Cervical cancer is one of the most widespread cancer and the fourth cancer cause leading to death in women on a global scale. We searched the SEER database and found a total of 95,218 cervical cancer cases before 2016, including 26,693 NSCC cases that were about 28 percent of the total. However, due to incomplete data, not all NSCC cases could be included in the study. There is evidence that nonsurgical treatment can be used at all stages of cervical cancer. Although surgical treatment is the primary choice of treatment in the early stage, there are still some patients who do not choose surgical treatment due to intolerance to surgery, contraindications to anesthesia or strong personal aspiration under the premise of not preserving fertility. Furthermore, most treatment guidelines also offer solutions with some differences. FIGO guidelines recommend that IA1-IB2 and IIA1 cases could be treated with radiotherapy, and IB3 and IIA2 cases should be CCRT. Nevertheless, National Comprehensive Cancer Network (NCCN) Guidelines advocate that pelvic external irradiation + cisplatin concurrent chemotherapy + brachytherapy are treated in the range from IB1 to IIB stage, and pelvic external irradiation and brachytherapy are applied for patients with IA stage cervical cancers. We can find similar views in some countries' guidelines[23–25]. Not to mention that in advanced cervical cancer, radiation and chemotherapy are the primary treatment. A meta-analysis suggested that surgical treatment had no effect on OS after radiotherapy or CCRT. So we could know that the amount of patients with NSCC is large, and our research is significative to assess prognosis and take further treatment measures.
In the present study, we assessed the prognostic factors that affected survival outcomes of NSCC patients in the SEER database (Tables 1 and 2). We created the nomogram to get the overall score to predict OS for NSCC patients (Fig. 1). We can conclude that ADC causes a worse prognosis than SCC, and it has been reported that the treatment response of ADC is less than optimal compared to SCC, especially radiation[27, 28]. And other types, including neuroendocrine carcinoma, have the worst prognosis. There was no statistically significant difference in well and moderately differentiated survival outcomes, nor between poorly differentiated and undifferentiated(Fig. 6c). The multivariate analysis in our training cohort, the impact of tumor diameter < 2 cm and 2-4cm subgroups on survival have no significant difference, which may suggests that it is unnecessary to increase this group among NSCC. However, we still chose 2 cm as a critical point to create the nomogram following the new FIGO staging system. Among all variables, extension, lymph node involvement, and metastasis displayed the high discriminating power, followed by chemotherapy and radiotherapy. The lymph node information in the cohort we studied was derived from biopsy or aspiration, but we could exert more clinically feasible methods to predict lymph node metastasis. Research shows that magnetic resonance imaging variables and 18F-fluorodeoxyglucose positron emission tomography  can improve the accuracy of predicting lymph node metastasis. Remarkably, degree of invasion and treatment measures had the compelling prognostic value for OS, which coincided with previous reports .
C-indexes of nomogramin training cohort and validation cohort can confirm the predictive accuracy and appreciable reliability of the model, which were higher than that of FIGO staging. The area under ROC curve (Fig. 2) showed the superiority of nomogram to other clinicopathological features ,including FIGO staging. The calibration curves (Fig. 3) models demonstrate the predictive performance of the nomogram. The DCA proves that nomogram has higher net benefit than FIGO staging(Fig. 4). We speculated that the fact that lymph node metastasis increases staging caused an uneven DCA curve for FIGO staging. Although such staging seems to improve net benefit, its rationality is questionable. In summary, our nomogram is a more accurate prognostic model than FIGO staging. Moreover, we can stratify patients according to their scores, and further treatment should be actively pursued if the case is in a high-risk group.
Our nomogram considered the effect of treatment on prognosis. The results suggested that lymphadenectomy had a positive effect on prognosis. Resection of the sentinel node during biopsy was also included. Previous studies have shown that resection of pelvic or para-aortic lymph nodes can be beneficial for locally advanced cervical cancer[11, 12]. It seems that lymphadenectomy plus radiotherapy may be a feasible option. In past studies, the position of radiation in treatment of cervical cancer has been clearly established, and even before 1999, CCRT was not a standardized treatment for advanced cases. Consider that most people received radiation and chemotherapy (regardless of order and regimen) and not just one of them, we divided them into four subgroups according to treatment: no treatment, radiotherapy, chemotherapy, radiotherapy and chemotherapy(R&C). This Kaplan-Meier survival analysis (Fig. 6i) showed that the prognosis of the R&C group was significantly better than that of the other subgroups(p < 0.01).The prognosis of radiotherapy alone was the second best, while chemotherapy alone and untreated group has no significant difference in the outcomes(p > 0.05). This result suggests that radiotherapy plus chemotherapy is the most beneficial for survival in most NSCC, followed by radiotherapy alone. And chemotherapy alone does not seem to be a worthwhile option. Changing the chemotherapy regimens and improving radiotherapy scheme provide another solution for the high-risk group . Choosing Cisplatin plus 5-Fluorouracil regimen is controversial when External Beam Radiotherapy is combined with platinum-containing chemotherapy, as many studies have shown that its survival outcomes are not significantly different from that of the cisplatin regimen, but acute hematological toxicity and drug resistance are increased. Considering the side effects and quality of life, too aggressive treatment regimens were also discouraged.
In recent years, we can encourage them to actively access potential treatment opportunities, such as participating in clinical trials of cutting-edge drugs . In the GOG240 trial, compared with the chemotherapy group alone, chemotherapy combined with bevacizumab group continued to show significant improvement in OS in persistent, recurrent, or metastatic patients. Two studies illustrated pembrolizumab had established clinical benefits in cervical cancer[38, 39]. More checkpoint inhibitor therapies deserve to be expected. Take a step back we could consider the surgical therapy. Suitable surgery can also be completed after removing contraindications in early-stage, and a pelvic exenteration is an option for advanced patients. As we know from the NCCN guidelines, complementary hysterectomy after concurrent chemoradiotherapy remains controversial for stage IB3 or IIA2 tumors. This approach does not improve OS and increases complications,so at that time the decision to finish surgery should be made more carefully.
The model has practicability and operability for clinical work, which can analyze the prognosis of patients, and provides a visual tool for negotiating treatment plans with patients. What we cannot deny is that this study has certain limitations. Firstly, selection bias may exist as a large number of cases were excluded because of incomplete information. The second limitation stemmed from the deficiency of information about infection status of HPV, values of tumor markers, details of radiotherapy and chemotherapy, and emerging therapeutic applications. Third, this nomogram requires further validation in a prospective cohort because the database is a retrospective collection. Additionally, the SEER database included the United States population, an validation in different countries remained necessary.
In this study, independent prognostic factors for OS in NSCC patients were identified, including age, histological type, grade, tumor size, extension, lymph node involvement, distant metastasis, lymph node removed, chemotherapy and radiotherapy, which participated in the construction of the nomogram prognostic assessment model for NSCC patients. After a series of tests, the nomogram was more accurate and reliable than FIGO staging in predicting 3 - and 5-year OS for NSCC women. The model has great clinical application value. Aggressive treatment is recommended for high-risk patients.