Yin X, Deng N, Ding XY, Chen JL, Sun W. CRAFITY score and nomogram predict the clinical efficacy of lenvatinib combined with immune checkpoint inhibitors in hepatocellular carcinoma. World J Gastroenterol 2025; 31(7): 101672 [DOI: 10.3748/wjg.v31.i7.101672]
Corresponding Author of This Article
Wei Sun, MD, Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing 100015, China. sunwei2134@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xue Yin, Na Deng, Xiao-Yan Ding, Jing-Long Chen, Wei Sun, Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Co-corresponding authors: Jing-Long Chen and Wei Sun.
Author contributions: Sun W and Chen JL designed the research study and acquired the funding, they contributed equally as co-corresponding authors; Yin X, Deng N, and Ding XY performed the research and contributed to data collection; Yin X contributed to data analysis, visualization, and manuscript preparation; and all authors have reviewed and agreed to the published version of the manuscript.
Supported by the Capital’s Funds for Health Improvement and Research, No. SF202222175.
Institutional review board statement: The study was reviewed and approved by the Institutional Ethics Committee of Beijing Ditan Hospital, Capital Medical University (approval No. KY2022014).
Informed consent statement: The requirement to obtain informed written consent was waived due to the retrospective nature of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The source data for this study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei Sun, MD, Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun East Street, Chaoyang District, Beijing 100015, China. sunwei2134@163.com
Received: September 23, 2024 Revised: December 3, 2024 Accepted: December 30, 2024 Published online: February 21, 2025 Processing time: 119 Days and 5.3 Hours
Abstract
BACKGROUND
The CRAFITY score is mainly utilized for hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab, with little investigation in its predictive capacity for alternative regimens, such as lenvatinib and programmed cell death protein 1 (PD-1) inhibitors, which are widely utilized in Chinese clinical practice.
AIM
To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.
METHODS
The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022. Patients were stratified according to CRAFITY score (based on baseline alpha-fetoprotein and C-reactive protein levels) into CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high groups. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis, and independent prognostic factors were identified through Cox regression analysis. Nomograms were created to forecast survival for a year.
RESULTS
The median PFS and OS were the longest for patients in the CRAFITY-low group, followed by those in the CRAFITY-intermediate and CRAFITY-high groups (median PFS: 8.4 months, 6.0 months, and 3.1 months, P < 0.0001; median OS: 33.4 months, 19.2 months, and 6.6 months, P < 0.0001). Both the objective response rate (5%, 19.6%, and 22%, P = 0.0669) and the disease control rate (50%, 76.5%, and 80%, P = 0.0023) were considerably lower in the CRAFITY-high group. The findings from the multivariate analysis showed that a nomogram which included the tumor number, prior transarterial chemoembolization history, and CRAFITY score predicted 12-month survival with an area under the curve of 0.788 (95% confidence interval: 0.718-0.859), which was in good agreement with actual data.
CONCLUSION
The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.
Core Tip: The CRAFITY score, integrating baseline alpha-fetoprotein and C-reactive protein levels, has been limitedly investigated in patients receiving lenvatinib and programmed cell death protein 1 (PD-1) inhibitors. This study found significant differences in progression-free survival and overall survival across CRAFITY score strata in patients treated with lenvatinib and PD-1 inhibitors. Lower CRAFITY scores were associated with better objective response rates and disease control rates. These findings suggest that the CRAFITY score is a promising predictive tool for treatment response and survival in patients with unresectable hepatocellular carcinoma receiving lenvatinib and PD-1 inhibitors.
Citation: Yin X, Deng N, Ding XY, Chen JL, Sun W. CRAFITY score and nomogram predict the clinical efficacy of lenvatinib combined with immune checkpoint inhibitors in hepatocellular carcinoma. World J Gastroenterol 2025; 31(7): 101672
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, largely due to the limited treatment options available for patients diagnosed at an advanced stage[1]. Sorafenib was the first systemic therapy recommended for advanced HCC, based on the results of SHARP and Asia-Pacific trials[2,3]. Recently, atezolizumab plus bevacizumab has supplanted sorafenib as the new standard first-line treatment for advanced HCC, demonstrating an overall response rate (ORR) of 29.8% and a 5.8-month survival benefit over sorafenib[4]. The IMbrave150 trial marked a shift in systemic therapy for HCC, transitioning from anti-angiogenic monotherapy to immunotherapy-based combination regimens[4]. Despite these advances, the response to programmed cell death protein 1 (PD-1) inhibitors in HCC patients remains highly heterogeneous, with approximately 30% of cases exhibiting intrinsic resistance[5]. This variability underscores the urgent need for reliable biomarkers to predict immunotherapeutic outcomes in HCC[6].
Alpha-fetoprotein (AFP) is the most common serologic marker of HCC, with re-expression observed in approximately 70%-80% of HCC patients [7,8]. AFP mediates immune escape in HCC by altering the proportion of CD4+ T/CD8+ T cells and exerting a suppressive effect on natural killer cells, T cells, and dendritic cells[8]. Additionally, AFP has been shown to be a potential predictor of immunotherapeutic efficacy in HCC[9-11]. While only about 60% of HCC patients exhibit elevated AFP levels, a bias is expected in cases with advanced HCC with normal AFP or non-advanced HCC with very high AFP[12]. C-reactive protein (CRP), an acute phase protein, is involved in opsonization for phagocytosis, complement activation, and direct-binding to Fc receptors[13]. Early CRP kinetics have been identified as a predictor of treatment response in cancer patients undergoing immune checkpoint inhibitor therapy[14]. However, CRP is a nonspecific biomarker that can be increased in various inflammatory, infectious, immunological, and oncologic conditions. Therefore, the use of CRP alone as a predictive marker in HCC may be limited and should be considered in conjunction with other biomarkers. The CRAFITY score, which integrates baseline CRP and AFP levels, offers a composite predictive tool for stratifying patients undergoing immunotherapy[15-18]. However, the utility of the CRAFITY score in patients receiving lenvatinib and PD-1 inhibitors, which is common in Chinese clinical practice, remains underexplored. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, inhibits platelet-derived growth factor receptor α, vascular endothelial growth factor receptors 1-3, fibroblast growth factor 1-4, KIT, and RET[19]. Compared to everolimus alone, the combination of lenvatinib and everolimus significantly prolonged progression-free survival (PFS)[20]. This study aims to evaluate the predictive value of the CRAFITY score in patients with unresectable HCC undergoing treatment with lenvatinib and PD-1 inhibitors, providing insights for more personalized therapeutic strategies.
MATERIALS AND METHODS
Patient selection
This observational study assessed the predictive significance of the CRAFITY score for overall survival (OS) in patients with advanced HCC receiving lenvatinib and a PD-1 inhibitor as immunotherapy. To achieve this aim, we performed a retrospective analysis of patients with unresectable HCC who received at least one dose of lenvatinib in combination with camrelizumab or sintilimab at Beijing Ditan Hospital, Capital Medical University, China, between January 2018 and January 2022. Patients were diagnosed with HCC based on histological or radiological criteria as defined by the American Association for the Study of Liver Diseases guidelines[21]. Eligible patients were stratified according to baseline AFP and CRP levels into CRAFITY-low (AFP < 100 ng/mL and CRP < 10 mg/dL), CRAFITY-intermediate (either AFP ≥ 100 ng/mL or CRP ≥ 10 mg/dL), and CRAFITY-high groups (AFP ≥ 100 ng/mL and CRP ≥ 10 mg/dL)[16]. The exclusion criteria were as follows: (1) Baseline AFP and CRP levels not available; (2) Increased CRP levels due to active infection or other systemic diseases; (3) Presence of cancers other than HCC; (4) Child-Pugh class C; and (5) Barcelona Clinic Liver Cancer (BCLC) stage D.
The study was conducted following the tenets of the Declaration of Helsinki, and the Ethics Committee of Beijing Ditan Hospital, Capital Medical University approved the study protocol. The data collected are anonymous, therefore the requirement for informed consent was waived. All patients were administered lenvatinib (12 and 8 mg/day orally for body weights ≥ 60 and < 60 kg, respectively) in combination with camrelizumab or sintilimab (200 mg intravenously every three weeks) until disease progression or intolerable toxicity. In addition, dose modifications or drug interruptions were made for each drug according to the medication guidelines.
Data collection
Patients’ baseline characteristics were recorded within 14 days before treatment, including age, sex, etiology, Eastern Cooperative Oncology Group performance status, cirrhosis, and line of therapy. Tumor size and number, portal vein tumor thrombus (PVTT), and extrahepatic metastasis (EHM) were assessed using magnetic resonance imaging and/or computed tomography images. Laboratory results, including biochemical tests and AFP, were recorded. Child-Pugh class and BCLC stage were calculated to determine liver function and tumor stage. The CRAFITY score was calculated by baseline AFP and CRP levels, and patients were stratified into CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high groups[16].
The response to treatment was evaluated by a specialized radiologist after 12 weeks of initial therapy and categorized according to the modified Response Evaluation Criteria in Solid Tumors as complete response (CR), partial response (PR), stable disease (SD), or progressive disease. Additionally, patients were distinguished based on objective response (CR + PR) and disease control (CR + PR + SD)[22]. OS was defined as the duration from lenvatinib plus PD-1 inhibitor therapy to patient death or last follow-up, while PFS was defined as the period from combination therapy commencement until disease progression according to modified Response Evaluation Criteria in Solid Tumors criteria or patient death.
Statistical analysis
Patients’ baseline characteristics were presented using descriptive statistics with median and interquartile range for continuous variables, number and percentage for categorical variables, and median and 95% confidence interval (CI) for survival data. ORR and disease control rate (DCR) were compared between the groups using the χ2 test or Fisher’s exact test. Survival curves for OS and PFS were compared using the Kaplan-Meier method and the log-rank test. In addition, univariate Cox regression was performed to screen covariates with P < 0.1, followed by multivariate Cox survival analysis, and variables with P < 0.05 were statistically significant. Finally, a predictive model was constructed using the selected variables, and the receiver operating curve and calibration curve were drawn to assess the model. All analyses were performed using R software (version 4.2.1).
RESULTS
Patient characteristics
A total of 221 HCC patients were treated with lenvatinib and PD-1 inhibitors between January 2018 and January 2022. Excluded patients were Child-Pugh class C (n = 4), those with active infection (n = 9), and those without baseline CRP and AFP data (n = 16). A total of 192 patients were included in this exploratory analysis. The baseline patient characteristics are summarized in Table 1. The majority of participants were male (n = 161, 83.9%), with a median age of 57.5 years (interquartile range: 50.0-64.0). Hepatitis B virus infection was identified as the predominant cause of HCC (n = 166, 86.5%). Other causes included hepatitis C virus (n = 15, 7.8%) and non-viral factors such as alcohol consumption or non-alcoholic steatohepatitis (n = 11, 6.6%). Cirrhosis was present in 160 patients (83.3%). At the initiation of immunotherapy, the proportions of patients with Child-Pugh class B, Eastern Cooperative Oncology Group performance status 1, tumor number ≥ 3, and tumor size ≥ 5 cm were observed to be 64 (33.3%), 78 (40.6%), 119 (62.0%), and 126 (65.6%), respectively. PVTT and EHM were observed in 101 (52.6%) and 90 (46.9%) patients, respectively, and overall, BCLC stage C was more common, accounting for 82.3%. Lenvatinib combined with sintilimab or camrelizumab was administered as a first-line regimen in the majority of patients (n = 147, 76.6%). To investigate the association between the CRAFITY score, survival outcomes, and response to immunotherapy, we categorized patients into three study cohorts based on their baseline CRP and AFP levels: CRAFITY-high (n = 40, 20.8%), CRAFITY-intermediate (n = 102, 53.1%), and CRAFITY-low (n = 50, 26.1%) (Figure 1). Patients in the CRAFITY-high group exhibited more advanced disease characteristics, with tumors ≥ 5 cm in diameter and a higher incidence of PVTT. In contrast, CRAFITY-low patients had better performance status and a higher proportion of transarterial chemoembolization (TACE) treatment. No significant differences were observed among the three groups regarding other baseline characteristics, with approximately 80% of patients having cirrhosis across all groups.
Across the whole study cohort as of 01 March 2023, 162 (84.4%) patients had progressed, and 92 (47.9%) patients died. Median PFS was 5.2 months (95%CI: 4.1-6.2), and the median OS was 17.7 months (95%CI: 15.8-26.3). Survival varied according to CRAFITY score: 17 (34.0%) patients died and 38 (76.0%) progressed in the CRAFITY-low group; 52 (51.0%) patients died and 90 (88.2%) progressed in the CRAFITY-intermediate group; and 23 (57.5%) patients died, and 34 (85.0%) progressed in the CRAFITY-high group. Kaplan-Meier analysis showed a significant difference in the probability of PFS between the groups (P < 0.0001) (Figure 2). Patients in the CRAFITY-low arm had the longest median PFS (8.4 months, 95%CI: 5.2-11.7), followed by the CRAFITY-intermediate arm (6.0 months, 95%CI: 4.3-6.8), and the shortest median PFS was observed in the CRAFITY-high arm (3.1 months, 95%CI: 2.7-4.1). Again, this statistical significance was observed in OS (P < 0.0001), with median OS of 33.4 months (95%CI: 21.4-not reach), 19.2 months (95%CI: 15.8-26.8), and 6.6 months (95%CI: 4.1-not reach) in the three groups, respectively (Table 2). Additionally, we found that non-cirrhotic patients had longer median PFS (8.6 vs 4.8 months, P = 0.14) and median OS (26.3 vs 17.1 months, P = 0.504) compared to cirrhotic patients, although these differences were not statistically significant (Figure 3).
Figure 3 Kaplan-Meier curves of progression-free survival and overall survival in patients with or without cirrhosis.
A: Kaplan-Meier curves of progression-free survival; B: Kaplan-Meier curves of overall survival. PFS: Progression-free survival; OS: Overall survival.
Table 2 Efficacy according to CRAFITY score, n (%).
All (n = 192)
CRAFITY-high (n = 40)
CRAFITY-intermediate (n = 102)
CRAFITY-low (n = 50)
P value
PFS, months (95%CI)
5.2 (4.1-6.2)
3.1 (2.7-4.1)
6.0 (4.3-6.8)
8.4 (5.2-11.7)
< 0.0001
OS, months (95%CI)
17.7 (15.8-26.3)
6.6 (4.1-NR)
19.2 (15.8-26.8)
33.4 (21.4-NR)
< 0.0001
Initial response
0.0277
CR
3 (1.5)
0 (0.0)
2 (2.0)
1 (2.0)
PR
30 (15.6)
2 (5.0)
18 (17.6)
10 (20.0)
SD
105 (54.7)
18 (45.0)
58 (56.9)
29 (58.0)
PD
54 (28.1)
20 (50.0)
24 (23.5)
10 (20.0)
ORR
33 (17.1)
2 (5.0)
20 (19.6)
11 (22.0)
0.0669
DCR
138 (71.9)
20 (50.0)
78 (76.5)
40 (80.0)
0.0023
Regression analysis
Univariate Cox regression analysis for the association of survival outcomes is shown in Table 3. PFS was associated with CRAFITY score (P < 0.001), cirrhosis (P = 0.032), history of resection (P = 0.093), line of therapy (P = 0.032), number of tumors (P = 0.021), and PVTT (P = 0.064). OS was associated with CRAFITY score (P < 0.001), history of TACE (P < 0.001), number of tumors (P = 0.009), and EHM (P = 0.047). Figure 4 shows the results of the multivariate analysis, where CRAFITY score was a variable significantly associated with PFS [CRAFITY-intermediate vs CRAFITY-high, hazard ratio (HR): 0.54, 95%CI: 0.35-0.82, P = 0.004; CRAFITY-low vs CRAFITY-high, HR: 0.38, 95%CI: 0.24-0.62, P < 0.001]. In addition, we found that tumor number ≥ 3 was an independent risk factor for OS (HR: 1.39, 95%CI: 1.01-1.93, P = 0.046). Independent predictive effects were also observed for OS (CRAFITY-intermediate vs CRAFITY-high, HR: 0.37, 95%CI: 0.22-0.61, P < 0.001; CRAFITY-low vs CRAFITY-high, HR: 0.26, 95%CI: 0.13-0.51, P < 0.001). In addition, a history of TACE was a significant protective factor for survival (HR: 0.31, 95%CI: 0.18-0.55, P < 0.001).
Figure 4 Forest plot of multivariate Cox regression for progression-free survival and overall survival.
A: Forest plot for progression-free survival; B: Forest plot for overall survival. PVTT: Portal vein tumor thrombus; TACE: Transarterial chemoembolization; EHM: Extrahepatic metastasis.
Table 3 Univariate Cox regression for progression-free survival and overall survival (95% confidence interval).
Characteristic
PFS, HR
PFS, P value
OS, HR
OS, P value
CRAFITY (intermediate vs high)
0.48 (0.32-0.72)
< 0.001
0.35 (0.21-0.58)
< 0.001
CRAFITY (low vs high)
0.33 (0.21-0.54)
< 0.001
0.21 (0.11-0.4)
< 0.001
Sex (male vs female)
0.83 (0.55-1.24)
0.359
1.54 (0.82-2.9)
0.181
Age (≥ 60 years vs <60 years)
0.82 (0.6-1.13)
0.221
0.89 (0.59-1.36)
0.6
ECOG PS (1 vs 0)
0.94 (0.68-1.29)
0.688
1.32 (0.87-1.98)
0.191
Cirrhosis (present vs absent)
1.4 (0.89-2.2)
0.14
1.23 (0.67-2.26)
0.504
Resection (yes vs no)
0.68 (0.44-1.06)
0.093
0.86 (0.5-1.46)
0.568
TACE (yes vs no)
0.8 (0.51-1.27)
0.352
0.24 (0.14-0.41)
< 0.001
Ablation (yes vs no)
0.83 (0.61-1.14)
0.259
0.71 (0.47-1.09)
0.116
Treatment line (later vs first)
0.66 (0.45-0.96)
0.032
0.82 (0.52-1.31)
0.404
Number (≥ 3 vs < 3)
1.46 (1.06-2.02)
0.021
1.84 (1.16-2.91)
0.009
Size (≥ 5 cm vs < 5 cm)
1.21 (0.87-1.68)
0.247
1.19 (0.78-1.83)
0.417
PVTT (present vs absent)
1.34 (0.98-1.83)
0.064
1.4 (0.92-2.11)
0.114
EHM (present vs absent)
1.12 (0.82-1.53)
0.472
1.52 (1-2.31)
0.047
Child-Pugh grade (B vs A)
0.97 (0.7-1.35)
0.849
1.37 (0.91-2.08)
0.135
BCLC stage (C vs B)
0.98 (0.65-1.48)
0.933
0.75 (0.44-1.25)
0.265
Response to treatment
The cohort of patients we included was evaluated radiologically, and CR and PR were achieved in three (1.5%) and 30 (15.6%) patients, respectively, with an ORR of 17.1%. SD was observed in 105 (54.7%) patients, and the DCR was 71.9%. CRAFITY score predicted treatment response in HCCs treated with lenvatinib in combination with PD-1 inhibitors (P = 0.0277). CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high showed CR in n = 1 (2.0%), n = 2 (2.0%), and n = 0 (0.0%); PR in n = 10 (20.0%), n = 18 (17.6%), and n = 2 (5.0%); SD in n = 29 (58.0%), n = 58 (56.9%), and n = 18 (45.0%); progressive disease in n = 10 (20.0%), n = 24 (23.5%), and n = 20 (50.0%). Although statistical significance was not reached (P = 0.0669), patients in the CRAFITY-high group tended to have a lower probability of objective response (5%, 19.6%, and 22%, P = 0.0669). The CRAFITY-high group had a significantly lower probability of disease control (50%, 76.5%, and 80%, P = 0.0023) (Table 2).
Predictive model
Finally, we developed a nomogram incorporating the CRAFITY score, previous TACE history, and tumor number to accurately predict one-year survival in patients accurately. The discrimination and calibration of this model were satisfactory, with an area under the receiver operating curve of 0.788 (95%CI: 0.718-0.859) (Figure 5).
Figure 5 Predictive model.
A: Nomogram for predicting overall survival at 1-year; B: Receiver operating curve of the nomogram; C: Calibration curve of the nomogram. TACE: Transarterial chemoembolization; AUC: Area under the curve; OS: Overall survival.
DISCUSSION
The CRAFITY score derived from serum AFP and CRP levels, serves as a valuable and accessible tool to predict the treatment response and survival in patients with HCC receiving immunotherapy[16]. In China, the combination of lenvatinib and PD-1 inhibitors is one of the most commonly used treatment regimens for HCC patients. While some studies have included small cohorts treated with this regimen, the limited sample sizes raise concerns about the accuracy of the CRAFITY score in this context[23,24]. Furthermore, no comprehensive analyses have yet validated the predictive accuracy of the CRAFITY score in a broader patient population. Our study aims not only to validate but also to enhance the predictive value of the CRAFITY score for this specific patient group.
In our cohort, the CRAFITY score successfully differentiated OS across 3 stratifications, with a median OS of 33.4 months for CRAFITY-low, 19.2 months for CRAFITY-intermediate, and 6.6 months for CRAFITY-high. These findings surpass those reported by Scheiner et al[16], who included only a small number of patients treated with tyrosine-kinase inhibitor plus immunotherapy in both training (4 patients, 2.7%) and validation cohorts (8 patients, 7.0%). Notably, these patients were not treated with this regimen for the first time[16,24,25]. Our results align with prior studies indicating that lower CRAFITY scores are associated with better PFS and OS[15,16,18,23,26-29]. Interestingly, while Yang et al[27] and Hatanaka et al[15] found no significant differences in DCR or ORR across CRAFITY score groups, our analysis revealed a significant correlation between higher CRAFITY scores and lower DCR and ORR. This suggests that the CRAFITY score may also serve as a predictive marker for tumor response in patients treated with lenvatinib and PD-1 inhibitors. Although non-cirrhotic patients exhibited longer median PFS and OS compared to cirrhotic patients, these differences did not reach statistical significance. This may be attributed to the relatively small sample size of non-cirrhotic patients. Furthermore, tumor burden, including factors such as PVTT and tumor size, likely played a more dominant role in determining survival outcomes, potentially overshadowing the impact of cirrhosis-related complications.
Inflammation is a hallmark of cancer and a key component of the tumor microenvironment, contributing to tumorigenesis and cancer progression[30]. Previous studies have demonstrated the prognostic value of inflammation indices in HCC patients, such as neutrophil-to-lymphocyte ratio, monocyte/granulocyte to lymphocyte ratio, serum AFP levels and CRP[31-34]. Among them, AFP is the most extensively utilized serum marker for monitoring disease development and progression in HCC[35]. Elevated serum levels of AFP have been associated with poorer prognosis across all stages of HCC, regardless of the therapy[36-41]. The REACH-2 trial identified AFP as a prognostic indicator for immunotherapy efficacy in HCC[9]. AFP contributes to immune evasion through two primary pathways: Extracellular AFP induces apoptosis in immune cells and weaken their antitumor function, while both extracellular and intracellular AFP promote the upregulation of immunosuppressive ligands or antigens, facilitating immune escape[26,42,43]. CRP functions as an acute-phase protein and serves as a widely acknowledged indicator of cancer-induced systemic inflammation[30]. Elevated CRP levels can impair the efficacy of immunotherapy by inhibiting Th1 differentiation and promoting Th2 differentiation of CD4+ T cells[44]. Zhang et al[45] found that patients with high CRP levels had shorter PFS compared to those with low CRP following PD-1 inhibitor treatment. Hatanaka et al[15] also indicated that CRP was a predictive factor of PFS and OS in patients treated with atezolizumab and bevacizumab. There were previous reports that support the present findings, further establishing CRP as a predictive factor for poor outcomes.
The CRAFITY score, originally developed for patients on PD-(ligand) 1-based immunotherapy, has been validated for predicting outcomes in patients treated with tyrosine-kinase inhibitor plus immunotherapy. However, its predictive validity (C-index < 0.7) still requires improvement for more effective clinical application[26,27,29]. In our analysis, Cox regression confirmed the independent predictive role of the CRAFITY score and highlighted tumor number ≥ 3 as an independent risk factor for OS, while a history of TACE emerged as a significant protective factor. Based on these findings, we developed a nomogram incorporating these three predictors to accurately predict one-year survival in patients. The prognostic nomograms exhibited ample discriminative ability, with an area under the curve of 0.788, effectively predicting overall survival in HCC patients undergoing combined lenvatinib and PD-1 inhibitor therapy.
Despite the valuable insights provided by our study, it is not without limitations. Firstly, as a retrospective study, selection bias is inevitable. Secondly, the research was conducted at a single center focusing on Chinese patients, and the sample size was limited. Therefore, a large-scale prospective study is necessary to validate the predictive efficacy of the CRAFITY score. Lastly, the absence of an external cohort limits the generalizability of our findings regarding the predictive value of the CRAFITY score in HCC patients treated with lenvatinib and PD-1 inhibitors.
CONCLUSION
The CRAFITY score has demonstrated its predictive value in HCC patients treated with lenvatinib in combination with PD-1 inhibitors, and has the potential to serve as a valuable tool for risk stratification and treatment guidance in this patient population. Further large-scale prospective studies are necessary to validate these results for broader clinical application.
ACKNOWLEDGEMENTS
We thank all participants for their efforts and contributions to this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade A, Grade B, Grade B
Novelty: Grade A, Grade A, Grade B, Grade B
Creativity or Innovation: Grade A, Grade A, Grade B, Grade B
Scientific Significance: Grade A, Grade A, Grade B, Grade B
P-Reviewer: Balbaa M; El-Bendary M S-Editor: Wei YF L-Editor: A P-Editor: Zhao S
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