Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score

J Hepatol. 2022 Feb;76(2):353-363. doi: 10.1016/j.jhep.2021.09.035. Epub 2021 Oct 12.


Background & aims: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need.

Methods: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204).

Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response.

Conclusions: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation.

Lay summary: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

Keywords: C-reactive protein; alpha-fetoprotein; immune checkpoint inhibitor; liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / physiopathology
  • Female
  • Germany
  • Humans
  • Immunotherapy / methods
  • Immunotherapy / statistics & numerical data
  • Italy
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / physiopathology
  • Male
  • Middle Aged
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies
  • Sorafenib / pharmacology
  • Sorafenib / therapeutic use
  • Switzerland
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Antineoplastic Agents, Immunological
  • Bevacizumab
  • atezolizumab
  • Sorafenib