Impact of therapeutic strategy on disease‐free and overall survival of early‐stage cervical cancer: Surgery alone versus preoperative radiation

Abstract Background and Objectives There is no international consensus for management of early‐stage cervical cancer (ESCC). This study aimed to retrospectively investigate disease‐free survival (DFS) and overall survival (OS) in patients with ESCC according to the therapeutic strategy used, surgery alone versus preoperative radiation following by surgery. Methods Data were retrospectively collected from 1998 to 2015 using the Gynecological Cancer Registry of the Côte d'Or. The inclusion criteria were FIGO 2018 ≤ IB2; squamous cell carcinoma, adenocarcinoma or adenosquamous type. Survival curves were compared using the log‐rank test. Results One hundred twenty‐six patients were included. Median survival was 90 months. There was no significant difference in DFS (HR = 0.91, 95%CI [0.32–2.53], p = 0.858) or in OS between surgery alone versus preoperative radiation following by surgery (HR = 0.97, 95%CI [0.31–2.99], p = 0.961). In the subgroup of patients with stage ≥IB1, there was no significant difference in DFS (HR = 3.26, p = 0.2) or in OS (HR = 3.87, p = 0.2). Conclusion Our study did not identify any difference in survival according to the treatment strategy. Preoperative radiation following by surgery can be an alternative to surgery alone for ESCC.

can be performed in women desiring fertility preservation. 4 In case of positive margins, a repeat conization should be performed. In case of positive margins or LVSI on the surgical specimen, radical hysterectomy should be performed.
Lymph node staging is not indicated in T1a1 LVSI-negative patients but can be considered in T1a1 LVSI-positive patients, by sentinel lymph node (SLN) biopsy. The SENTICOL-3 study investigated 3-year disease-free survival (DFS) and health-related quality of life (HRQoL) after SLN mapping or SLN plus pelvic lymph node dissection (LND) in patients with early-stage cervical cancer. 5 For stage IA2, in the absence of LVSI on the conization specimen, hysterectomy of type A according to the Querleu-Morrow classification or type I of the Piver and Rutledge classification may be performed. 6,7 Conversely, in case of LVSI, Querleu-Morrow type B or Piver and Rutledge type II hysterectomy should be performed. 6,7 In women desiring fertility preservation, two therapeutic options are possible: (i) conization with LND; or (ii) trachelectomy using an abdominal, vaginal or minimallyinvasive approach, associated with LND. Parametrial resection is not recommended. As for stage IA1, SLN alone cannot be recommended outside prospective clinical trials. 5  Trachelectomy is an option in patients desiring fertility preservation.
Radiotherapy associated with brachytherapy alone can be considered in case of unfavorable prognosis or anticipated high surgical morbidity.
For intermediate and high-risk patients, preoperative brachytherapy followed by type A surgery is an acceptable option. For FIGO stage IB2, the FIGO recommendations propose primary surgery or primary radiation therapy, depending on the patient's comorbidities and local availability and expertise in the different treatment options.
Surgery plays a central role in the management of early-stage cervical cancer. Retrospective data regarding preoperative brachytherapy in early-stage cervical cancer suggest that it is effective and well tolerated. [8][9][10] In recent years, therapeutic strategies for early-stage cervical cancer have evolved. For tumors measuring less than 2 cm, fertility preservation and de-escalation of therapy are now major issues at stake in the therapeutic management of young patients. At present, there is no international consensus regarding the gold standard for management of early-stage cervical cancer. To be eligible, patients had to meet the following inclusion criteria: be ≥18 years old; have a first diagnosis of histologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of stage IB2 or lower according to FIGO 2018; had data regarding the treatment received, including primary surgery or preoperative radiation therapy. Patients meeting any one or more of the following criteria were excluded: history of pelvic radiation, concomitant radiochemotherapy, pathological nodes in histology, adjuvant radiotherapy, total radiation dose <50 Gy, >66 Gy or not documented.
The surgery group comprised patients who underwent surgery (hysterectomy, trachelectomy or conization) as the only form of treatment for early-stage cervical cancer. The radiation therapy group comprised patients who had radiation therapy (brachytherapy and/or radiotherapy) followed by surgery (hysterectomy, trachelectomy or conization).

| Statistical analysis
Categorical variables are presented as number and percentage, and quantitative variables as mean and standard deviation or median and interquartile range. Variables were compared using the Chi 2 or Fisher's exact test for qualitative variables and the student's t-test for quantitative variables.
The Kaplan-Meier method was used to describe disease-free survival (DFS) and overall survival (OS). Survival was determined for the entire population and subgroup analysis was performed for ≥ IB1 population and in patients who had hysterectomy. Survival curves were compared using the log rank test. Adjusted survival curves were estimated using the direct adjusted survival method via a Cox model adjusted for FIGO stage and pelvic lymphadenectomy. Test results were considered significant when the p-value was <.05. Recurrence was defined as any lesion identified on biopsy and histologically diagnosed as recurrent invasive cervical cancer. DFS was defined as the time (in months) from the date of the initial histological diagnosis to the date of the first histological diagnosis of recurrence or death. Patients who did not have recurrence or death were censored at the date of last follow-up. OS was defined as the time (in months) from the date of the initial histological diagnosis to the date of death (all causes). Patients who were still alive at the cut-off date were censored.
Survival data were available for all patients in 2018, allowing for at least 3 years of follow-up for all patients. Survival curves were compared using the log rank test. All statistical analyses were performed using RStudio Team (2020) software. RStudio: Integrated Development for R (RStudio, PBC, Boston, MA) http://www.rstudio.com/ and SAS version 9.4 (SAS institute Inc., Cary, NC, USA).

| Patients features
Among 490 patients with early-stage cervical cancer, 302 were excluded because the FIGO stage was greater than IB2, 6 were excluded because they had pTNM stage III, 8 were excluded due to missing data about the treatments received, 6 because they did not undergo surgery, 27 because they received adjuvant pelvic radiation after primary surgery, 3 because they received concomitant radiochemotherapy, and 12 because the radiation dose received was either <50 Gy, >66 Gy or not documented ( Figure 1).
Finally, 126 patients were included in the present analysis: 80 patients in the surgery group, and 46 in the radiation group. Average age at diagnosis was 46.9 years; 65 patients had stage IA tumors, and 61 had stage ≥IB1. The predominant histological type was squamous cell carcinoma (84.1%). Prior conization was performed in 60.3%. Hysterectomy was performed in 84.1% of patients (36.8% by laparotomy, 28.3% minimally invasive surgery (coelioscopy or robotassisted) and 19.8% by the vaginal approach). Half the patients (50.8%) underwent pelvic LND, while 4.8% had SLN plus LND. Finally, 11 recurrences were observed, most of which were local pelvic recurrence (72%) ( Table 1).
The majority (76%) of patients in the radiation therapy group receive neoadjuvant brachytherapy alone, 21.8% received brachytherapy plus radiotherapy, while only one patient received radiotherapy alone. The mean total dose of radiation received (by brachytherapy or radiotherapy) was 59.1 Gy.
T A B L E 1 Characteristics of the study population (N = 126).   To limit bias between groups, patients who received adjuvant radiotherapy were excluded from the analysis. Regarding preoperative radiation, to limit the bias related to the radiation dose received, we excluded patients who received less than 50Gy because they were potentially undertreated, and we also excluded patients who received more than 66Gy because they did not have adjuvant surgery because of the radiation dose and the risks of significant morbidity.

| DISCUSSION
Although both therapeutic strategies seemed to be equivalent in terms of survival, there were differences in terms of morbidity and  15,16 When surgery is the chosen treatment option, radical colpohysterectomy with pelvic LND is the reference in early-stage cervical cancer. In our study, most patients underwent radical hysterectomy F I G U R E 3 DFS and OS for stage ≥ IB1 (Surgery vs. preoperative radiation).
(54.1%) and pelvic lymphadenectomy was recommended for stages ≥IA2. Due to comorbidities and operative difficulties, some patients did not benefit from pelvic lymphadenectomy (2 patients in the radiation group). Because of the inclusion period, the SLNs performed were in study protocol (SENTICOL).
The main complication of this surgery is lesions of the urinary and digestive tracts, with bladder dysfunction, and impaired sexual and digestive function related to lesions of the autonomic nervous system. 17 With a view to de-escalating therapy and preserving fertility, several surgical techniques appear comparable, in terms of DFS and OS, with considerable reductions in short-and long-term complications. 18 Radical trachelectomy is the therapeutic option retained in patients desiring fertility preservation. A systematic review of the literature by Nezhat et al. 18  (28% vs. 13%), but did not affect 5-year OS (81% vs. 77%) or DFS (75% and 73%). 6,20 Several risk models have been studied to identify subgroups of patients who might be eligible for less radical therapy. 19,21 Currently, the ongoing randomized, phase III SHAPE study is prospectively comparing the efficacy and safety of radical hysterectomy with pelvic LND versus simple hysterectomy and pelvic node dissection in patients with low-risk early-stage cervical cancer. 22 In this context, conization with SLN biopsy appears to be an attractive therapeutic option in patients with IB1 lesions desiring fertility preservation. 23  biopsy is safe and has been shown to yield a low rate of falsenegatives (3.6%). 28 It also significantly reduces the complications of surgery, notably lymphoedema of the lower limbs (87% vs. 42%, p = .03). 29 In a study of data from the SENTICOL study, 60.5% of detected SLNs were in the external iliac and interiliac basin, while a substantial proportion were in unusual locations, namely 19.6% in the common iliac, 11.8% in the para-aortic, and 6% in the parametrium. 30 Ultrastaging of SLNs makes it possible to identify micrometastases and isolated tumor cells, although the impact of these findings remains to be demonstrated. 31,32 Surgery and radiotherapy are the mainstay of treatment for earlystage cervical cancer. However, in years to come, new treatment options will be developed. Neoadjuvant chemotherapy makes it possible to reduce the tumor size, and in this context, may be a viable treatment option for women desiring fertility preservation, by enabling conservative surgery. 33 Response to neoadjuvant chemotherapy has been shown to be an independent prognostic factor for survival. 34 The CONTESSA/NEOCON-F study is an ongoing prospective, multicenter, phase II trial evaluating the safety of neoadjuvant chemotherapy followed by fertility-sparing surgery in young women with stage IB2 lesions. 33 This ongoing study should help to achieve standardization of management for young patients desiring fertility preservation. While chemotherapy appears to enable de-escalation of surgical therapy, vaccination is also among the new options currently being investigated for the treatment of cervical cancer, notably in the VOLATIL study. 35 This ongoing phase II study will evaluate the clinical impact and immunological efficacy of combining a CD4-help T-inducer vaccine (universal cancer peptide vaccine, UCPVax) associated with atezolizumab for the treatment of locally advanced or metastatic HPV-positive cancers (HPV16+). Limitations of this study include its retrospective nature, its small size, and the absence of some data on factors that influenced the choice of treatment strategy.
The results of this pilot observation should be treated with caution.

| CONCLUSIONS
The optimal management of early-stage cervical cancer is not currently standardized. Our study, comparing surgery alone versus preoperative radiation therapy, did not identify any difference in DFS (p = .858) or OS (p = .961) according to the treatment strategy. In the subgroup of patients with ≥IB1 disease, we also failed to show any significant difference in DFS (p = .2) or OS ( p = .2). Cervical cancer counts among the only solid tumors for which increasing mortality has been observed in recent years. 36