88:226774. [3] FIGO 26th Annual Report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2006;95:1257. [4] Yamaguchi H, Ueda M, Kanemura M, Izuma S, Nishiyama K, Tanaka Y, Noda S. Clinical efficacy of conservative laser therapy for early-stage cervical cancer. Int J Gynecol Cancer 2007;17:4559. [5] Tseng CJ, Horng SG, Soong YK, Hsueh S, Lin HW. Conservative conization for microinvasive carcinoma of the cervix. Am J Obstet Gynecol 1997;176:100910. [6] Bisseling KC, Bekkers RL, Rome RM, Quinn MA. Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature. Gynecol Oncol 2007;107:42430. [7] Covens A, Shaw P, Murphy J, DePetrillo D, Lickrish G, Laframboise S, Rosen B. Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IAB carcinoma of the cervix? Cancer 1999;86:22739. [8] Dursun P, LeBlanc E, Nogueira MC. Radical vaginal trachelectomy (Dargent's operation): a critical review of the literature. Eur J Surg Oncol 2007;33:93341. [9] Marchiole P, Benchaib M, Buenerd A, Lazlo E, Dargent D, Mathevet P. Oncological safety of laparoscopic-assisted vaginal radical trachelectomy (LARVT or Dargent's operation): a comparative study with laparoscopicassisted vaginal radical hysterectomy (LARVH). Gynecol Oncol 2007;106: 13241. [10] Beiner ME, Covens A. Surgery insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer. Nat Clin Pract Oncol 2007;4:35361. [11] Boss EA, van Golde RJ, Beerendonk CC, Massuger LF. Pregnancy after radical trachelectomy: a real option? Gynecol Oncol 2005;99: S1526. [12] Rob L, Charvat M, Robova H, Pluta M, Strnad P, Hrehorcak M, Skapa P. Less radical fertility-sparing surgery than radical trachelectomy in early cervical cancer. Int J Gynecol Cancer 2007;17:30410. [13] Landoni F, Parma G, Peiretti M, Zanagnolo V, Sideri M, Colombo N, Maggioni A. Chemo-conization in early cervical cancer. Gynecol Oncol 2007;107:S1256. [14] Plante M, Lau S, Brydon L, Swenerton K, LeBlanc R, Roy M. Neoadjuvant chemotherapy followed by vaginal radical trachelectomy in bulky stage IB1 cervical cancer: case report. Gynecol Oncol 2006;101:36770. [15] Robova, H. Pluta, M. Hrehorcak, M. Skapa, P. Rob. L. High-dose density chemotherapy followed by simple trachelectomy: full-term pregnancy. Int J Gynecol Cancer. In press.