In China, it is estimated that approximately 98.9/1,000 new cases will be diagnosed with cervical cancer in 2015, while approximately 30.5/1,000 women would die from this disease. It ranks as the second most commonly diagnosed cancer among Chinese women [1]. According to the International Federation of Gynecology and Obstetrics (FIGO version 2009), stage IVB cervical cancer patients (disseminated cervical cancer) are classified as diagnosed with distant metastasis as the first manifestation [2]. Patients who develop distant metastases are rarely curable. The 5-year survival of stage IVB patients is poor and approximately 50% of these patients show a fatal outcome within 1 year [345].

No standard treatment is available for patients with stage IVB cervical cancer compared with locally advanced cervical cancer. International guidelines propose cisplatin-based combination chemotherapy for widespread metastatic disease with possible addition of bevacizumab. Chemotherapy is useful for the treatment of recurrent or stage IVB cervical cancer who are not candidates for radiation or extensive surgery [6]. However, either bevacizumab or traditional chemotherapy have shown unsatisfactory effect on eliminating the primary cervical cancer and metastases. Even worse, responses to chemotherapy are often of short duration. In patients with stage IVB cervical cancer, the combined use of radiotherapy and chemotherapy has already been proved to improve survival than previously reported [789]. However, the role of surgery in treating stage IVB patients is still in controversy and has not been fully illustrated. Therefore, in the present study, we tried to analyze the impact of surgery of primary sites on stage IVB cervical cancer patients from a population-based database, the Surveillance, Epidemiology and End Results (SEER). We compared the outcomes of stage IVB cervical cancer patients receiving chemoradiotherapy (CRT) alone and surgery combined with CRT, which may contribute to clinical practice.

Until now, the optimal treatment of stage IVB cervical cancer patients still remains controversial. Lack of case numbers and the diversity of clinical manifestations of stage IVB patients leads to deficiency of related researches. Thanks to SEER database, 1,144 stage IVB cervical cancer patients with treatment information were available for analysis. In this study, we retrospectively evaluated clinical characteristics and survival of stage IVB cervical cancer patients. The increasing AJCC T stage and visceral metastasis was reported as independent risk factors of OS for stage IVB cervical cancer patients receiving CRT. Furthermore, to our knowledge, our study first found that survival advantage significantly favors patients who underwent surgery plus CRT compared with CRT alone, revealing the important role of surgery in stage IVB cervical cancer patients.

Two types of metastasis were defined according to metastasis type of stage IVB cervical cancer patients. If the involved sites are all lymph nodes outside of the pelvis and para-aorta, the type of metastasis is designated as lymphatic metastasis; otherwise, the type of metastasis is designated as hematogenous metastasis. Specifically, patients with hematogenous metastasis had a 5.3-fold higher risk of death than those with lymphatic metastasis [12]. In the present study, we found that stage IVB cervical cancer patients without visceral metastasis shown to have superior survival rates than those without visceral metastasis, which was consistent with previous studies [9121314]. Also, with increasing local tumor stage, we found that death risk increased gradually. Above all, the rationale for deeming all patients with different local tumor stage and different types of metastases as same stage IVB cervical cancer is debatable. Logically, more detailed sub-classification for stage IVB cervical cancer patients deserves further consideration in clinical practice.

According to the latest National Comprehensive Cancer Network guidelines (cervical cancer, version 2.2019), patients with metastatic cervical cancer may benefit from aggressive local therapy for oligometastatic disease include those with nodal, lung, liver or bone metastasis. The satisfied local control can be achieved either by radiotherapy or by surgery [15]. From literature review, the use of radiotherapy and multiagent chemotherapy are amenable to patients with stage IVB cervical cancer and resulted in higher survival rates [78]. Kim et al. [9] uncover the positive role of CRT in 24 stage IVB cervical cancer patients with lymphatic metastasis. Another study, which enrolled patients presenting with para-aortic and left supraclavicular lymph nodal metastases, recommended curative concurrent chemoradiation therapy as a feasible modality with acceptable late toxicity and high response rates [16]. Above all, CRT should be considered in patients who have only lymph node metastasis with good performance status [13]. However, the impact of surgery has not been discussed. Generally, stage IVB is considered inoperable. Despite the use of surgery being contraindicated in metastatic cervical cancer, it may be used highly personalized either for in case of particularly favorable clinical outcome or palliative intent. Promising data from studies disclose new perspectives of surgery in locally advanced cervical cancer (LACC) patients [151718192021]. In our study, compared with CRT group, addition of surgery was inclined to prolong OS in multivariate analysis, which extended from 19 to 32 months, which offers more possibility for the treatment of stage IVB cervical cancer. The potential importance of surgery in this group of patients might be explained as follows. Although CRT can dramatically reduce the tumor burden, it can leave residual resistant cancer stem cells in the primary lesions more or less, which might turn out to be the source of uncontrolled recurrence or metastasis afterwards. Previous studies have reported the rate of residual disease on surgical specimen after CRT ranges from 32% and 59% [222324252627]. Surgery contributes to eliminate the lesion, especially the chemoresistant and radioresistant stem cells, thus stops the source of further progression, which may enhance the cytotoxic effects of chemotherapy [2128]. On the other hand, as a local treatment, surgery can effectively relieve the symptoms of bleeding, pain and excising the involved lesions of surrounding organs. This resulted in a better quality of life. Thus, surgery combined with CRT is not only useful for local control but also reduces the incidence of disease progression, which turns to longer survival.

Although surgery improves local control of neoplasia, sometimes local control of neoplasia may not translate into OS if this set of patients are accompanied with extra residual tumor. In a recent meta-analysis, Shim et al. [29] reported that adjuvant hysterectomy indeed did not improve survival in patients with LACC. Furthermore, in a phase II clinical trial, for LACC patients, radiotherapy-chemotherapy followed by surgery with intraoperative radiation therapy in LACC patients seems to be effective only for patients with pathological complete response to treatment or partial response with residual tumor limited to the cervix. Houvenaeghel et al. [24] reported that adjuvant surgery could improve the outcome of patients with bulky residual tumor (≥2 cm) after CRT for LACC. Therefore, surgery should be contraindicated for some sub-group patients. Patients with visceral metastasis may not benefit from surgery. Perhaps, patients may undergo surgery of metastatic sites simultaneously when diagnosed with oligometastatic disease [30]. Besides, surgery may be done with caution to patients with advanced tumor grade (II–IV), larger tumor size (more than 4 cm) and no regional lymph node metastasis.

In addition, we must acknowledge some limitations in this study. First, due to the retrospective nature of this study, some biases were inevitable in spite of some advanced statistical methods were applied. Future randomized controlled trials are desperately in need. Besides, the study was conducted with a highly selected population. Patients who received either chemotherapy or radiotherapy, accounting for 33% (923/2,733) of the whole stage IVB cervical cancer population, were excluded from the analysis. Patients with stage IVB cervical cancer is a very heterogeneous population regarding the primary tumor well as the location and number of distant metastasis. The disease spread pattern is the major determinant when deciding which treatment be applied primarily. This is a major limitation of our study. We also excluded some surgical procedures which can be regarded diagnostic including LEEP, local tumor excision, and simple hysterectomy. However, it did not assure that the surgery was not diagnostic. This is another factor that could cause selection bias. Second, detailed information regarding the treatment information and surgical morbidity was not available from SEER database. We did not know either the administration method of chemotherapeutic drugs (including dose, cycles, and regimens, etc) and radiation or the sequence of chemotherapy, radiotherapy and surgery. This is another a major limitation of our study which can affect the results. Additional hysterectomy following radiation is a controversial issue even in locally advanced cervical cancer without distant metastasis. A recent randomized clinical trial reported that post-radiation hysterectomy had no therapeutic impact [31]. Future analysis should specify different treatment modalities to elucidate the true significance of surgery in stage IVB cervical cancer patients. Also, the lack of information about any imaging investigation performed before surgery to check the treatment response was another limitation. If imaging had been performed, we could know whether patients with stable or progressive disease were excluded as surgical candidates. Moreover, more detailed surgery information such as residue tumors, surgical complications or the quality of life after surgery should also be weighted in subsequent studies in case of the increased risk of adverse effect in patients. Finally, there are limited data about the outcome of patients treated with curative surgery (including surgery of primary sites and surgery of metastatic sites). For patients with oligo metastasis, it remains elusive whether curative surgery combined with CRT improves OS or not. Nevertheless, this is the first paper discussing the clinical characteristics and the effect of surgery in stage IVB cervical cancer patients, which might provide some guide in our clinical practice.

In conclusion, surgery combined with CRT may be used to achieve longer survival in patients with stage IVB cervical cancer patients. However, it deserves large scale prospective clinical trials to confirm.