Data from our database were automatically converted into SPSS (Statistical Package for the Social Sciences 17.0; SPSS Inc, Chicago, IL). Data on pregnancies after NSRAT were added to this SPSS file. Patients and control subjects were compared concerning tumor characteristics, operative data, and postoperative data using either the χ2 test or Fisher exact test, whichever was more appropriate (categorical data) or Student t test (continuous data). Apart from 2- and 5-year recurrence-free survival and overall survival, local recurrence–only rates were calculated. Local recurrence was defined as recurrence located at the ostium (“neocervix”) of the uterus (NSRAT cohort) or vaginal vault (NSRH cohort). Kaplan-Meier curves were constructed, and the log-rank test used to compare survival curves. The recurrence-free survival was defined as the time in months from the date of surgery to diagnosis of recurrence or last follow-up, and overall survival was defined as the survival from the date of surgery until death or last follow-up. Patients were censored in the survival analysis whenever follow-up ended without the occurrence of death. Statistical significance was assumed whenever P < 0.05. Analyses were not performed on intention-to-treat- basis; women in whom fertility-preserving surgery could not be completed were not included in this study. According to local guidelines, it was not necessary to apply for approval by the local ethical committee.
A total of 28 women (cases) were treated by NSRAT between January 1, 2000, and February 1, 2011, and 77 control subjects were selected. Because of lack of eligible women, it was not possible to include 3 control subjects for each case. The mean follow-up was 47.3 months (range, 6–122 months) and 51.8 months (range, 11.0–129.6 months), respectively. The mean age was 31.2 years (range, 21–37 years) for the cases and 44.2 years (range, 32–73 years) for the control group. Patient and tumor characteristics are presented in Table 2. As expected, women treated with NSRAT were significantly younger (P < 0.05). With respect to the known prognostic factors (histological subtype, infiltration depth, presence of lymph-vascular space invasion, and linear extension), there was no significant difference between patients and control subjects (Table 2). The reported tumor characteristics are based on the surgical specimen. Three patients received neoadjuvant chemotherapy before the NSRAT because of tumor size of or greater than 40 mm. Surgical data are presented in Table 2. Apart from length of surgery (median duration, 255 vs 210 minutes, P < 0.01), there were no significant differences between both groups. None of the women in both the NSRAT and the NSRH cohorts needed adjuvant treatment after surgery; hence, all women had negative node status, negative vaginal margins, and no parametrial invasion because each of this features would necessitate adjuvant treatment.
Overall recurrence rates were 7.4% (95% confidence interval [CI], 0.00%–16.9%) and 14.3% (95% CI, 6.3%–22.3%) for NSRAT and NSRH, respectively (P = 0.45). Median follow-up for these patients with recurrence was as follows: 68.5 months (range, 15–122 months) for NSRAT and 77.5 months (range, 37.1–129.6 months) for NSRH. Local recurrence–only rates were 3.6% (95% CI, 0.00%–10.6%) and 7.8% (95% CI, 1.7%–13.9%) (P = 0.91). None of the women who received neoadjuvant chemotherapy before NSRAT had recurrent disease. Survival data are presented in Table 3. Figure 1 displays the Kaplan-Meier curve of 2 years’ disease-free survival (P = 0.19, log rank). Among the 28 women in the NSRAT group, 2 women had recurrent disease. One of these is alive and in complete remission after chemoradiation (recurrence after 50 months); the other woman died of disease after 15 months (recurrence after 11 months). Both patients were compliant with our follow-up protocol and were submitted at least every 4 to 6 months to gynecologic physical examination. In the control group, 11 of 77 women had recurrent disease, of whom 2 women died of disease (after 13.7 and 28.2 months, respectively) (Table 3). Site of recurrence is detailed in Table 3. Details on the 2 patients treated with NSRAT with recurrent disease are listed in Table 4.
Nerve sparing was successful in the vast majority of women: at least 1-sided in 89.3% and 96.1% (in NSRAT and NSRH, respectively). All failures were due to the inability to identify the hypogastric nerve. There were a few postoperative complications (NSRAT, NSRH): voiding problems: 3.6% (urgency) and 18.2% (urgency, cystitis, stress-incontinence); defecation problems (10.7%): 11.7% (constipation in all women); and sexual dysfunction (3.6%; 1.3% dyspareunia in all women). Moreover, there were 2 cases of deep vein thrombosis in the control group (2.6%), whereas the incidence rates of lymph edema were 3.6% and 14.3% after NSRAT and NSRH, respectively. The maximum length of suprapubic catheterization was 7 days (n = 1 NSRAT and n = 4 NSRH); in all other women, the suprapubic catheter was removed on day 5.
Of the 26 women in the NSRAT group without recurrent disease, only 17 (65.4%; 95% CI, 46.7%–84.0%) tried to conceive. Two of the 3 women who had neoadjuvant chemotherapy successfully conceived. Details on the patients treated with neoadjuvant chemotherapy are listed in Table 5. The overall pregnancy rate showed to be 52.9% (95% CI, 28.7%–77.2%) of those women aiming to get pregnant. There were 12 spontaneous pregnancies in 7 patients and 2 in vitro fertilization pregnancies in 2 patients. There were no fetal losses and no premature deliveries. All deliveries were after 37 weeks of pregnancy and by cesarean section. Four patients (24%; 95% CI, 3.0%–44.0%) are in the course of in vitro fertilization, one of these as a result of male infertility. The remaining 4 patients aiming to conceive are either awaiting spontaneous pregnancy or in the course of analyzing subfertility. Two women were pregnant at the time of NSRAT surgery, 7 and 12 2/7 weeks’ gestation, both resulting in a spontaneous miscarriage at, respectively, 9 1/7 and 13 5/7 weeks’ gestation.
Our case-control study shows that NSRAT appears safe and effective with regard to fertility preservation in women with early-stage cervical cancer. Local recurrence rate and overall survival and disease-free survival do not differ significantly after NSRAT and NSRH in our cohorts (Table 3). Moreover, site of recurrence does not differ between both groups. The non–statistically significant difference in overall recurrence rate (7.4% and 14.3% after NSRAT and NSRH, respectively) is, however, remarkable and may be due to selection, although the number of high-risk patients did not differ significantly between both cohorts. Our data implicate that, although numbers are small, NSRAT is safe in women with early-stage cervical cancer who wish to preserve fertility. Pregnancy rate is as high as 53% (95% CI, 28.7%–77.2%), indicating that NSRAT is effective in preserving fertility. Literature on abdominal trachelectomy is scarce, but our survival rates and pregnancy rates seem to be similar to those reported by others.12,13,22,23 A recent literature review by Pareja et al24 looking at surgical, oncological, and obstetrical outcomes shows that abdominal radical trachelectomy is a safe option for patients with early-stage cervical cancer.
Other recent studies have shown results of surgical treatment for early-stage cervical cancer by RVT in combination with pelvic lymphadenectomy with regard to fertility preservation.10,25–27 These reports show that RVT is performed mostly in small cancers. For example, in the large series on VRT recently published by Speiser et al,27 the median tumor size is microscopic, whereas in our series the median tumor size at histological examination after surgery is 13.5 mm (mean, 17.3; range, 0.1–38 mm; Table 2). Because parametrial involvement is extremely rare in tumors less than 20 mm, especially in the absence of lymphovascular space infiltration (LVSI), one can argue whether these patients need a parametrectomy at all.28 In women with small tumors (ie, <20 mm), an excisional cone or simple trachelectomy with pelvic lymphadenectomy has shown excellent survival and low recurrence rates, although the median follow-up was only 16 months.29,30 These data indicate that we may end up performing excisional cones in the low-risk patients (small tumor <20 mm in diameter without LVSI) and NSRAT in the higher-risk patients (larger tumors, with LVSI) with early-stage cervical cancer who wish to preserve fertility.
Because of small numbers, we could not differentiate the risk of recurrence for high- and low-risk women. As mentioned above, there is much debate about the need for parametrial resection and whether parametrial resection is in the detection of local spread or nodal spread. In this respect, it is important to compare the presence of nodes in the parametrium after (type 2) RVT and conventional RH: 8% versus greater than 90% of specimen.26,31 Hence, if nodal spread is considered an issue, RVT may leave a significant percentage of nodes undetected, especially if sentinel node detection is not performed.
Apart from tumor size, another important reason to prefer the abdominal approach above the vaginal route to perform a trachelectomy is the possibility of selectively sparing the autonomic nerves in the pelvis, as this is technically not possible in vaginal trachelectomy. Although there are, to our knowledge, no data on autonomic nerve damage after radical trachelectomy, there is abundant evidence that the pelvic autonomic nerves are damaged during RH.32 This damage is thought to be the leading cause of the well-known long-term bladder, bowel, and sexual morbidity after conventional RH.2 Because there is solid evidence that nerve-sparing surgery reduces these complications,13,33,34 it seems more than logic to adopt nerve-sparing surgery in radical trachelectomy, especially because nerve-sparing surgery is considered safe and feasible in early-stage cervical cancer.7,35 Nerve-sparing was successful in the vast majority of both our patients and control subjects (89.3% and 96.1%, respectively). However, from the analysis of the dysfunctions, possibly due to nerve damage, it can be concluded that failed nerve-sparing surgery does not inevitably lead to dysfunction, nor will nerve-sparing surgery fully prevent dysfunctions. Clearly, autonomic function does not mimic autonomic nerve damage as suggested in our recent longitudinal in-depth analysis of bladder, bowel, and sexual function after conventional RH and NSRH.36
The main risk factors for recurrence of cervical cancer are tumor size more than 20 mm, stromal invasion of more than 10 mm, and presence of LVSI.28 Our cases were treated with neoadjuvant chemotherapy if tumors were 40 mm or more in their largest diameter on histological examination. Others have proposed neoadjuvant chemotherapy for bulky cervical cancers in women who wish to preserve fertility as well: it is suggested to decrease the number of positive nodes, and it reduces tumor volume before surgery, permitting less radical and hence more successful fertility-preserving surgical techniques.37,38 Although not much has been published about the use of neoadjuvant chemotherapy in fertility preservation, the data on its use in cervical cancer are abundant, and this protocol is considered safe and effective.39,40 Although small, our series adds data to support the use of neoadjuvant chemotherapy mainly because it does not hamper fertility preservation.
As the aim of the radical trachelectomy is to preserve fertility, it is also important to consider the condition and functionality of the uterus after surgery with regard to possible pregnancies. Because of cervical incompetence (both mechanical and with regard to prevention of infection), second-trimester abortion and premature delivery are the main concerns after trachelectomy.23 Because the uterine arteries are ligated in conventional trachelectomy, the blood supply to the uterine corpus may be reduced. Collateral circulation from the utero-ovarian ligaments is considered to keep the uterine tissue viable, but it is thought to provide reduced blood supply to the corpus leading to decreased fertility, less placental function, and consequently probably a higher risk of premature rupture of membranes and premature labour.30 As described in detail, our technique allows specific sparing of the ascending branch of the uterine artery, resulting in better blood supply to the uterine corpus during pregnancy. This uterine artery–sparing technique is used by others as well.14 In our opinion, the fact that none of our cases had either second-trimester abortion or fetal growth retardation may have been in relation to the sparing of the ascending branches of the uterine artery.
In this study, 2 experienced gynecologic oncologists have performed all surgeries. We have collected 28 cases for NSRAT in a period of a little more than 10 years. Incorporating our technique into one’s clinic armamentarium needs consideration of the learning curve and experience, which are needed for achieving good results. Moreover, with the interpretation of our results, we have to take the small sample size and observational design of our study into account. Both may have led to bias. For example, women with nonfavorable characteristics may have been counseled to non–fertility-preserving treatment. Moreover, we had to include a lower-than-intended number of control subjects. Although post hoc comparison of both groups does not show any differences with regard to the well-known risk factors for local recurrence, and data were collected prospectively, the previously mentioned methodological weaknesses need to be taken into account and incorporated into counseling respective women.
This study demonstrates that NSRAT results in recurrence and survival rates that do not differ from those after conventional treatment (NSRH) in women with early-stage cervical cancer. The overall pregnancy rate after NSRAT was 53%. There was no fetal loss or premature delivery in our series. In our opinion, NSRAT is feasible and safe and should be offered to women with early-stage cervical cancer who want to preserve their fertility. In women with larger tumors, neoadjuvant chemotherapy can be administered to down-stage the tumor and allow for fertility-sparing surgery. In both situations, we have to bear in mind that the level of evidence of our study is moderate. That is why treating gynecologic-oncologists are obliged to give full and detailed information, and both counseling and treatment should be centralized to gain and maintain experience.
1. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Lymphedema and bladder-emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer
. 2006; 16: 1130–1139.
2. Pieterse QD, Maas CP, ter Kuile MM, et al. An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gynecol Cancer
. 2006; 16: 1119–1129.
3. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Vaginal changes and sexuality in women with a history of cervical cancer. N Engl J Med
. 1999; 340: 1383–1389.
4. Maas CP, Trimbos JB, DeRuiter MC, et al. Nerve sparing radical hysterectomy: latest developments and historical perspective. Crit Rev Oncol Hematol
. 2003; 48: 271–279.
5. Trimbos JB, Maas CP, Deruiter MC, et al. A nerve-sparing radical hysterectomy: guidelines and feasibility in Western patients. Int J Gynecol Cancer
. 2001; 11: 180–186.
6. Trimbos JB, Maas CP, Deruiter MC, et al. [Nerve sparing radical hysterectomy in the case of cervical cancer]. Ned Tijdschr Geneeskd
. 2003; 147: 1344–1347.
7. Rob L, Halaska M, Robova H. Nerve-sparing and individually tailored surgery for cervical cancer. Lancet Oncol
. 2010; 11: 292–301.
8. Raspagliesi F, Ditto A, Fontanelli R, et al. Nerve-sparing radical hysterectomy: a surgical technique for preserving the autonomic hypogastric nerve. Gynecol Oncol
. 2004; 93: 307–314.
9. de Kroon CD, Gaarenstroom KN, van Poelgeest MI, et al. Nerve sparing in radical surgery for early-stage cervical cancer: yes we should! Int J Gynecol Cancer
. 2010; 20: S39–S41.
10. Plante M, Gregoire J, Renaud MC, et al. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol
. 2011; 121: 290–297.
11. Diaz JP, Sonoda Y, Leitao MM, et al. Oncologic outcome of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma. Gynecol Oncol
. 2008; 111: 255–260.
12. Abu-Rustum NR, Sonoda Y, Black D, et al. Fertility-sparing radical abdominal trachelectomy for cervical carcinoma: technique and review of the literature. Gynecol Oncol
. 2006; 103: 807–813.
13. Cibula D, Velechovska P, Slama J, et al. Late morbidity following nerve-sparing radical hysterectomy. Gynecol Oncol
. 2010; 116: 506–511.
14. Hong DG, Lee YS, Park NY, et al. Robotic uterine artery preservation and nerve-sparing radical trachelectomy with bilateral pelvic lymphadenectomy in early-stage cervical cancer. Int J Gynecol Cancer
. 2011; 21: 391–396.
15. Martin A, Torrent A. Laparoscopic nerve-sparing radical trachelectomy: surgical technique and outcome. J Minim Invasive Gynecol
. 2010; 17: 37–41.
16. Li J, Wang LJ, Zhang BZ, et al. Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review. Arch Gynecol Obstet
. 2011; 284: 779–783.
17. de Jongh FE, de Wit R, Verweij J, et al. Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer. Eur J Cancer
. 2002; 38: 2005–2013.
18. Benedetti-Panici P, Greggi S, Colombo A, et al. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol
. 2002; 20: 179–188.
19. Delgado G, Bundy B, Zaino R, et al. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol
. 1990; 38: 352–357.
20. Trimbos JB, van den Tillaart SA, Maas CP, et al. The Swift operation: a modification of the Leiden nerve-sparing radical hysterectomy. Gynecol Surgery
. 2008; 5: 193–198.
21. Querleu D, Morrow CP. Classification of radical hysterectomy. Lancet Oncol
. 2008; 9: 297–303.
22. Bernardini M, Barrett J, Seaward G, et al. Pregnancy outcomes in patients after radical trachelectomy. Am J Obstet Gynecol
. 2003; 189: 1378–1382.
23. Nishio H, Fujii T, Kameyama K, et al. Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women. Gynecol Oncol
. 2009; 115: 51–55.
24. Pareja R, Rendon GJ, Sanz-Lomana CM, et al. Surgical, oncological, and obstetrical outcomes after abdominal radical trachelectomy—a systematic literature review. Gynecol Oncol
. 2013. In press.
25. Beiner ME, Hauspy J, Rosen B, et al. Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study. Gynecol Oncol
. 2008; 110: 168–171.
26. Lanowska M, Morawietz L, Sikora A, et al. Prevalence of lymph nodes in the parametrium of radical vaginal trachelectomy (RVT) specimen. Gynecol Oncol
. 2011; 121: 298–302.
27. Speiser D, Mangler M, Kohler C, et al. Fertility outcome after radical vaginal trachelectomy: a prospective study of 212 patients. Int J Gynecol Cancer
2011; 21: 1635–1639.
28. Beiner ME, Covens A. Surgery insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer. Nat Clin Pract Oncol
. 2007; 4: 353–361.
29. Fagotti A, Gagliardi ML, Moruzzi C, et al. Excisional cone as fertility-sparing treatment in early-stage cervical cancer. Fertil Steril
. 2011; 95: 1109–1112.
30. Rob L, Pluta M, Skapa P, et al. Advances in fertility-sparing surgery for cervical cancer. Expert Rev Anticancer Ther
. 2010; 10: 1101–1114.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Cervical cancer; Fertility preservation; Radical surgery; Pregnancy; Survival; Neoadjuvant chemotherapy