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Abstract
Objective Conization/simple trachelectomy is feasible in patients with early-stage cervical cancer. Retrospective data suggest that conization with negative lymph nodes could be a safe option for these patients. This study aims to provide oncologic and obstetric outcomes of a large series of patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IB1 cervical cancer managed by conization.
Methods Patients with early cervical cancer and a desire to preserve fertility who underwent conization and pelvic lymphadenectomy from January 1993 to December 2019 in two Italian centers were included. Inclusion criteria were: age >18 years and ≤45 years, 2018 FIGO stage IB1, no prior irradiation or chemotherapy, absence of pre-operative radiologic evidence of nodal metastases, a strong desire to preserve fertility, and absence of concomitant malignancies. We excluded patients with confirmed infertility, neuroendocrine tumor, clear cell or mucinous carcinoma.
Results A total of 42 patients were included. The median age was 32 years (range 19–44) and median tumor size was 11 mm (range 8–20). Squamous cell carcinoma was found in 27 (64.3%). Grade 3 tumor was present in 7 (16.7%) patients and lymphovascular space involvement was detected in 15 (35.7%). At a median follow-up of 54 months (range 1–185), all patients were alive without evidence of disease. In the entire series three patients experienced recurrence resulting in an overall recurrence rate of 7.1%. All the recurrences occurred in the pelvis (2 in the cervix and 1 in the lymph nodes), resulting in a 3-year disease-free survival of 91.6%. Twenty-two (52%) patients tried to conceive; 18 pregnancies occurred in 17 patients and 12 live births were reported (6 pre-term and 6 term pregnancies). Two miscarriages were recorded, one first trimester and one second trimester fetal loss.
Conclusions Our study showed that conization is feasible for the conservative management of women with stage IB1 cervical cancer desiring fertility. Oncologic outcomes appear favorable in this series of patients. Future prospective studies will hopefully provide further insight into this important question.
- cervical cancer
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HIGHLIGHTS
Conization showed similar survival outcomes with respect to trachelectomy in patients with IB1 cervical cancer.
Conization showed better obstetric outcomes than trachelectomy in patients with IB1 cervical cancer.
Conization could be considered for fertility-sparing treatment in patients with stage IB1 FIGO cervical cancer.
Introduction
Cervical cancer is the fourth most common cancer in women worldwide.1 During the last decade, screening programs have favorably impacted prognosis. However, up to 40% of patients diagnosed with early-stage cervical cancer are of reproductive age.2 As a result, gynecologic oncologists are encouraged to search for increasingly effective fertility-sparing treatments. Currently, international guidelines suggest that radical hysterectomy is the main treatment for patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 IA2–IB2. However, radical trachelectomy may be proposed to select young patients desiring a fertility-sparing option.3 4 Data reported in the literature show that radical trachelectomy has oncologic results similar to those of radical hysterectomy,5 6 but also that surgical radicality could impact obstetric outcomes.7 8
In this context, some have proposed a less invasive surgical approach such as simple trachelectomy or conization with the goal of decreasing post-operative complications and achieving better obstetric outcomes.9–20 Therefore, cervical conization is considered a feasible choice in very low-risk early-stage cervical cancer such as 2018 FIGO stages IA1–IA2,3 but it is under evaluation for 2018 FIGO stage IB1. Our study aims to evaluate long-term obstetric and oncologic outcomes in patients with 2018 FIGO stage IB1 cervical cancer managed by conization and pelvic lymphadenectomy.
Methods
This is a retrospective multi-center study including patients with early-stage cervical cancer with stage IB1 disease according to the 2018 FIGO staging system21 desiring to preserve fertility who underwent conservative management with simple conization and surgical lymph nodal assessment from January 1993 to December 2019. After approval by the Institutional Review Board, data were retrieved from the electronic database of Fondazione Policlinico Universitario A Gemelli-IRCCS and the Gynecologic Oncology Division of San Gerardo Hospital.
Patient demographics, clinical, pathological and follow-up data were retrospectively collected and all patients provided informed consent regarding data collection. Inclusion criteria were: age >18 years and ≤45 years, 2018 FIGO stage IB1, no prior irradiation or chemotherapy, absence of radiologic evidence of lymph nodal metastases at pre-operative staging, a strong desire to preserve fertility, and absence of concomitant malignancies at the time of diagnosis. We excluded all patients with infertility, neuroendocrine, clear cell or mucinous carcinoma. Pre-operative work-up included gynecologic bimanual examination with colposcopy and cervical biopsy, chest X-ray, squamous cell carcinoma antigen serum levels assessment, and trans-vaginal ultrasound pelvic and MRI.
All patients underwent loop electrosurgical excision procedure (LEEP) or cold knife conization and laparoscopic lymph node assessment as primary treatment. If the margins of the cone specimen were positive or the tumor was <3 mm from the surgical excision, a second conization was performed to achieve negative margins. Patients with histologically confirmed lymph node metastasis were managed according to institutional guidelines and were excluded from the statistical analysis. In both institutions, all surgical specimens were evaluated by dedicated pathologists. No cervical cerclage was placed in any patient at the time of conization.
Descriptive statistics were performed to analyze the data. Survival outcomes were evaluated in terms of rate of recurrence, rate of death, disease-free survival, and overall survival. The disease-free survival was defined as the time elapsed between surgery and recurrence or date of the last follow-up. The overall survival was defined as the time elapsed between surgery and death or date of last follow-up. Life tables were computed using the product limit estimates by the Kaplan–Meier method. Obstetric outcomes were evaluated in terms of pregnancy rate, live birth rate, and pre-term delivery rate. The pregnancy rate was defined as the number of patients carrying one or more pregnancies out of the total numbers of patients trying to conceive. The live birth rate was determined as the total number of live births out of the total number of pregnancies. The pre-term delivery rate was calculated as the number of pre-term births (24–36 gestational weeks) compared with the total number of pregnancies.
Statistical Package for Social Sciences software version 25.0 (IBM Corporation, Armonk, New York, USA) was used to perform all statistical calculations.
Results
Forty-two patients were included. The pathological and clinical characteristics are summarized in Table 1. The median age of the patients was 32 years (range 19–44). Twenty-seven (64.3%) patients had a histologic diagnosis of squamous cell carcinoma; lymphovascular space invasion was present in 15 (35.7%) patients. All patients had a pathological tumor size <20 mm with a median value of 11 mm (range 8–20). The conization technique used was LEEP in 18 patients (42.9%) and cold knife in 14 patients (33.3%). In four patients (9.5%) both techniques were used while, in six (14.3%) patients, this information was not available. All patients had a pathological evaluation of lymph node status. Twenty-nine (69.1%) patients underwent pelvic lymphadenectomy, four (9.5%) underwent sentinel lymph node dissection, and nine (21.4%) had both procedures. None of the patients underwent para-aortic lymph node dissection. Adjuvant treatment was not administered to any patient.
Pathological and clinical characteristics of the series
The median follow-up was 54 months (range 1–185). As shown in Figure 1, the 2-year, 3-year, and 5-year disease-free survival was 100%, 91.6%, and 87.3% respectively. No death was recorded, resulting in an overall survival of 100% (Figure 1). Among the entire series, three patients experienced a relapse resulting in a recurrence rate of 7.1%. Two had a squamous cell carcinoma and one had an adenocarcinoma. Times to recurrence were 32 months, 36 months, and 49 months, respectively. Two relapses were on the cervix and one patient had parametrial relapse with ureteral infiltration. After counseling, all three patients decided to undergo hysterectomy. In the patient with parametrial recurrence, given that the ureteral infiltration would have required reconstructive surgery after radiation therapy, it was decided to perform radical surgery associated with ureteral re-implantation as first treatment. After surgery, the surgical resection margins were negative, >1 cm from the tumor border, and it was decided not to administer adjuvant therapy.
Overall survival (OS) and disease-free survival (DFS) of the series.
One patient had recurrence in the cervix and underwent a radical hysterectomy. The second patient had recurrence during pregnancy and received platinum-based chemotherapy up to 35 weeks of gestation and a cesarean section with concomitant radical hysterectomy. Subsequently, adjuvant radiotherapy was administered. The characteristics at the first diagnosis and at the time of recurrence of the three patients are summarized in Table 2. No patient experienced distant recurrence. In addition to the three patients with recurrence, a further four patients underwent hysterectomy during the follow-up period: in one the reason is unknown; one patient had a CIN 2 lesion 3 years after the conization and, after counseling, she chose non-conservative treatment; and two patients underwent hysterectomy during surgery due to a secondary tumor (colon and ovary, respectively).
Clinico-pathological characteristics of patients with recurrence
Obstetric outcomes are reported in Table 3. Ten patients already had a child while two patients had an early abortion and fetal loss in the second trimester. Among the 42 patients included in this study, 22 (52.4%) tried to conceive and 12 achieved a pregnancy, resulting in a pregnancy rate of 54.4%. The median time from the fertility-sparing surgery to pregnancy was 2 years. Two patients had two pregnancies and the total number of pregnancies was 14. The live birth rate was 85.7% (12 live babies) with a pre-term delivery rate of 42.9%: one for oncologic reasons and the other five caused by cervical insufficiency (35.7%). Two miscarriages (14.3%) were recorded, one was a first trimester fetal loss and the other a second trimester loss. Table 4 summarizes the obstetric characteristics of the pregnancies in our series. After pregnancy, only one patient decided to undergo hysterectomy.
Obstetric outcomes
Pregnancies reported in our series
Discussion
Our results show that conization can provide a safe oncologic outcome along with a satisfactory obstetric outcome in the conservative management of women with 2018 FIGO stage IB1 cervical cancer desiring fertility.
Several authors have shown that appropriate selection of patients allows for acceptable oncologic outcomes with the optimum obstetric results. Indeed, the risk of parametrial infiltration in patients with a tumor size <20 mm with no lymph node metastasis and no lymphovascular space invasion is reported to be less than 1%.22–26 For this reason, less radical surgery may be considered to reduce the sequelae of parametrial resection.25 In the literature, only retrospective analyses are published on the role of conization in cervical cancer. Prospective trials are in progress with the aim of demonstrating the efficacy of non-radical surgery in the treatment of low-risk early-stage cervical cancer (ConCerv, NCT01048853 and GOG 278, NCT01649089).
To date, cervical conization with or without lymph node assessment is included in the international guidelines as a valid fertility-sparing treatment for women with 2018 FIGO stage IA1–IA2 tumors. Instead, in 2018 FIGO stage IB1, more radical surgery such as radical trachelectomy with lymphadenectomy is the recommended fertility-sparing approach.3 4 However, a less invasive treatment such as conization should also be considered in patients with 2018 FIGO stage IB1 disease, considering the improved obstetric results of this treatment compared with radical trachelectomy. In our study, conization allowed for a good oncologic and obstetric outcome. The recurrence rate in our series (7.1%) is similar to that in patients reported in the literature with tumors ≤2 cm who underwent radical hysterectomy or radical trachelectomy (range 4.3–8.8%).27–29
Pregnancy rates in our study are similar to those reported in the literature for women who underwent fertility-sparing surgery (54.4% vs 56%, respectively),30 but the live birth rates are significantly higher than those reported for patients who underwent radical trachelectomy (85.7% vs 74%).30 Instead, in our series the pre-term delivery rate was higher than data reported in the literature. The miscarriage rate in our study was 14.7%, which is lower than the previously reported rate of 24.4% in patients who underwent radical trachelectomy.30 On the other hand, our results are similar to the miscarriage rate of 14.8–15.5% reported for cervical conization in two systematic reviews.30 31
To our knowledge, this is the largest series of patients with 2018 FIGO stage IB1 cervical cancer who underwent conization as fertility-sparing treatment reported in the literature. We acknowledge that the retrospective nature of the study and the small number of patients could affect the quality of our results. However, we chose to focus our attention on a specific subset of cases with FIGO stage IB1 disease since we believe that, to date, these patients represent a group that requires a better definition of fertility-sparing strategies.
Conclusion
As we await the results of ongoing prospective trials, conization seems to have improved obstetric outcomes compared with radical trachelectomy, with similar rates of recurrence and mortality. Therefore, this procedure could be considered a feasible option for the treatment of women with FIGO stage IB1 cervical cancer who desire to preserve fertility.
References
Footnotes
FF and LPA are joint first authors.
Twitter @frafanfani, @luigianchora, @annafagottimd
FF and LPA contributed equally.
Contributors All the authors participated in the trial design and manuscript preparation/revision.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Data availability statement Data are available upon reasonable request to star.center@policlinicogemelli.it.