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Editorial: redrawing the boundaries for surgical intervention in hepatocellular carcinoma

alpha‐2‐macroglobulin was specifically chosen to be used in the multivariate analysis to take into account this ‘fibrosis factor’. The very early prognostic values of low apoA1 and low haptoglobin were much higher in patients without cirrhosis as shown in Table S3 and much more significant at 10 years than at 5 years; both these elements do not support the statement that LCR1 is a surrogate marker of fibrosis severity. As stated in the article, there is now accumulating evidence to support the prognostic value of apoA1, haptoglobin and GGT as ‘surrogate markers of hepatoprotective capacity or liver cell repair’ independent of any other possible diagnostic value for fibrosis. The second issue was that ‘the authors do not report the direct comparison to other non‐invasive fibrosis scoring systems which is crucial information to make its way into practice.’ We feel that because of the resources needed for this type of validation, the field of diagnostics should function like therapeutics, and a new test should be compared to the recognised comparator, and not to the competitors. When we began this prospective cohort, US guidelines were already ‘to identify cirrhosis in chronic liver disease by biopsy or validated non‐invasive biomarker, and to follow these cases with cirrhosis with or without AFP’. We applied these guidelines as our comparator in patients with cirrhosis. There is no standard comparator in patients without cirrhosis. Therefore, although our tests are not perfect, our results in patients without cirrhosis show that patients at high risk could be identified 10 years before the cancer and suggest that they should be monitored with the same surveillance protocol as those with cirrhosis. The third issue was the comparison to other tests for the diagnosis of contemporaneous hepatocellular carcinoma. Our long‐term prospective cohort was designed to look for incident cancers, not for contemporaneous cancers. The performances are always greater for contemporaneous than for incident cancers, as we observed in the article. For the diagnosis of 121 contemporaneous cancers, the AUROC of LCR2 (0.905) was higher (P < 0.001) than that of AFP (0.796; 0.741‐0.840) (Table S9). The fourth comment was that ‘dynamic changes in biomarkers show promise for HCC detection’. We repeated LCR1 measurements in 3931 patients, 3.6 years after inclusion. Three cancers occurred in the 245 cases with improved LCR1 (1.2%) vs 140 (3.6%) in the 3646 without improvement (P = 0.03). In 1856 patients with 4‐year repeated measurement of LCR1‐LCR2, the AUROCs remained both significant, 0.821 and 0.837, and higher than repeated AFP (0.706) (Table S10b). Finally, we fully agree that independent external validations are needed.