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A new prognostic model predicting hepatocellular carcinoma early recurrence in patients with microvascular invasion who received postoperative adjuvant transcatheter arterial chemoembolization
In this study, we aimed to develop a prognostic model to predict HCC early recurrence (within 1-year) in patients with microvascular invasion who received postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE).
Methods
A total of 148 HCC patients with MVI who received PA-TACE were included in this study. The modes were verified in an internal validation cohort (n = 112) and an external cohort (n = 36). Univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors relevant to early recurrence. A clinical nomogram prognostic model was established, and nomogram performance was assessed via internal validation and calibration curve statistics.
Results
After data dimensionality reduction and element selection, multivariate Cox regression analysis indicated that alpha fetoprotein level, systemic inflammation response index, alanine aminotransferase, tumour diameter and portal vein tumour thrombus were independent prognostic factors of HCC early recurrence in patients with MVI who underwent PA-TACE. Nomogram with independent factors was established and achieved a better concordance index of 0.765 (95% CI: 0.691–0.839) and 0.740 (95% CI: 0.583–0.898) for predicting early recurrence in training cohort and validation cohort, respectively. Time-dependent AUC indicated comparative stability and adequate discriminative ability of the model. The DCA revealed that the nomogram could augment net benefits and exhibited a wider range of threshold probabilities than AJCC T stage.
Conclusions
The nomogram prognostic model showed adequate discriminative ability and high predictive accuracy.
Primary liver cancer (PLC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide according to 2020 global cancer statistics, and 75%–85% of primary liver cancer was hepatocellular carcinoma (HCC) [
]. For the vast majority of HCC patients, surgical resection is the mainstay of curative treatment options. In addition, surgical resection provides better clinical outcomes than local ablation particularly among patients with well-preserved hepatic function [
Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation?.
Liver Transplant.2013; 19 (official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society): 411-419https://doi.org/10.1002/lt.23605
], which is the main cause of death in the long-term follow-up assessment. Early recurrence depends on the biological aggressiveness of the primary tumour, particularly the likelihood of MVI and satellitosis [
Microvascular invasion (MVI) was defined as the presence of tumour cells within a vascular lumen lined by the endothelium that is visible only by microscopy and considered as a critical determinant of early recurrence and survival of HCC [
] also reported that the 3-year cumulative incidence of recurrence was increased from 3.3% to 12.8% in patients with MVI compared with MVI absent within Milan criteria. Multiple features of MVI carry prognostic of HCC significance, some studies have indicated that high-risk MVI patients did significantly worse in regard to both recurrence and survival [
A novel prognostic nomogram based on microvascular invasion and hematological biomarkers to predict survival outcome for hepatocellular carcinoma patients.
Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria.
Present treatments to prevent postoperative recurrence in HCC patients with MVI included postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE), postoperative radiotherapy and radiofrequency ablation (RFA), and targeted therapy and immunotherapy. PA-TACE was the most common adjuvant therapy after curative resection, which can be performed 1–2months after curative resection of HCC [
The effects of several postoperative adjuvant therapies for hepatocellular carcinoma patients with microvascular invasion after curative resection: a systematic review and meta-analysis.
]. Through arterial injection of chemotherapeutic drugs and embolizing agents, TACE has been proposed to theoretically eliminate intrahepatic micro-metastases or residual tumour foci, thus preventing recurrence and improving patient survival after resection of HCC [
Postoperative adjuvant transcatheter arterial chemoembolization after R0 hepatectomy improves outcomes of patients who have hepatocellular carcinoma with microvascular invasion.
Survival benefits from adjuvant transcatheter arterial chemoembolization in patients undergoing liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.
]. Many studies have demonstrated that PA-TACE markedly prolonged long-term survival outcomes and reduced tumour recurrence rates for HCC patients with MVI [
Postoperative adjuvant transcatheter arterial chemoembolization should be considered selectively in patients who have hepatocellular carcinoma with microvascular invasion.
]. Although PA-TACE can reduce tumour recurrence rates for HCC patients, however, the 1-year recurrence rate of HCC patients with MVI underwent TACE was about 30%, and the 2-year recurrence rate was higher [
Postoperative adjuvant transcatheter arterial chemoembolization should be considered selectively in patients who have hepatocellular carcinoma with microvascular invasion.
]. The early recurrence-free rate of HCC patients with MVI who undergoing TACE is still not very ideal.
Therefore, in this study, we aimed to develop a nomogram model to predict the probability of 1-year recurrence-free survival in HCC patients with MVI undergoing PA-TACE after surgical resection. An accurate prognosis estimation of early recurrence can help clinical surgeons choose more appropriate therapeutic measures for recurrent patients based on a risk-benefit assessment.
2. Materials and methods
2.1 Patients
A total of 482 HCC patients were selected, but finally, 148 HCC patients with MVI who received PA-TACE were included at the Ningbo Medical Center Lihuili Hospital from July 2016 to November 2020 were included. The inclusion criteria were as follows: (1) pathologically diagnosed HCC; (2) treated by intended cure resection, which was defined as negative margins with no residual tumour based on the histological examination; (3) MVI positive; and (4) received one-time PA-TACE. The exclusion criteria were as follows: (1) received preoperative anticancer medication; (2) received anticancer medicine before recurrence; (3) history of other cancers; and (4) incomplete clinical or follow-up data. The study was approved by the ethics committee of Ningbo Medical Center Lihuili Hospital (Approval number: KY2022PJ021). All research procedures complied with the relevant guidelines and regulations. Informed consent was obtained from all patients before inclusion. We confirmed that this study was conducted following the Declaration of Helsinki.
2.2 Laboratory examination and follow-up
Laboratory examinations included blood biochemistry, complete blood count and pathological examination. The albumin-bilirubin (ALBI) score and inflammatory markers were calculated according to our previous study [
Albumin-bilirubin (ALBI) and monocyte to lymphocyte ratio (MLR)-Based nomogram model to predict tumor recurrence of AFP-negative hepatocellular carcinoma.
Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.
]. The cut-off value of biomarkers was set according to the Health Industry Standard of the People's Republic of China published by the National Health Commission of the People's Republic of China. Patients were defined as hypertensive based on the ‘gold standard’. Type 2 diabetes mellitus (T2DM) was diagnosed according to the World Health Organization criteria. Anatomic or nonanatomic resection was performed after the clinical evaluation, and all the obtained surgical specimens were histologically assessed by different pathologists.
All patients were followed up by imaging techniques after treatment to the time of death or last follow-up (US and/or CT scan every 3 months during the first 1 year after surgery and every 3 or 6 months after). Patients also received a routine liver function review, and serum AFP analysis during follow-up visits. Follow-up was aimed at the determination of recurrence-free survival (RFS). RFS was calculated from the date of curative resection to the date when tumour recurrence was diagnosed. The preoperative and tumour recurrence diagnoses were based on criteria set forth in the guidelines for the diagnosis and treatment of primary liver cancer in China [
Department of Medical Administration and Management, National Health Commission of the People's Republic of China [Guidelines for diagnosis and treatment of primary liver cancer in China (2022 edition)].
Quantitative variables are reported as medians with interquartile ranges or mean with standard deviation. Categorical variables are presented as absolute counts and percentages. Quantitative variables were analyzed with Student’s t-test or the Mann-Whitney U test, and categorical variables were compared with the chi-squared test or Fisher’s exact test. LASSO regression analysis was used for data dimensionality reduction and element selection. Independent prognostic factors of RFS were identified by univariate and multivariate Cox proportional hazards regression. Subsequently, a new nomogram was formulated to predict prognosis based on the results of Cox regression analysis. Nomogram performance was assessed via internal validation and calibration curve statistics (concordance index was calculated to measure discrimination with 1000 bootstrapping techniques). Nomogram risk score was calculated for stratification of 1-year RFS according to the nomogram model. Patients were divided into different risk groups (low-; moderate-; high-) with the cut-off points automatically calculated using X-tile software [
] (version 3.6.1; Yale University, New Haven, CT, USA). Survival curves were calculated using the Kaplan–Meier method and the log-rank test. A time-dependent area under curve (AUC) of receiver operating characteristic (ROC) was used to validate the nomogram model performance. Decision curve analysis (DCA) was conducted to determine the clinical benefit of the nomogram by quantifying the net benefits along with the increase in threshold probabilities.
Univariate and multivariate Cox regression were performed using SPSS 25.0(IBM Corporation, 2020, USA). LASSO regression, nomogram, time-dependent AUC, DCA, and survival curve were performed or plotted using R version 3.6.2 (http://www.r-project.org/), with package dependencies: “rms”, “glamet”, “ggDCA”, “rmda” “survival”, “survminer”, “ggpubr”, and “timeROC”. P < 0.05 was considered statistically significant.
3. Results
3.1 Prognostic outcomes of HCC
A total of 148 HCC patients with MVI who received PA-TACE met the inclusion criteria were enrolled. 148 HCC patients were randomly allocated to a training cohort (n = 112) and an internal validation cohort (n = 36) in a ratio of about 3:1 (Fig. 1). In training cohort, the median follow-up time was 18 (1–63) months. All patients were followed up for more than 12 months. The 1-year recurrence-free survival rate was 62.0%. In validation cohort, the median follow-up time was 13 (1–36) months. 1-year recurrence-free survival rate was 67.0%. All baseline characteristics are summarized in Table 1.
3.2 Dimensionality reduction and element selection
The LASSO coefficient profiles of the features were plotted. The optimum parameter (lambda) selection in the LASSO model performed tenfold cross-validation through minimum criteria. The partial likelihood deviance (binomial deviance) curve is presented versus log (lambda). Dotted vertical lines are shown at the optimum values by performing lambda.min and lambda.1se. Finally, age, ALT, SIRI, AFP, tumour diameter, and PVTT were selected according to the optimum value corresponding to the minimum value of lambda (Fig. 2.).
Fig. 2Nomogram model elements selection using the LASSO regression model. (A) Coefficient profiles plot (B) Optimum parameter (lambda) selection.
3.3 A new nomogram prognostic model and calibration curve evaluation
We incorporated the age, ALT, SIRI, AFP, tumour diameter, and PVTT into the univariate and multivariate Cox regression equations. Multivariate Cox regression analysis indicated that AFP level greater than 20 ng/ml (>400 VS < 20, HR = 3.305, 95% CI: 1.481–7.374, P = 0.004), SIRI (HR = 1.265, 95% CI: 1.101–1.452, P = 0.001), ALT greater than 50 μg/ml (>50 VS < 50, HR = 0.419, 95% CI: 0.198–0.885, P = 0.023), tumour diameter (HR = 1.106, 95% CI: 1.003–1.220, P = 0.043) and PVTT (HR = 2.141, 95% CI: 1.062–4.315, P = 0.033) were independent prognostic factors of HCC early recurrence in patients with MVI who undergoing PA-TACE (Table 2). Incorporating ALT, SIRI, AFP, tumour diameter and PVTT, the nomogram model was established and achieved a better concordance index of 0.765 (95% CI: 0.691–0.839) and 0.740 (95% CI: 0.583–0.898) for predicting early recurrence in training cohort and validation cohort, respectively (Fig. 3A). The calibration curves for the 1-year RFS rates were largely overlapped with the standard lines in training cohort (Fig. 3B) and validation cohort (Fig. 3C). The resultant nomogram could accurately distinguish the1-year RFS of HCC patients with MVI who undergoing PA-TACE and had better consistency between the predicted probability and the observed probability of 1-year RFS.
Table 2Univariate and multivariate Cox analysis for early recurrence of HCC patients with MVI who received postoperative adjuvant TACE.
Fig. 3Developed prognosis nomogram model for HCC early recurrence in patients with MVI who underwent PA-TACE. (A) Nomogram model composition. (B) Calibration curve plots of training cohort; (C) Calibration curve plots of validation cohort.
3.4 Nomogram model risk stratification and clinical benefit assessment
HCC patients with MVI who undergoing PA-TACE were divided into different risk groups based on the risk scores calculated by the nomogram model to judge the discriminatory abilities of the nomogram for 1-year RFS. The optimal cut-off points were auto-calculated by X-tile software. The risk scores calculated can divide HCC patients into the high-risk group (>97), moderate-risk group (76–97) and low-risk group (<76). Survival curves were calculated to compare the 1-year RFS rates in three different risk groups using the Kaplan–Meier method, and the results showed a significant discriminatory ability for early recurrence risks in the patients based on the nomogram risk scores (P < 0.05, Fig. 4).
Fig. 4Risk stratification of nomogram model for HCC early recurrence in patients with MVI who underwent PA-TACE.
The DCA revealed that the nomogram model could augment net benefits and exhibited a wider range (0.20-1.00) of threshold probabilities by risk stratification than the American Joint Committee on Cancer (AJCC) T stage (Fig. 5A).The time-dependent AUC of area under the ROC curve indicated the comparative stability and adequate discriminative ability of the nomogram model for predicting1-year RFS of HCC patients with MVI who undergoing PA-TACE at all time points (Fig. 5B).
Fig. 5Assessment of developed nomogram model. (A) The DCA for nomogram model and AJCC T stage. (B) Time-dependent AUC for nomogram model.
As one of the most critical factors predictive of HCC recurrence, MVI was an independent risk factor of tumour relapse and metastasis even in patients with small-sized HCC [
Postoperative adjuvant transcatheter arterial chemoembolization after R0 hepatectomy improves outcomes of patients who have hepatocellular carcinoma with microvascular invasion.
]. But there is no prediction model for early recurrence of HCC patients with MVI who undergoing PA-TACE. In this study, the nomogram prognostic model that enabled risk assessment of 1-year RFS has been developed and validated in HCC patients with MVI who underwent PA-TACE. The constructed nomogram model included ALT, SIRI, AFP, tumour diameter, and PVTT. Individuals with higher total points had a greater probability of 1-year recurrence rate. For example, if ALT was ≤50 U/L, with tumour diameter = 8, SIRI = 2, AFP was 20–400 ng/mL, and positive PVTT of individuals, the corresponding total point was 103.5, and the probability of 1-year RFS was approximately 26%. The developed nomogram could accurately distinguish the probability of recurrence and showed a better discriminative ability, with a C-index of 0.765 (95% CI: 0.691–0.839) and 0.740 (95% CI: 0.583–0.898) in training cohort and validation cohort, respectively. Our nomogram model was superior to the AJCC T stage and useful in the pre-treatment counseling of HCC patients with MVI who are appropriate candidates for TACE. Time-dependent AUC indicated comparative stability and adequate discriminative ability of the model. Using this nomogram, physicians can give a reasonably accurate prediction of recurrence probability for resectable HCC patients with MVI after PA-TACE.
As a prototypical inflammation-related cancer, approximately 90% of HCC burden is associated with prolonged hepatitis due to viral hepatitis, excessive alcohol intake, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) [
]. The immune microenvironment and inflammatory markers are all parts of the systemic inflammatory response and play an important role in cancer development, progression, invasion, and metastasis [
]. The present study first confirmed that the SIRI could be used to predict the 1- year recurrence of HCC patients with MVI who underwent PA-TACE. As a systemic inflammation response index in the peripheral blood, the SIRI is low in cost of examination and simple to calculate by monocyte × neutrophil/lymphocyte, and can be measured repeatedly. Activated circulating monocytes can secrete multiple proinflammatory cytokines, that are involved in tumour development and progression [
]. In the peripheral blood or tumour microenvironment, neutrophils can produce vascular endothelial growth factor (VEGF), which stimulates tumour development and progression [
]. In contrast, a low lymphocyte count is associated with systemic inflammatory responses and is known to promote cancer progression through effects on cell-mediated immunity [
High systemic inflammation response index (SIRI) indicates poor outcome in gallbladder cancer patients with surgical resection: a single institution experience in China.
] reported that Higher pretreatment peripheral blood SIRI level was significantly related to poorer tumour response in patients with HCC who undergoing PA-TACE. Preoperative SIRI was also found to be an independent predictor for RFS in early stage HCC after radiofrequency ablation [
A systemic inflammation response index (SIRI)-Based nomogram for predicting the recurrence of early stage hepatocellular carcinoma after radiofrequency ablation.
]. In this study, we demonstrated that SIRI was also an effective inflammatory predictor of 1-year recurrence in HCC patients with MVI who underwent PA-TACE.
Since the identification of serum alpha-fetoprotein (AFP) in the 1970s, it is a well-established diagnostic and prognostic indicator of increased tumour virulence and is associated with worse tumour phenotype and aggressiveness in HCC [
Development and validation of prognostic nomograms for single large and huge hepatocellular carcinoma after curative resection. vol. 155. European journal of cancer,
Oxford, England19902021: 85-96https://doi.org/10.1016/j.ejca.2021.07.009
] found that ≥2 cm was associated with early recurrence, but ≥5 cm should be cautiously monitored for early extrahepatic recurrence in patients with poorly differentiated HCC. PVTT is the most common form of macrovascular invasion and is found in approximately 10%–40% of all HCC patients at the time of diagnosis [
]. Patients with PVTT usually have an aggressive disease course, higher recurrence rates and worse overall survival. Recent studies also indicated that TACE combined with radiotherapy or sorafenib maybe could produce better prognosis results than TACE alone for PVTT [
Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis.
]. Therefore, the therapeutic effect of solely TACE is limited for higher AFP, large HCC and PVTT, combination of targeted and immunotherapy is necessary.
In addition, we found the relatively lower ALT level (<50 U/L) was associated with greater early recurrence risk. This was controversial with present studies that high ALT level will accelerate the recurrence and might be potential predictors of outcome in HCC with HBV [
Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.
Preoperative serum gamma-glutamyl transferase to alanine aminotransferase ratio is a convenient prognostic marker for Child-Pugh A hepatocellular carcinoma after operation.
]. Especially for HCC patients with MVI, the early recurrence was mainly result of metastasis of cancer cells. More importantly, ALT level and hepatitis activity could be altered by the anti-HBV therapy. Ju MJ et al. [
Preoperative serum gamma-glutamyl transferase to alanine aminotransferase ratio is a convenient prognostic marker for Child-Pugh A hepatocellular carcinoma after operation.
] found that a high GGT/ALT ratio was associated with high early recurrence rates, more recurrence-related deaths and various aggressive tumour characteristics. Additionally, AST/ALT of 80 IU/L or more was an independent risk factor for the recurrence of primary solitary hepatitis C-related HCC after curative resection [
Risk factors for recurrence after curative resection of hepatitis C-related hepatocellular carcinoma in patients without postoperative interferon therapy.
There are limitations to this study. First, this research is a single central retrospective cohort study. Second, we only developed single center internal validation of the nomogram prediction model with a representative sample size, and external validations of multicentre studies are still needed and indispensable.
5. Conclusion
In conclusion, the nomogram prognostic model for HCC early recurrence in patients with MVI who underwent PA-TACE showed adequate discriminative ability and high predictive accuracy, suggesting it could benefit surgeons on decision-making.
The author reports no conflicts of interest in this work.
Acknowledgment
Our research was Funded by Ningbo medical and health brand discipline(PPXK2018-03), Science and Technology program of Zhejiang Health(2021KY1035). Medical Health Science and Technology Project of Zhejiang Province(2019ZD047), Science and Technology program of Zhejiang Health(2022KY293).
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Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation?.
Liver Transplant.2013; 19 (official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society): 411-419https://doi.org/10.1002/lt.23605
A novel prognostic nomogram based on microvascular invasion and hematological biomarkers to predict survival outcome for hepatocellular carcinoma patients.
Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria.
The effects of several postoperative adjuvant therapies for hepatocellular carcinoma patients with microvascular invasion after curative resection: a systematic review and meta-analysis.
Postoperative adjuvant transcatheter arterial chemoembolization after R0 hepatectomy improves outcomes of patients who have hepatocellular carcinoma with microvascular invasion.
Survival benefits from adjuvant transcatheter arterial chemoembolization in patients undergoing liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.
Postoperative adjuvant transcatheter arterial chemoembolization should be considered selectively in patients who have hepatocellular carcinoma with microvascular invasion.
Albumin-bilirubin (ALBI) and monocyte to lymphocyte ratio (MLR)-Based nomogram model to predict tumor recurrence of AFP-negative hepatocellular carcinoma.
Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection.
High systemic inflammation response index (SIRI) indicates poor outcome in gallbladder cancer patients with surgical resection: a single institution experience in China.
A systemic inflammation response index (SIRI)-Based nomogram for predicting the recurrence of early stage hepatocellular carcinoma after radiofrequency ablation.
Development and validation of prognostic nomograms for single large and huge hepatocellular carcinoma after curative resection. vol. 155. European journal of cancer,
Oxford, England19902021: 85-96https://doi.org/10.1016/j.ejca.2021.07.009
Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis.
Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.
Preoperative serum gamma-glutamyl transferase to alanine aminotransferase ratio is a convenient prognostic marker for Child-Pugh A hepatocellular carcinoma after operation.
Risk factors for recurrence after curative resection of hepatitis C-related hepatocellular carcinoma in patients without postoperative interferon therapy.
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