FIGO IVB cervical cancer patients benefit from locoregional surgery: a retrospective study from the SEER database


 Background: We aimed to analyze the clinical value of primary site surgery in improving survival of initial metastatic cervical cancer. Methods: A population-based retrospective study which analyzed clinical data extracted from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database was conducted. Stratified analysis was employed to evaluate the effect of cervical surgery on cervical cancer specific survival (CCSS) and overall survival (OS). Then COX regression models were performed to adjust potential confounders, and assess the survival benefit of cervical surgery for patients with primary metastatic cervical cancer. Results: The median CCSS and OS in the surgery group were more than twice of that in the group without surgery. Primary site surgery conferred prognosis superiority for patients with metastases merely to lung, and other site or distant LN, but not multiple metastasis and bone, liver. Pelvic lymph node dissection conducted in combination with cervical surgery provided a survival advantage over hysterectomy. Moreover, an aggressive treatment that integrated locoregional surgery with radiotherapy or chemotherapy showed the better survival when compared to surgery alone. The survival advantage provided by primary site surgery was not influenced by the histological type, lymph node status. Finally, after adjusting confounders using COX regression, local cervical surgery reduced the cancer related and overall mortality rate by about 30%. Conclusions: Surgical procedures could promote the survival of patients with primary metastatic cervical cancer, and should be considered as a therapeutic option for carefully chosen patients.


Background
Cervical cancer remains to be one of the most common tumors affecting women worldwide, ranking third for cancer incidence and fourth for mortality (1). Among patients with newly diagnosed cervical cancer, roughly 10% have distant metastasis at their initial diagnosis (2), and have a dismal prognosis, with poor median survival time usually less than 1 to 2 years (3,4).
For International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer, platinum-based chemotherapy, angiogenesis inhibitor bevacizumab and immunotherapy are the choice of treatment, and continuous to be considered palliative. Moreover, the studies of locoregional radiation therapy combined with system therapy for primary metastatic cervical cancer are emerging, and showed that locoregional radiotherapy would confer a substantial longer survival than system therapy alone (5)(6)(7)(8)(9)(10). Nevertheless, the role of local surgery for these cervical cancer patients is still not established. In tradition, since FIGO IVB cervical cancer is considered incurable, surgical treatment is only recommend as a palliative treatment to relieve symptom such as pain, bleeding, and obstruction. Additionally, it has been reported that primary tumor mass inhibit remote metastasis by a circulating angiongenesis inhibitor, and once tumor removal, metastasis neovascularize and grow (11), but this viewpoint has not supported by clinical evidence. Growing studies have demonstrated prolonged survival of metastatic diseases when aggressive local surgeries were carried out (12-16). Sriram Venigalla and his colleagues proved that cervical cancer patients with disseminated disease would benefit from locally definitive treatment (concurrent chemotherapy or definitive surgery), and median OS time elevated 9.1 months. However, only 14% patients of definitive treatment group undergo definitive surgery, and the relative role of surgery on survival was not investigated (7).
To further examine the benefits of primary tumor resection for cervical cancer patients, we analyzed a large data from the National Cancer Institute's Surveillance, Epidemiology, and End Result (SEER) program database to conduct this populationbased epidemiologic study. Sites of metastasis, histological type, surgical pattern, chemotherapy, radiotherapy, T stage and lymph node status were stratified in the analysis of OS and cervical cancer specific survival (CCSS). We hypothesized that FIGO IVB cervical cancer patients would benefit from locoregional surgery.

Data Acquisition and Processing
We identified cervical cancer cases from the SEER database using the official software SEERStat 8.3.6 on September 20, 2019. The demographic, clinicopathological and follow-up data of 23873 women with cervical cancer diagnosed from 2010 to 2016 was obtained. After screening the data based on the 7th AJCC staging system, 1483 IVB patients with at least one distant metastasis and definite information on surgery of primary site were included in this study.
Patients were classified based on whether they underwent locoregional surgery to remove the primary cervical tumor after the initial diagnosis. Age at diagnosis was categorized into three groups, younger than 40, 41 to 60, 61 to 80, 81 and older.
Based on race, patients were categorized as White, Black, and others. Histological type included squamous cell carcinoma (SCC), adenocarcinoma (ADC), and others.
Based on 7th AJCC staging system, patients with N0 were allocated as lymph node negative, N1 were positive. According to surgery pattern, patients were assigned into the "Hysterectomy" and "Radical Hysterectomy" groups. Data on chemotherapy, radiation, distant surgery were extracted, but the exact regimens, cycles, dose, and site were not in the SEER database.

Statistical analysis
Chi-square tests or Wilcoxon signed-ranks test were used to compare the distribution difference of locoregional surgery and demographic characteristics. For CCSS, only death due to cervical cancer was considered as an event occurrence, while for OS, it was death due to any cause. Survival time was calculated using Kaplan-Meier methods, and compared by log-rank test. Univariate and multivariate Cox proportional hazards model was performed to evaluate the effects of demographic factors on CCSS and OS using the hazard ratio (HR) and 95% confidence intervals (95% CI). Variables that showed statistical significance in the univariate analysis or were considered as important for survival were then enrolled in multivariate analysis using a stepwise conditional method. Data analysis was performed using the software SPSS 22.0 and a 2-sided p value of less than 0.05 was considered to be statistically significant.

Analysis of CCSS and OS
To analyze the effects of local surgery on CCSS and OS in patients with metastatic cervical cancer, log-rank test were performed between surgery and nonsurgery groups. As illustrated in Fig. 1, locoregional surgical treatment conferred a prominent survival advantage. The median CCSS and OS were 37 and 28 months for the surgery group, 13 and 11 months for the non-surgery group ( Fig. 1A and Additional file 1).
In order to eliminate the bias of site-specific metastasis on survival analysis, data were stratified based on the distant organs involved (multiple site, bone, liver, brain and lung, other site or distant LN), and CCSS was evaluated based on whether or not surgery of the primary tumor was performed in mentioned-above patient groups. Owing to the limited number of patients with isolated brain metastasis, they were excluded from this evaluation. Patients with isolated lung and other site or distant LN involved benefitted from primary site surgery (p = 0.03 for lung only; p < 0.0001 for other site or distant LN) (Fig. 1E, F). Nevertheless, the locoregional treatment could not prolong the survival of patients with bone, liver and multiple sites metastasis. Furthermore, the aggregate effects of surgical resection of primary and metastatic lesions on survival were also evaluated. It showed that survival was better for patients who underwent resection for distant organs, and significantly better for patients whose primary cervical tumors were resected ( Fig. 2A).
Local surgeries were categorized into the "Hysterectomy" group (without regional lymph node dissection) and "Radical hysterectomy" group (with regional lymph node dissection). In all cases, pelvic lymph node dissection provided additional survival advantage to the cervical cancer patients (Fig. 2B).
The effects of chemotherapy and/or radiotherapy together with local surgery on survival in patients with metastatic cervical cancer were next analyzed ( Fig. 2C-F). Prognosis was better for patients who underwent locoregional resection combined with chemotherapy or radiation compared with those received surgery/chemotherapy/radiation alone. Chemotherapy conferred similar OS and CSSS to locoregional surgery, while radiation provided worse survival compared to surgical treatment.
Data stratified on the basis of histology, and lymph node status showed that they did not affect the survival advantage provided by locoregional surgery. More advanced AJCC T stage, less advantage gained from primary site surgery.
Eventually, survival benefit disappeared for T4 tumor.

Univariate and multivariate analysis
Univariate and multivariate analysis were then performed to evaluate the effects of the clinicopathological factors on CSSS and OS ( Table 2). As illustrated in Table 2, patients with age between 41 and 80 were at a lower risk of cancer-related death compared to those younger than 40. Compared to white race, black women were at a higher risk of mortality. Tumors with higher AJCC T stage had a poor prognosis. When the lymph node was affected, CCSS was worse than in cases with negative nodes. For treatment, regional LN surgery, chemotherapy and radiation prolonged cancer-related and overall survival for cervical cancer with primary metastasis, while surgery of distant metastasis did not show any significance in CSSS and OS. Except for only brain metastasis, women with isolated organ metastases had better OS and CSSS compared to those with multiple distant organ involved.
Local cervix surgery reduced the cancer-associated and overall mortality rate by about 33% and 31%, which demonstrated that regional resection of primary tumor is an independent prognosis factor and is of vital significance in prolonging the survival of cervical cancer patients with primary metastasis.

Discussion
Usually, the treatment for FIGO IVB cervical cancer has been and continues to be Cancer Database, revealed that patients who underwent definitive local therapy (either concurrent chemoradiation or surgery) had a 43% reduced mortality risk compared to those who received conservative therapy (systemic therapy with or without palliative radiation)(7). Similar conclusion was drawn by a Chinese study, which illustrated that chemotherapy combined with definitive pelvic radiotherapy would significantly prolong the OS by 7.3 months when compared to chemotherapy alone or with palliative pelvic radiotherapy (5). Another two studies which enrolled patients from SEER or National Cancer Database, also demonstrated that radiotherapy would decrease 28-31% mortality risk for primary metastatic cervical cancer (6,8).  25). Unfortunately, we could not obtain data on surgical margin status from the SEER database. We found that the advantage of surgery did not showed in patients with T4 stage (invasion into neighboring structures such as bladder and rectum), and there were prominent survival differences between women who had hysterectomy and those had a radical hysterectomy. It's well known that a clear surgical margin is difficult to achieve in patients with tumors progression to neighboring organs. Pelvic lymph node dissection would also contribute to lower the tumor burden, and stop cancer cell spreading to distant organs through lymphatic pathway. Consequently, we preferentially hold the opinion that definitive surgery to remove primary tumor clearly vitally improves the therapeutic efficacy by lowering the tumor burden.
As for treatment, radiotherapy and chemotherapy were also independent prognostic factors for FIGO IVB cervical cancer. Moreover, an aggressive treatment approach that combines chemotherapy or radiation with surgical management of primary tumors may lead to improved survival compared with abovementioned treatments alone, and the survival advantage of combined treatment over palliative treatment is even greater than that of single treatment add together. Therefore, local surgical combined with systemic therapy is recommended for primary metastatic cervical cancer with good performance. Regrettably, SEER database does not include information on chemotherapy regimen and cycles or radiation field size and dose, which would have allowed us to analyze survival based on chemotherapy modalities as well as the extent of radiotherapy administered.
There were several inevitable limitations in the present study. First, there is an inherent patient selection bias as it is a population-based retrospective study.
Second, details of the systemic therapy, radiotherapy, performance status, and surgical margin were lacking, which could also affect prognosis. Third, the detail on how metastasis diagnosed was unavailable, which may affect the result to some extent. Consequently, these results should be prudently interpreted with these limitations in mind.

Declarations
Ethics approval and consent to participate The SEER database was publicly available and all the research data were deindentified. So no ethic approval and informed consents were needed in this study.

Consent for publication
Not applicable.

Availability of data and materials
The data were retrieved from publicly accessible database "Surveillance, Epidemiology, and End Results" (SEER), the website is "https://seer.cancer.gov/". The definite data used in this study is available from the corresponding author on reasonable request.

Competing interests
All authors declare that they have no conflict of interest.   CCSS curves stratified by histological type, lymph node status and T stage.'

Supplementary Files
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