Hepatocellular carcinoma (HCC) is a prevalent malignancy derived from liver cells and poses a tremendous threat to global health (1). Most patients are already in advanced stages when first diagnosed (2). Patients diagnosed with advanced HCC are not eligible for curative surgery. Systemic therapy is the main treatment for patients with advanced HCC. Recently, with the emergence of targeted agents and immune-based combination therapy, the systemic therapeutic options for HCC have expanded (2–5). Sorafenib, lenvatinib, and atezolizumab combined with bevacizumab have been recommended as first-line systemic therapies (6). However, there are several limitations. The clinical benefit varies widely among patients. Some patients have long-term benefits, while others develop primary resistance. Adverse reactions also limit the clinical application. There is an urgent need to find better biomarkers to assess the treatment response in the early stage.

Serum biomarkers are noninvasive, labor-saving, and inexpensive tools for disease prediction, diagnosis, and monitoring. Alpha-fetoprotein (AFP) is a glycoprotein that is widely used in HCC detection, screening, monitoring, and prognosis evaluation (7). Almost 70% of HCC patients show an elevated AFP level in their serum (8). Overexpression of baseline AFP is considered an indicator of poor oncological biology, burden, and survival (9).

In addition to the prognostic impact of baseline biomarker levels, the response of biomarkers to malignant tumors after treatment is increasingly recognized as an effective tool to assess treatment efficacy and predict tumor response (10). Previous studies of patients with HCC have demonstrated early AFP response in transcatheter arterial chemoembolization, chemotherapy, and radiotherapy (3, 11–29). However, due to the limited published data on AFP in newly developed immune-based combination therapy and targeted agents, a small number of studies have assessed the value of early AFP response in advanced HCC patients receiving systemic therapy.

The present study was performed with the aim of investigating whether an early AFP response is associated with systemic therapy in advanced HCC patients by utilizing a multicenter database. We aimed to provide clinicians with data on treatment efficacy monitoring and planning for decision-making.

With the therapeutic techniques constantly advancing, immune-based combination therapy and targeted agents have attracted increasing attention as effective systemic therapy methods. Further exploration of biomarkers associated with clinical efficacy and survival benefits is urgent. AFP is an available serum biomarker that is routinely used in clinical practice in many regions of the world for HCC. However, studies utilizing AFP to predict treatment efficacy and survival benefit in systemic treatment for advanced HCC are limited. Our study analyzed advanced HCC patients with high AFP levels receiving systemic therapy. The patients with early AFP response had significantly longer OS (P < 0.001) and PFS (P < 0.001). By performing multivariate analysis, early AFP response was confirmed as a prognostic factor for both OS and PFS. In the present study, we further verified the role of early AFP response in predicting prognosis for advanced HCC patients receiving systemic therapy, which is consistent with published studies (11, 12, 18, 27).

As a well-identified biomarker, early AFP response has demonstrated incomparable predictive value in both systemic and locoregional therapies for HCC patients. However, these studies assessed early AFP response using different criteria. It is difficult to make a widely recognized, accurate, and clinically significant definition of early AFP response. On the one hand, choosing an appropriate baseline AFP value is crucial for clinicians. Some studies analyzed patients with baseline AFP ≥ 40 ng/ml (30). Some studies chose 20 ng/ml as the baseline (12). This is because AFP is not distinctive and specific for cancer diagnosis: serum AFP may not demonstrate elevated levels in approximately 30-40% of HCC patients, and AFP fluctuations are seen not only in HCC but also in chronic liver diseases caused by cirrhosis or chronic viral hepatitis (7). To rule out the interfering factors mentioned above, our study excluded patients whose AFP levels were positive but low (20-200 ng/mL) and negative (< 20 ng/mL). We also strictly set the baseline AFP level (≥ 200 ng/ml) to ensure higher specificity. For the analysis, a relatively high baseline was chosen to capture real changes related to HCC and minimize the effects of background sources and hospital changes on different tests. On the other hand, selecting a precise time point to measure serum AFP levels is also crucial for clinicians. In a recent study, the first follow-up choice was 7 days after treatment (31). Some studies detected serum AFP levels at 90 days after treatment, and another study was performed at 180 days (32–34). These studies all drew a similar conclusion that early AFP response is independently related to the progression rate and overall survival rate after treatment of HCC. However, considering the half-life of AFP to be 5~7 days, 7 days seems too short, while 90 days or 180 days are too late to start early adjuvant treatments against progression. Therefore, in this analysis, the time period of 4-6 weeks after treatment was selected as the first follow-up.

In the present study, we found that there was a close correlation between early AFP response and imaging findings in most patients. The rates of ORR and DCR in the patients with early AFP response were significantly higher than those in the patients with no AFP response (38.4% vs. 11.8%, P = 0.001, and 76.8% vs. 54.1%, P = 0.003). Our results are consistent with many previous studies. Chan et al. reported on the correlation between AFP response and the achievement of imaging response (12). Another study reported that patients with AFP response versus no response had a significantly higher ORR (68.4% vs. 7.1%; P < 0.001) and DCR (84.2% vs. 36.0%; P = 0.009) (35). Early AFP response may be considered a supplement or alternative to RECIST v1.1 to systemic therapy for HCC.

For several years, circulating tumor cells, microRNAs or DNAs have been used to predict accurate prediction and early detection of tumor progression. However, sophisticated technology and expensive costs limit their applicability. High AFP secreted by tumor cells is a feature of HCC. Once the tumor has progressed after treatment, more AFP will be produced, and the serum AFP levels will be elevated. The present study provides further proof of this theory. Clinicians may consider changing treatment regimens when tumor progression occurs.

There are some limitations to the present study. First, as a retrospective study, it has its intrinsic defects. Second, in addition to tumor response, changes in AFP may also be affected by cirrhosis or chronic viral hepatitis. Although we set a stricter baseline AFP level (200 ng/ml) to minimize the effects of background sources, further studies with long-term follow-up are still needed. Third, the generalizability of the study might be restricted to the Chinese population since most HCC patients in the present study had a history of HBV infection and related diseases. In contrast, HCC cases in the United States and Europe are mainly caused by HCV infection and overconsumption of alcohol. The study needs to be verified in different populations.

In conclusion, the present study revealed that an early AFP response may be applied as an indicator to predict survival and surveillance progression in patients with advanced HCC receiving targeted agents or immune-based combination therapy. For HCC patients with high AFP levels, an early AFP response is a noninvasive and practical alternative endpoint to assess the long-term tumor prognosis of patients. If an AFP response is not reached in the first follow-up, it is necessary to actively consider strengthening the frequency of examinations or changing the treatment plan in time.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by The Institutional Review Board of the First Hospital of Jilin University. The patients/participants provided their written informed consent to participate in this study.

GH and BL contributed equally to this work. Study design: N-YW, GH, and CL. Data collection and acquisition: GH, BL, Z-QF, CL, J-PZ, R-YZ, YZ, HZ, and N-YW. Manuscript preparation: GH and BL. Critical revision: N-YW. Final approval of manuscript: All authors. All authors contributed to the article and approved the submitted version.