In this study, we estimated the role of liver fibrosis or cirrhosis in hepatocellular carcinoma using the national SEER database for the first time. In order to eliminate selection bias, PSM was performed in this population-based research. Processed with the combination of clinical and pathological covariates, the propensity score matching made a comparable distribution of the clinicopathological characteristics between the F0 and F1 cohorts, thus bringing about a result that was similar to random allocation[21]. After PSM analysis, patients with severe fibrosis or cirrhosis patients in HCC showed a significantly worse prognosis, thus, more precision estimates of disease severity and proper follow-up surveillance for progression of hepatic decompensation and recurrence of hepatocellular carcinoma were needed. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and excessive drinking are major and common factors that contribute to cirrhosis and developing HCC [22, 23]. More advanced fibrosis or cirrhosis stages result in decompensation of the liver in the progression of HCC. Therefore, detection and intervention of fibrosis and its risk factors at an early stage is the most important thing for potential reversal.
Based on population-based database, we constructed a nomogram to evaluate the definite 1-, 3- and 5-year OS and CSS probabilities of patients with HCC concomitantly suffer from severe fibrosis or cirrhosis, then, the ability of the nomograms were verified concerning its discrimination and calibration. As a result, the nomograms were performing well in both the validation set and the training set. In the perspective of net benefit and clinical efficacy, the novel models showed wider range of threshold probabilities than some conventional systems.
According to our results, the type of therapy was the strongest predictor of outcome. In fact, liver transplantation(LT), derived from both cadaveric and living donation, often represents the only curative treatment which is able to simultaneously cure the HCC and the liver cirrhosis. Mazzaferro et al described that selected patients can achieve more considerable survival benefit compared with those of whom transplanted for benign cases in a published landmark paper.[24, 25] The success of LT is not subjected to the severity of liver dysfunction, it could be able to improve survival and the quality of life in selected patients with end-stage liver disease[2, 3, 24]. However, this option may be precluded to a significant number of patients because of age, comorbidities, tumor characteristics, shortage of donor organs and some other limitations[26]. Certainly, when these factors hinder the chance of LT, liver resection should be considered as a precious option. Due to severe complications (severe portal hypertension, thrombocytopenia etc.) in patients with advanced cirrhosis, Barcelona Clinic Liver Cancer (BCLC) algorithm recommend hepatectomy as the preferred therapy for patients with single tumor and well-preserved liver function (Child-Pugh A). But a recent study pointed out that hepatectomy for HCC in Child-Pugh B cirrhosis could be also feasible, after careful preoperative assessment based on patients’ features, liver function and tumor pattern as well as decreasing surgical stress[27]. Unlike hepatectomy, terrible liver function does not mean a contraindication of real-time image-guided local radiofrequency ablation(RFA). Patients with tumors less than 3 cm and Child-Pugh A or B who have no indication for hepatectomy are candidates for RFA[3]. A retrospective study that contained 7,185 patients concluded that hepatectomy might contribute a lower rate of recurrence than RFA in small HCC. Another single-center study described that patients who underwent hepatectomy had a longer OS[28, 29]. Nearly 40% of the cases did not receive operation, and the reason for the non-operation therapies was that it was contraindicated or was not recommended. It indicated that severe fibrosis or cirrhosis patients with HCC were more likely to suffer from an end stage of HCC.
Tumor size is the core element of AJCC 8th edition T stage and an integral part of the AJCC 8th edition TNM stage system. T stage was always considered as a crucial predictor for HCC [30, 31]. The present study has indicated that advanced T stage meant higher risks of OS and CSS. Meanwhile, heavier weight from T stage in calculating overall survival than cancer-specific survival was observed, indicating that CSS were more largely depended on the intrinsic nature of HCC. Tumor grade, another factor showed inherent feature of tumor, is widely accepted as one of the most effective prognostic factors of outcome in patients with HCC both after hepatectomy and LT, as shown by many series study of these topics[32–38]. In accordance with the previous study, our study indicated that a poorly differentiation was associated with a worse prognosis. AFP has been highly applied not only in diagnostic biomarker but in evaluating the outcome of HCC for years. Previous studies found that high AFP level before treatment was an independent predictor concerned with tumor grade, progression and survival[39].The present study supported that the AFP level is an negative and independent predictor for both CSS and OS of severe fibrosis or cirrhosis patients with HCC.
The predictive value was not observed for N stage in this study. The proportion of patients with lymph node (LN) metastasis was fairly low. T diagnosis of LN metastasis was based on intraoperation exploration and pathological confirmation, rather than imaging examination in present study. It might result in the lower rate of LN metastasis.
Additionally, based on the risk stratification of prognostic curves, the novel nomogram-predicted models had better discrimination than that of AJCC systems both in OS and CSS, as shown in Fig. 5. For overall survival, the AJCC 7th edition system was underperformed in stratifying stages I and II patients. The AJCC 8th stage systems shown good prognostic stratification for patients, but its C-index was only 0.650(95%CI, 0.626–0.674, training set) and 0.662(95%CI,0.629–0.695, validation set) respectively. However, in both sets, four sub-groups(the low-A risk, low-B risk, moderate risk and high risk groups) in our nomograms had significant differences in OS and CSS, and showed better accuracy and discrimination in both short-term and long-term survival prediction. The most likely reason is that the AJCC system only take the tumor size, positive regional LN and metastasis into consideration. These result indicated that our nomograms were able to use as a conventional tool for predicting the short-term and long-term outcome of severe fibrosis or cirrhosis patients with HCC. However, it was ignored that racial differences, differentiation grades, and therapy methods were also independent predictors for prognosis.
As is known to us, this study established the first nomogram model for predicting the outcomes of severe fibrosis or cirrhosis patients with HCC. By calculating the score of the variables, clinicians can not only predict the prognosis immediately and accurately but also obtain valuable information to choose treatments and predict survival rates before therapy option. Meanwhile, doctors can easily distinguish different level risk of patients after treatment, careful and regular follow-up should be made in high-risk populations. Then, SEER database provided multicenter clinical data, made our results more applicable to the general population than that at a single institution.
However, some limitations were still existed. Firstly, This was an retrospective observational study exposed to potential confounding bias. Therefore, a 1:1 PSM analysis was performed to simulate a realistic scenario of two homogeneous populations. Then, liver function is also a vital factor for the prediction of both cirrhosis and HCC, but the data was not available from the SEER database in our nomograms. Therefore, external validation should be performed by using an independent external dataset for the prognostic nomograms developed in this study in the future. and further randomized evidence is required to verify the conclusions of our study.