Preoperative albumin-to-fibrinogen ratio predicts chemotherapy resistance and prognosis in patients with advanced epithelial ovarian cancer

This retrospective study was approved by the Medical Institutional Ethics Committee of Hwa Mei Hospital and Zhejiang province. Eligible subjects with newly diagnosed EOC admitted at the Department of Gynecology, Hwa Mei Hospital, University Of Chinese Academy Of Sciences from 2010 to 2017 were enrolled into this study population. The inclusion criteria were as follows: (a) newly histologically diagnosed advanced EOC patients with the International Federation of Gynecology and Obstetrics (FIGO) stage III or IV; (b) available preoperative serum expressions of Alb and Fig; (c) patients who underwent neoadjuvant chemotherapy (NAC) followed by debulking surgery; (c) patients with adequate clinicopathological data and (d) patients with a follow up for at least 12 months. The exclusion criteria were as follows: (a) patients who had clinical evidence of infection or inflammatory conditions; (b) patients who were with other malignancies; (c) patients who were with autoimmune or hematological diseases, abnormal liver or renal function and (d) patients who were lost to follow-up or without complete data. Informed consent was obtained from all the enrolled patients who underwent cytoreduction and chemotherapy.

A same experienced pathologist who was blinded to this study was invited to review all the surgical specimens and make the pathological evaluation. All the included patients underwent three courses of adjuvant first-line platinum-based chemotherapy before the primary cytoreduction surgery. Each enrolled patient was required to perform the examinations of whole body computed tomography (CT) or positron emission tomography/computed tomography (PET/CT). The tumor stage was determined for all patients following the guidance FIGO system. Demographics, clinicpathological parameters and preoperative laboratory tests were collected from medical records. Preoperative fasting peripheral blood samples were obtained on 1 day prior to operation and were then processed within 48 h for laboratory variable detections. The blood cells, C-reactive protein (CRP), Alb, Fib and CA125 were detected using the obtained blood samples. The AFR was calculated by Alb (g/L)/Fib (g/L) ratio.

At each visit during follow up, clinical, imaging examinations and the serum CA-125 expression were assessed for treatment evaluation. The primary end point of this study was PFS, overall survival (OS), or the last follow up (December, 2017). The chemotherapy responses was assessed following the guidance of the Response Evaluation Criteria in Solid Tumors (RECIST) [16]. Chemotherapy sensitivity was defined as complete response (CR) or partial response (PR), whereas chemotherapy resistance was defined as stable disease (SD) or progressive disease (PD). PFS was defined as the duration from the date of initial surgery to the evidence of tumor progression, death or follow up deadline. OS was defined as the duration from the date of initial surgery to death or the last follow-up.

Statistical analyses were performed with the software of GraphPad prism (version. 5.0, GraphPad Inc., San Diego, CA, USA) and SPSS (version 19.0, SPSS Inc., Chicago, IL, USA). Data are presented with number with proportion, or mean ± standard deviation (SD). The predictive value of AFR for the OS as well as the cut-off value was evaluated by receiver operating characteristic (ROC) curve analysis and the Youden index. The comparisons between categorical variables were performed with the Chi-square test, while continuous variables with Student t test or Mann–Whitney U test as appropriate. The univariate and multivariate analyses were performed to evaluate the prognostic factors using the Cox proportional hazard model and only those factors with a p value < 0.1 in the univariate mode were further analyzed in the multivariate mode. OS and PFS were calculated using Kaplan–Meier method and the log-rank test. A two-sided P < 0.05 was accepted as statistically different.

A total of 375 subjects were primarily enrolled according to the inclusion criteria and 62 were excluded due to the exclusion criteria (10 had infection or inflammatory conditions, 12 were with other malignancies, 13 were with autoimmune or hematological diseases, 20 were with abnormal liver or renal function and 27 were lost to follow-up or without complete data). Finally, 313 advanced EOC patients with a mean age of 64.4 years were included the analysis. As shown in Fig. 1a, the ROC curve analysis showed that the cutoff value of AFR in predicting OS was determined to be 7.78 with an area under the curve (AUC) of 0.773, 95% CI of 0.710–0.835, a sensitivity of 64.32% and a specificity of 77.78%, respectively (P < 0.001). According to the baseline cutoff value, all the 313 were categorized into two groups, 151 (48.2%) in the low-AFR group (AFR ≤ 7.78) and 162 (51.8%) in the high-AFR group (AFR > 3.45). The baseline demographic and clinicopathological characteristics associated with AFR are detailed exhibited in Table 1. In comparison with the low-AFR group, patients in the high-AFR group showed a lower age (P = 0.004), ECOG PS (P = 0.016), histological grade (P = 0.042) and FIGO stage (P = 0.032). High AFR expression was significantly associated with an increased incidence of first-line platinum-based chemotherapy resistance (P = 0.033). Patients with preoperative AFR ≤7.78 had a higher prevalence of postoperative residual tumor larger than 1 cm (P = 0.005). However, no statistically differences were noted between the high-AFR and low-AFR groups in respect to BMI, smoking and alcohol habits, preoperative comorbidities and histological type (P > 0.05). Other laboratory tests including blood cells analyses, CRP and CA125 were also analyzed. As shown in Table 2, the results indicated that high AFR expression was significantly associated with lower expressions of CRP (P = 0.033) and CA125 (P = 0.002). No significant differences were observed in blood cell analyses between low-AFR and high-AFR groups (P > 0.05).

As shown in Table 3, potential risk factors for PFS in advanced EOC patients were assessed by univariate and multivariate Cox proportional regression analyses. Potential risk factors with a P value < 0.1 by the univariate Cox analysis including Age, histological grade, FIGO stage, chemotherapy resistance, residual tumor, CA125 and AFR were enrolled into the multivariate Cox analysis. The results indicated that chemotherapy resistance (HR: 1.84, 95 CI%: 1.12–2.88, P = 0.032), CA125 (HR: 1.42, 95 CI%: 1.02–2.05, P = 0.042) and AFR (HR: 1.38, 95 CI%: 1.04–1.82, P = 0.019) were independent risk factors for PFS in advanced EOC patients. Furthermore, chemotherapy resistance (HR: 1.30, 95 CI%: 1.01–1.67, P = 0.032), residual tumor (HR: 1.48, 95 CI%: 1.01–2.21, P = 0.046) and AFR (HR: 2.19, 95 CI%: 1.18–3.67 P = 0.021) were significant risk factors for OS in advanced EOC patients by multivariate Cox analysis (Table 4).

To further analyze the prognostic values of preoperative AFR in advanced EOC patients, the Kaplan-Meier curves of PFS and OS are then performed. As shown in Fig. 1b and c, a low preoperative AFR (≤7.78) was significantly associated with a worse PFS and OS by log-rank test (P < 0.001).