Hepatocellular carcinoma, or HCC, is the most common primary cancer arising in the liver. When tumors cannot be surgically removed, treatment becomes substantially more difficult because the disease may involve major blood vessels, occupy large portions of the liver or have spread beyond the organ. One approach is transarterial chemoembolization, known as TACE, in which physicians guide a catheter through the blood vessels to arteries feeding a tumor. Chemotherapy is delivered locally, while embolic material blocks the tumor’s blood supply. The procedure can expose cancer cells to high drug concentrations and deprive them of oxygen, but it does not always eliminate all malignant tissue.

The other components of the combination attack the disease through different biological pathways. Lenvatinib is a tyrosine kinase inhibitor that blocks signaling proteins involved in blood-vessel formation and tumor growth. HCC tumors often stimulate the development of new vessels to secure oxygen and nutrients; inhibiting pathways involving vascular endothelial growth factor receptors can restrict that support. PD-1 inhibitors work through the immune system. PD-1 is a checkpoint protein on immune cells that can be exploited by tumors to suppress T-cell activity. Blocking the PD-1 pathway may restore part of the immune response against cancer. In principle, TACE can release tumor antigens and alter the tumor environment, lenvatinib can restrain angiogenesis, and immunotherapy can mobilize immune cells against remaining cancer cells.

Although this three-part treatment, abbreviated T-L-P by the researchers, has shown encouraging activity, its effects vary considerably from one patient to another. Some patients experience substantial tumor shrinkage and prolonged disease control, while others progress despite treatment. Clinicians therefore need practical ways to identify likely responders and recognize patients whose disease or underlying liver dysfunction may limit the benefit. The research team, led by Pengpeng Zhu and Kaile Tian, examined medical records from patients who began T-L-P therapy between 2020 and 2022. The investigators randomly or administratively divided the study population into a training cohort of 90 patients, used to develop the model, and a validation cohort of 64 patients, used to test whether it retained its predictive value.

The researchers first assessed objective response rate, or ORR, which measures the proportion of patients whose tumors met predefined criteria for complete or partial shrinkage. They also examined disease control rate, which includes responses as well as stable disease. In the training cohort, 44 of 90 patients, or 48.9 percent, achieved an objective response, while 72 patients, or 80 percent, achieved disease control. In the validation cohort, the corresponding figures were 38 of 64 patients, or 59.4 percent, for objective response and 52 patients, or 81.3 percent, for disease control. These results describe outcomes in the selected study population and should not be interpreted as proof that the treatment will produce the same response rates in every clinical setting.

Statistical analysis identified three independent factors associated with objective response. The first was an alpha-fetoprotein concentration above 100 nanograms per milliliter. AFP is a protein produced during fetal development that can reappear at high levels in some people with HCC, although it is neither present in every case nor specific to this cancer. The second factor was a tumor burden score above 8. TBS combines tumor size and number into a single measure, generally increasing as tumors become larger or more numerous. The third was Child-Pugh class B liver function, a category indicating more substantial impairment than class A. The Child-Pugh system incorporates measures such as bilirubin, albumin, blood clotting, fluid accumulation and encephalopathy to estimate the liver’s functional reserve.

Each of these features was assigned one point in the ATC score, producing a range from zero to three. The name reflects the principal variables used in the model: AFP, tumor burden and Child-Pugh classification. Patients with no risk factors had a score of zero and were designated low risk; those with one factor had an intermediate-risk score of one; and those with two or three factors were placed in the high-risk group. The score is not a molecular test and does not directly measure immune activity, drug concentration or genetic mutations. Instead, it combines readily available indicators of tumor biology and the liver’s ability to withstand both cancer and treatment.

The differences between the groups were striking. In the training cohort, the estimated two-year overall survival rate was 83.57 percent for patients with an ATC score of zero, 64.13 percent for those scoring one and 20.69 percent for those scoring at least two. Two-year progression-free survival, which measures the length of time before the cancer worsens or the patient dies, was 66.48 percent, 46.55 percent and 9.33 percent in the same groups. The validation cohort showed a similar pattern: two-year overall survival was 94.12 percent for score zero, 64.71 percent for score one and 25.93 percent for scores of two or three. Two-year progression-free survival was 82.35 percent, 47.06 percent and 16.67 percent, respectively.

To evaluate discrimination, the investigators used the area under the receiver operating characteristic curve, or AUC. This statistic summarizes how well a model distinguishes between patients who do and do not experience an outcome, with a value of 0.5 representing chance performance and values closer to 1 indicating stronger discrimination. The ATC score achieved an AUC of 0.826 in the training cohort and 0.811 in the validation cohort. According to the study, this performance was better than that of any individual component alone. The validation result is particularly important because a model can appear highly accurate in the same data used to build it but lose performance in a separate group.

The researchers say the score could support treatment planning by providing an early estimate of expected benefit from T-L-P therapy. A patient with a low score might be considered a strong candidate for continuing an intensive combination approach, assuming treatment is otherwise safe and appropriate. A high score could prompt closer monitoring, more detailed discussion of alternatives or consideration of clinical trials designed for patients with difficult-to-treat disease. The model might also help researchers balance participants across risk categories in future studies, making it easier to determine whether a new therapy helps patients with poor baseline prognoses rather than simply reflecting differences between trial populations.

The results nevertheless come with important limitations. The study was retrospective, meaning the investigators analyzed existing records rather than assigning treatment prospectively under a controlled protocol. All 154 patients received the same general treatment combination, but unmeasured differences in disease characteristics, supportive care or clinical decision-making could have influenced the outcomes. The sample was also relatively small and drawn from institutions in China, so the model requires testing in larger, geographically diverse populations before it can be considered broadly reliable. In addition, a score that predicts response at the group level cannot determine an individual patient’s fate. Some people with high scores may respond exceptionally well, while some with low scores may not benefit.

The findings add to a growing effort to make combination therapy for advanced liver cancer more precise. TACE, targeted therapy and immune checkpoint blockade each affect a different part of the tumor ecosystem, but the same complexity that creates therapeutic potential also makes outcomes difficult to anticipate. The ATC score offers a deliberately simple framework built from clinical information already collected in routine care. Its next test will be prospective validation: researchers will need to apply the score before treatment begins, follow patients under standardized conditions and determine whether it improves decisions rather than merely describing prognosis. Until then, the model is best viewed as a promising research tool—one that could help clinicians move closer to matching the right treatment intensity to the biology of an individual patient.

HCC is a particularly complex cancer because treatment decisions are shaped not only by the size and number of tumors, but also by liver function, cirrhosis, vascular invasion, tumor biology and the patient’s overall health. These variables determine whether a tumor can be removed surgically, treated locally, targeted with radiation or managed with drugs that circulate throughout the body. BEACON-HCC brings these factors together in a clinical framework intended to reflect the way multidisciplinary liver cancer teams increasingly make decisions.

For nearly three decades, many physicians have used the Barcelona Clinic Liver Cancer, or BCLC, system to classify HCC and recommend treatment. According to Mark Yarchoan, M.D., an associate professor of oncology at the Johns Hopkins University School of Medicine and a BEACON-HCC co-author, the therapeutic landscape has changed substantially since the BCLC system was developed. New radiation techniques, catheter-based treatments and immune-based drug combinations have expanded the options available to patients, sometimes creating a gap between formal staging recommendations and the treatments offered at specialized centers.

One important difference concerns tumors that have invaded blood vessels. Under traditional staging approaches, vascular invasion often places a patient in an advanced disease category for which systemic therapy alone is recommended. However, Yarchoan said that vascular invasion does not always eliminate the possibility of remission or aggressive local treatment. In a prospective clinical trial at Johns Hopkins, selected patients with vascular invasion underwent potentially curative surgical resection, suggesting that some individuals classified as having advanced disease may still benefit from carefully chosen interventions aimed at eliminating the tumor.

Radiation therapy is another area in which clinical practice has evolved. Earlier versions of the BCLC framework gave external beam radiation therapy a limited role, but newer clinical evidence supports its use in selected patients as either a primary treatment or part of a combined strategy. External beam radiation uses high-energy photons or other radiation beams to damage the DNA of cancer cells, preventing them from dividing and eventually causing tumor cell death. Modern image-guided techniques can focus radiation on liver tumors while reducing exposure to surrounding healthy tissue.

BEACON-HCC also incorporates transarterial radioembolization, a minimally invasive procedure that exploits the liver’s distinctive blood supply. Liver tumors receive much of their blood from the hepatic artery, while healthy liver tissue is supplied predominantly by the portal vein. During radioembolization, physicians guide a catheter into arteries feeding the tumor and release tiny radioactive particles, often called microspheres. The particles become lodged near the cancer and deliver radiation from inside the tumor, allowing treatment to be concentrated in the diseased tissue.

Systemic therapies are included as another major component of the framework. These treatments can include immune checkpoint inhibitors, which help restore the immune system’s ability to recognize and attack cancer cells, as well as targeted drugs that interfere with signaling pathways involved in tumor growth and blood-vessel formation. Combination regimens may work throughout the body while also being paired with surgery, radiation or catheter-based procedures. The framework is intended to accommodate these evolving combinations rather than restrict patients to a single treatment category.

The 20 authors evaluated BEACON-HCC using 29 de-identified patient cases collected from their institutions. Each case included clinical information and tumor imaging. The authors independently selected an initial treatment approach from options including surgical resection, liver transplantation and other locoregional or systemic therapies. The same cases were also reviewed by 18 North American HCC specialists who had not participated in developing the framework. Across the cases, the experts’ recommendations matched BEACON-HCC in 96.6% of decisions, compared with 72.4% agreement with the BCLC 2025 recommendations.

The authors emphasize that BEACON-HCC is not intended to replace clinical judgment or function as a rigid algorithm. Instead, it provides a structure for tumor boards and multidisciplinary clinics, where hepatologists, oncologists, surgeons, interventional radiologists and radiation oncologists weigh competing risks and benefits. Jeffrey Meyer, M.D., an associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins, said the framework recognizes both the expanding range of available treatments and the unresolved questions surrounding their optimal use.

The need for more flexible treatment guidance is underscored by the continuing burden of HCC. It is the third-leading cause of cancer-related death worldwide and the leading cause of cancer-related death among patients with cirrhosis. Despite advances in screening and therapy, five-year survival remains below 25%. The BEACON-HCC authors say the framework will need to evolve as new systemic drugs, radiation technologies and liver-directed procedures enter clinical practice, but they hope it will help clinicians make more individualized decisions in a disease where no single factor reliably determines the best treatment.

Subject of Research: Hepatocellular carcinoma treatment and clinical decision-making

Article Title: Johns Hopkins Liver Cancer Experts Co-Author New Treatment Framework for Hepatocellular Carcinoma

News Publication Date: Aug. 7 (year not specified)

Web References: Johns Hopkins Medicine news release; Hepatology journal publication on BEACON-HCC

References: HCC-LIVE consortium, “BEACON-HCC” treatment framework, Hepatology

Image Credits: Johns Hopkins Medicine

Keywords: hepatocellular carcinoma, HCC, liver cancer, BEACON-HCC, BCLC, radiation therapy, radioembolization, immunotherapy, vascular invasion, multidisciplinary cancer care