AJCC stage loses prognostic power over time in hepatocellular carcinoma, SEER analysis finds

The prognostic weight of AJCC tumor stage in hepatocellular carcinoma (HCC) fades as patients survive longer, according to a population-based conditional survival analysis published in Discover Oncology. The study, based on 21,492 HCC patients diagnosed between 2004 and 2022 in the Surveillance, Epidemiology, and End Results (SEER) database, classified tumors according to the AJCC seventh edition and tracked how the association between stage and survival changed over the first five years after diagnosis.

The researchers used time-varying Cox models with restricted cubic splines and landmark analyses to evaluate overall survival (OS) and net cancer-specific survival (CSS) at years 0 through 5. Primary models adjusted for age, sex, race, and area-level income. Competing risk and sensitivity analyses were also performed, and prediction models underwent internal validation using a random 7:3 split, with assessment of discrimination, calibration, and exploratory decision curves.

The central finding was that stage-associated hazard ratios attenuated over time. Adjusted hazard ratios for stages III and IV versus stage I decreased by year 5, although stage IV remained associated with higher mortality. The most striking illustration came from five-year conditional OS for stage IV disease: this estimate rose from 3.6 percent (95% CI 3.0–4.4 percent) at baseline to 47.5 percent (33.9–59.9 percent) among patients who had already survived five years after diagnosis.

Conditional survival, the approach used here, re-estimates survival prospects by conditioning on the time a patient has already lived beyond diagnosis. Rather than relying on the survival curve fixed at the moment of diagnosis, it updates risk as elapsed survival accumulates. In this dataset, the discriminative performance of the models at the year-5 landmark was modest: AUCs ranged from 0.625 to 0.694 for overall survival and from 0.623 to 0.703 for cancer-specific survival. Mean predicted mortality risks were close to, but slightly lower than, the observed risks.

To make the estimates usable in practice, the authors developed a web-based conditional survival calculator. The study’s conclusions, however, are framed cautiously: while a higher initial AJCC stage is associated with greater early mortality, its prognostic influence wanes over time, and conditional survival estimates may support real-time risk reassessment by incorporating time already survived. The authors state that external validation is required before these models can guide clinical decisions.

Several limitations follow from the design. The analysis is retrospective and observational, drawing on a single population-based registry, and the models were validated internally rather than in an independent cohort. The reported AUCs indicate moderate discrimination, and the calibration showed slight underprediction of observed risk. The findings therefore describe statistical associations in SEER data rather than established clinical guidance, and the authors explicitly flag the need for external validation before any clinical application.

Within those limits, the study adds quantitative detail to a known pattern: the prognostic separation created by AJCC staging is strongest early after diagnosis and narrows among longer-term survivors. For patients with advanced-stage HCC who have survived several years, the conditional estimates reported here suggest that initial stage alone conveys less information about subsequent mortality than it does at the time of diagnosis.

Subject of Research: Time-varying prognostic impact of AJCC staging on survival in hepatocellular carcinoma using conditional survival analysis of SEER data

Article Title: Time-varying prognostic impact of AJCC staging on overall survival and cancer-specific survival in hepatocellular carcinoma: a conditional survival analysis using population-based data

Article References: Wu, J., Lv, H., Yang, X., & Chen, Y. (2026). Time-varying prognostic impact of AJCC staging on overall survival and cancer-specific survival in hepatocellular carcinoma: a conditional survival analysis using population-based data. Discover Oncology. https://doi.org/10.1007/s12672-026-06183-7

Image Credits: AI Generated

DOI: 10.1007/s12672-026-06183-7

Keywords: hepatocellular carcinoma, AJCC staging, conditional survival, overall survival, cancer-specific survival, SEER database, time-varying Cox models, prognosis, hazard ratio, survival prediction, population-based study, Time-varying