Cervical cancer is mostly a disease of women at reproductive age. According to the latest GLOBOCAN report data, 20.78% of total number of patients with cervical cancer in Europe is younger than 39 years. There is an increasing demand for treatment that allows preserving fertility in women diagnosed with cervical cancer. Traditional treatment of early invasive cervical cancer beyond stage IA-1 according to the International Federation of Gynecology and Obstetrics (FIGO) has been radical hysterectomy and pelvic node dissection, or chemoradiation, which renders the patient infertile. Radical trachelectomy (RT) procedure has emerged as a fertility-sparing alternative to standard treatment of women with early-stage cervical cancer.
The current review was based on the systematic MEDLINE search that yielded 218 articles, of which 75 were selected for further analysis based on the number of patients and the quality of the study.
DEVELOPMENT OF RT
In 1952, Novak1 presented an operation that is radical to cancer but conservative in the sense of not mutilating the woman’s genitalia, which could be performed in women of reproductive age with cervical cancer in situ, who request to be operated on conservatively. He stated that this operation would be a radical dissection of lymph nodes and radical extirpation of the cervix and the upper part of the vagina, together with the corresponding paracervical and paravaginal tissues by laparotomy. In 1957, Aburel reported subcorporeal extended colpotrachelectomy in patients with cervical cancer. These techniques did not find common interest. Dargent was the first to report systematic conservative treatment of patients with early-stage IA1-IIA cervical cancer according to FIGO by vaginal RT (VRT) with laparoscopic pelvic lymphadenectomy in 1994. Abdominal RT (ART) with conservation of the uterus was revised by Smith.
CURRENT INDICATIONS AND PATIENT SELECTION
Radical trachelectomy is a treatment option in patients with stage IA1 L1V0, IA2 V0, or IB1 V0 cervical cancer according to FIGO desiring to preserve their fertility. Tumor histological diagnosis should be squamous cell or adenocarcinoma. Neuroendocrine tumors or small cell cancers of the cervix are more likely associated with lymph node metastases, lymphovascular space invasion (LVSI), and local and distant failure. Therefore, RT is not considered suitable for patients with neuroendocrine tumors. Other various indications reported as managed with RT are malignant peripheral nerve sheath tumor of uterine cervix, recurrent endometrial cancer in the cervical stump, adenocarcinoma in situ suspicious for invasion in the cervical stump after supracervical hysterectomy, clear cell carcinoma, rhabdomyosarcoma, or any other sarcomatous tumor of the cervix and/or upper vagina in pediatric patients.
Women with reproductive potential desiring to preserve fertility are candidates for RT. Pelvic lymph nodes must be free of tumor, which should be proven histopathologically. In the early stages of the development of trachelectomy, it was intended to treat FIGO stage IA1-IIA tumors of the cervix by VRT. Later, it became evident that tumor diameter is of utmost importance for candidate selection. In lymph node–negative patients, overall recurrence and mortality for patients with squamous cell carcinoma less than 2 cm in diameter with stromal invasion less than 10 mm and without LVSI seems to be similar to the outcome achieved with standard radical hysterectomy and pelvic lymphadenectomy.2 Tumor size greater than 2 cm and LVSI were identified as the major predictive factors for an adverse outcome in lymph node–negative patients.2 Thus, patients whose tumor size exceeds 2 cm are not eligible for RT. The rate of positive lymph nodes and LVSI in patients with FIGO IA1-IB1 cervical cancer is reported to be 16% to 27% and 39% to 41%, respectively. The rate of positive lymph nodes and the need for hysterectomy or adjuvant treatment are higher than the expected rate of 10%. Twenty-seven percent of patients needed hysterectomy or adjuvant pelvic radiation postoperatively.
Sonoda et al3 used similar criteria listed in Table 1 and calculated that 48% of patients treated with radical hysterectomy were eligible for laparoscopic VRT. These strict criteria are necessary to obtain oncological safety and allow a cure of more than 90% of patients. It is claimed that ART is not limited to these strict selection criteria4: patients with a tumor diameter greater than 2 cm, LVSI, clear cell carcinoma of vagina and/or cervix, or cervical cancer in the first trimester of pregnancy have been treated. Besides, ART can be performed if vaginal anatomy is distorted and if the entire parametrium has to be resected. The level of evidence for ART is low, and better-quality data are needed to be able to advise this type of treatment to patients.
ABORTION OF RADICAL TRACHELECTOMY
If pelvic lymph nodes or paracervical tissue are found to be tumor involved, VRT is aborted, and lymphadenectomy is completed at the pelvic and para-aortic area and followed by primary chemoradiation. If a permanent section confirms tumor-involved resection margins or endocervical tumor-free margin less than 5 mm or a tumor diameter more than 20 mm (taking also into account the volume of tumor removed by prior conization), radical hysterectomy or primary chemoradiation has to be performed. Abortion rate of VRT is reported in up to 12% of patients.4,5
PREOPERATIVE WORKUP AND STAGING
A fertility workup can be considered for those patients with a history of infertility, which consist of 5% to 25% of RT patients. The aim of preoperative workup was to identify high-risk patients who are likely to fail to have a conservative oncological approach. Therefore, tumor site and extension should be evaluated by clinical examination. Clinical staging using FIGO is mandatory. Most patients underwent conization, which allowed to measure the tumor size histopathologically. Assessment of tumor extension to the internal cervical os and isthmus is critical and is not always possible. Therefore, a conization or reconization can be useful before RT to improve correct patient selection.
Overall accuracy of staging by computed tomography and magnetic resonance imaging is reported to be 53% and 86%, respectively. Magnetic resonance imaging is superior to computed tomography in determining lesion diameter and parametrial invasion.6 However, actual diagnostic accuracy may be lower in general because these reports are from expert centers. Magnetic resonance imaging with saline hydrocolpos is reported to delineate tumor extension better, particularly in evaluating the distance of the tumor to the internal cervical os. Computed tomography/magnetic resonance imaging and fluorodeoxyglucose–positron emission tomography are of limited value in evaluating lymph node status in patients with early-stage cancer. Surgical evaluation of lymph nodes is mandatory. Staging of cervical cancer is determined at the time of primary diagnosis and cannot be altered. Management of women with early-stage cervical cancer by conservative surgery depends mainly on lymph node status. Thus, TNM classification must be adjunct to the FIGO classification.
Radical trachelectomy can be performed by the vaginal route after laparoscopic pelvic lymphadenectomy or by the abdominal route (Figs. 1 and 2). Total laparoscopic RT, laparoscopic and robotic assisted RT, and nerve-sparing RT techniques have been reported in small case series. Vaginal RT is based on the vaginal radical hysterectomy technique according to Schauta-Stoeckel. Abdominal RT is based on the abdominal radical hysterectomy according to Wertheim. Total laparoscopic RT can be an alternative to VRT for surgeons with limited experience on radical vaginal operation. Because of small sample size and longer operation time, robotic RT currently seems not a valid alternative to VRT.
It remains to be shown if blood supply to the ovary and the fallopian tube with or without reanastomosis of divided vessels can preserve uterine and fallopian tube function and provide an optimal environment for subsequent pregnancies. New arterial vascularization from the ascending branches of uterine arteries or other arteries was identified in 2 patients who underwent RT, and these new vessels seemed to supply blood to the remaining cervix. There is no clear consensus if a cervicoisthmic cerclage should be done during RT or only after the patient became pregnant. Primary cerclage might impair fertility by inducing subsequent cervical stenosis, erosions, and/or chronic discharges.
Abdominal RT has been performed successfully in pregnant patients with FIGO stage IB1 cervical cancer in the first trimester and second trimester, with preservation of uterine arteries However, this type of surgery is experimental, and results are inevitably prone to selection bias. Thus, this type of surgery can only be performed in a few expert centers after thorough discussion with a tumor board and detailed counseling of the patient.
The complication rate of VRT is 4% to 6% and similar to laparoscopic-assisted radical hysterectomy.4,5,7–9 Intraoperative complications were significantly higher in the VRT group compared with the ART group (13% vs 2%) in 1 study. The most common intraoperative complication of VRT is urinary tract injury. However, if the surgeon is constantly exposed to radical vaginal surgery, no injuries of the urinary tract, bowel, or blood vessels and no conversion to laparotomy are observed. Rates of conversions to laparotomy or secondary surgeries for parametrial bleeding, blood vessel injury, lymphocele, suprapubic, or vulvar hematoma range between 0% and 9%.5,8,9 Postoperative complications such as dysmenorrhea (24%), dyspareunia (20%), menstrual abnormalities (17%), excessive vaginal discharge (14%), recurrent candidiasis (14%), bladder hypotonia (4%–16%), vulvar edema (12%), lymphocele (3%–11%), chronic pelvic pain (10%), isthmic stenosis (10%), amenorrhea (7%), vulvar hematoma (7%), suprapubic hematoma (4%), lymphedema (3%), urinary tract infection (2%), and femorocutaneous nerve palsy (1%) are reported. Complication rates for ART seem to be similar to those of abdominal radical hysterectomy and are not different from VRT.
Surgical specimen of the cervix has at least 3 to 4 cm of parametrial tissue in ART. Approximately 2 cm of parametrial tissue is resected in VRT. However, during the laparoscopic phase of surgery, the lateral half of the cardinal ligament is cleaned from lymph nodes, which is therefore equivalent to a type 3 procedure. The endocervical margin can be examined either by longitudinal or by transverse section to identify if tumors extend to within less than 5 mm of the endocervical margin. A transverse section allows examining the entire surface of the specimen, whereas by longitudinal sections, the distance between the tumor and the endocervical margin is measured. Correlation of frozen sections and permanent sections of the endocervical margin might be lower in adenocarcinoma compared to squamous cancer. A gross examination of RT specimens and longitudinal frozen section is reported to be useful in case of macroscopically visible tumor and of no use if no tumor is visible.
There is no consensus and no generally accepted guidelines on the follow-up protocol in patients after RT. We advocate that patients should be followed up at a 3-month interval for the first 2 years because most recurrences occur in the first 24 months, then at 6 months for 3 years, and thereafter, the patient goes back into regular screening. Follow-up is also important to monitor risk of complications and subsequent pregnancy rates. In contrast to follow-up examination to patients having been treated for cervical cancer by radical hysterectomy or chemoradiation, patients with preservation of part of the cervix need regular control of the remaining cervix, which can be done by cytology, colposcopy, and human papillomavirus testing.
ONCOLOGICAL SAFETY, OUTCOME, AND PROGNOSTIC FACTORS
Overall progression-free survival rates were similar for VRT and radical hysterectomy in patients with stage IA-IB1 cervical cancer according to FIGO. Overall recurrence rate after VRT is 3% to 6% and death rate is 2% to 5%.4,5,8,10 It is too early to assess the recurrence rates of ART (Table 2). A recurrence rate of 9.8% has been reported in 61 patients who underwent ART. However, 5 of 6 patients with recurrence have had a tumor diameter greater than 20 mm. One had a histological diagnosis of adenocarcinoma, with a tumor diameter less than 20 mm. Forty percent of recurrences occur in the parametrium or the pelvic sidewall, and 25% to 30% were in the pelvic, para-aortic, and/or supraclavicular lymph nodes. The rest occurred at intra-abdominal sites or distant sites.
Adenocarcinoma may be associated with a higher recurrence rate; however, the association is not statistically significant.8 Recurrence is significantly higher in tumors greater than 2 cm (25%–29%). In addition, the presence of LVSI and/or deep stromal invasion greater than 10 mm is shown to be of prognostic significance for a poor outcome. Five-year recurrence-free survival rate is reported to be 95% for the RT and 100% for the radical hysterectomy in stage IB1 cervical cancer patients in a matched case-control study. In this study, 3 recurrences and 1 recurrence were diagnosed in the RVT and radical hysterectomy groups, respectively, and the oncological safety was found to be comparable to that of radical hysterectomy.
FERTILITY AND OBSTETRIC OUTCOME
Fertility might be impaired after RT because of anatomical and physiological changes such as adhesions, cervical stenosis, and/or loss of cervical function. Data on fertility and obstetric outcome are particularly based on results of VRT patients. Vaginal RT may be more protective to fertility compared to ART. Fifty-nine percent of patients received fertility treatment after ART; however, the number of patients treated with ART is still too low to draw such a conclusion. Conception rate after RT is cumulatively increasing over time from 37% to 70% during a 5-year period.
About 10% to 13% of VRT patients are infertile; this rate is comparable to the general population, and infertility might have existed before the operation or might have resulted from the operation. Intrauterine insemination and in vitro fertilization/embryo transfer are associated with good results in RT patients, although cannulation of the uterine cavity might be more difficult and dilatation might be necessary. The prevalence of infertility and use of assisted reproductive technology may be higher in patients after ART than in patients after VRT.
More than 900 trachelectomies worldwide have been reported so far, resulting in 300 pregnancies and 196 live births. However, 57% of the patients did not attempt to conceive after RT.11 Seventy percent of these patients became pregnant.11 Pregnancy rates after ART are lower than after VRT and simple trachelectomy/cone biopsy. Pregnancy rate has been reported to be 30% and 15% after VRT and ART, respectively, with 186 live births of 618 VRTs and 20 live births of 147 ARTs.
There is no clear consensus on the interval waiting time between RT and attempting pregnancy. Complete healing of the tissue may last up to 3 months, and the longer the interval, the lower the risk of recurrence. These time marks have to be considered when counseling the patient. Because the procedure usually is limited to small tumors prognosis, there might be no need to wait. Pregnancy complications such as pregnancy loss and preterm delivery are particularly expected in these patients.
The rate of first-trimester miscarriage is comparable to that of the general population, but second-trimester losses are increased in patients after RT compared to that in the general population. First-trimester and second-trimester miscarriage is reported in 21% and 8% of RT patients, respectively.12 First-trimester complete abortions can be managed conservatively without removing the cerclage and no curettage. In cases of second-trimester miscarriage or incomplete abortion, use of prostaglandins, cervical laminaria insertion, or removal of the cerclage is suggested, followed by adequate procedure (curettage) if necessary.
Fifty percent of women deliver beyond 37 weeks, whereas 21% to 28% delivered prematurely before 37 weeks and 12% of patients had delivered before 32 weeks. Pregnancy outcomes after VRT are given in Table 3.
The outcome of pregnancy after conization is influenced by the depth and size of the cone tissue removed and by the volume of remaining cervical tissue. This statement also holds true for RT. The incidence of premature rupture of membranes and preterm delivery is inversely related to the amount of preserved cervical tissue after RT.
MORE CONSERVATIVE PROCEDURES AND NEOADJUVANT CHEMOTHERAPY
Conization for stage IA1 tumors is a commonly accepted fertility-preserving approach. Rate of complete negativity for residual disease after cone trachelectomy in specimen is reported to be 38% to 67%. Smith et al retrospectively analyzed radical hysterectomy specimens of women with stage IA1-IB1 cervical cancer according to FIGO to identify patients in whom conization and pelvic lymphadenectomy is sufficient. Of these patients, 26% were found to be eligible for fertility-sparing surgery such as cold-knife conization with pelvic lymph node dissection. Fifty-three patients of 202 had favorable pathologic characteristics including low-risk histological diagnosis, tumors 2 cm in size or less, and no LVSI present, and none had parametrial involvement or positive lymph nodes. Lanowska et al analyzed the parametrium of specimens of 112 patients treated with VRT for the presence of lymph nodes. The presence of small lymph nodes in the parametrium of specimens of RT is low (7.1%). In patients with early-stage cervical cancer, the incidence of metastasis was less than 1%.
Preoperative assessment of the volume of the parametrium may indicate which patients need parametrial resection. Seventeen women with stage IA2-IB1 cervical cancer according to FIGO, tumor size less than 20 mm, no evidence of lymph node metastases, and younger than 45 years underwent conization and laparoscopic pelvic lymphadenectomy. There were 4 patients with lymphovascular invasion. No recurrences were observed after a median follow-up of 16 months. Two of 5 patients seeking parenthood conceived spontaneously. In 4 women, secondary radical hysterectomy was performed because of positive lymph nodes and/or they were abstained from chemotherapy. The limitations of the study were its small sample size and short follow-up.
Neoadjuvant chemotherapy (NACT) followed by fertility-sparing surgery has emerged as a possible alternative to conventional treatment in locally advanced cervical cancer.13 Neoadjuvant chemotherapy is evaluated for tumors greater than 2 cm in diameter to allow treatment by RT, simple trachelectomy, or conization NACT can decrease the tumor volume before the surgery, thus enabling the complete removal of the tumor with negative margins, while preserving the adequate amount of cervical tissue, which improves the chance for a successful pregnancy. Gottschalk et al reported a case of full-term delivery after laparoscopic lymphadenectomy and neoadjuvant chemotherapy (paclitaxel 200 mg/m2 and cisplatin 100 mg/m2) followed by VRT in bulky stage IB1 cervical cancer. Although successful pregnancies after neoadjuvant chemotherapy with conization have been reported, gonadotoxic effect of chemotherapy is of concern.
The study conducted by Robova was based on the confirmed benefit of NACT in stage IB2 cervical cancer, before performing radical hysterectomy. It included 5 patients with tumors greater than 2 cm or infiltrating more than a half of the stroma, who received 3 cycles of dose-dense NACT at a 10-day interval (cisplatin plus ifosfamide in squamous cell cancer or cisplatin plus doxorubicin in adenocarcinoma). Lymphovascular space involvement was not considered an exclusion criterion. The NACT was followed by laparoscopic pelvic lymphadenectomy and simple trachelectomy. At the time of publication, 2 of these patients had already delivered full-term babies. By the end of 2010, this series of patients was enlarged to 15 cases. Seven of these women delivered babies, and 1 woman was at her third trimester of pregnancy. Neoadjuvant chemotherapy followed by conservative surgery can be a feasible treatment for women with tumors greater than 2 cm or those with tumors that infiltrated more than half of the stroma.
The oncological safety of neoadjuvant chemotherapy and more conservative surgery must be investigated further.
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