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For years, patients with early-stage hepatocellular carcinoma (HCC) who had multiple liver nodules were typically referred for less-invasive locoregional therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). The logic seemed sound: to avoid surgical trauma in people who often already have cirrhosis or limited liver function. Now, a new national multicenter meta-analysis suggests that, in carefully selected patients, this approach may need to be reconsidered.

Published in the Journal of Liver Cancer, the study pooled 15 studies and 2869 patients with multinodular HCC classified as early-stage HCC — a group of individuals with multiple nodules still classified as having early-stage disease. The analysis showed more favorable outcomes for liver resection in terms of overall survival and disease-free survival when compared with both RFA and TACE.

“This is a group that has always generated a lot of controversy because these are technically operable patients but historically directed toward less invasive methods,” surgical oncologist Felipe José Fernández Coimbra , MD, PhD, Hospital A. C. Camargo, São Paulo, Brazil, one of the authors of the study, told Medscape’s Portuguese edition. “Our goal was to critically review this gap and understand whether the accumulated data supported the automatic prioritization of nonsurgical treatments or not.”

The Patient Who Defies the Guidelines

In practice, this clinical profile often sparks multidisciplinary discussion. The tumor is still in an early stage, with no advanced disease or metastases, but the presence of multiple nodules traditionally dampens surgical enthusiasm. Added to this is the fact that many of these patients have chronic liver disease, especially cirrhosis resulting from viral hepatitis, alcohol consumption, or metabolic dysfunction-associated steatohepatitis.

In other words, it is not enough to remove the tumor. It is necessary to ensure that the remaining liver will support recovery. For this reason, international consensus has shifted to prioritizing strategies such as RFA, which destroys the tumor using image-guided heat, or TACE, which combines arterial embolization with intra-arterial chemotherapy. These are less invasive procedures that can be repeated and, in many cases, performed during a short hospital stay. The new study questions whether this preference continues to make sense in all cases.

What the Analysis Found

When comparing the available treatments, the authors observed a statistical advantage for surgery in two primary outcomes: overall survival and disease-free survival. In the comparison between liver resection and RFA, the analysis favored surgery both in overall survival (risk ratio [RR], 1.38; 95% CI, 1.03-1.84) as in disease-free survival (RR, 2.16; 95% CI,1.26-3.70). Compared to TACE, resection also showed an advantage in overall survival (RR, 2.11; 95% CI, 1.37-3.25) and disease-free survival (RR, 2.77; 95% CI, 1.04 -7.36).

For Coimbra, the biologically most plausible explanation lies in local tumor control, “When we perform resection, we remove the lesion and also assess the surgical margins. This tends to reduce residual tumor persistence and may explain part of the observed gain in disease-free survival.”

He emphasized, however, that the study does not propose indiscriminate surgery. “The message is not to operate on everyone. It is to recognize that this patient needs to be evaluated on an individual basis and that surgery may be underutilized in good candidates.”

Identifying the ‘Good Candidate’

For surgical oncologist Héber Salvador , MD, former president of the Brazilian Society of Surgical Oncology, the study’s main contribution is to put patient selection back at the center of the conversation. “For many years, multiple small nodules have functioned almost as an automatic veto against surgery. The study points out that this may be too simplistic, but the benefit is particularly evident in patients with good hepatic reserve, low portal pressure, preserved clinical status, and favorable anatomy for resection.”

In practice, this usually means patients in class A of the Child-Pugh score— a tool used to estimate liver function — without significant signs of portal hypertension, without decompensated ascites, and with sufficient remaining liver volume after surgery.

Peripheral lesions, for example, tend to facilitate smaller and safer resections. Central tumors, however — those near major vessels or those requiring extended hepatectomy — can completely alter the risk-benefit balance. “There is no single answer,” summarized Salvador. “There is a right patient for each strategy.”

The Impact of Surgical Advances

Part of the changing landscape stems from the very transformation of liver surgery. Procedures that once required large incisions, led to significant bleeding, and involved long recoveries can now be performed via laparoscopy or robotics in experienced centers.

This reduces the length of hospital stay, postoperative pain, and complications in many cases, while also expanding eligibility for some patients.

“When many of the old guidelines were created, liver surgery had a different risk profile,” noted Coimbra. “Current results also reflect safer surgery, better anesthesia, better intraoperative imaging, and better perioperative care.”

Salvador agrees but issues a warning: technological advancements are not distributed evenly. “Excellent results depend on volume, training, and an integrated team. It is not enough to simply have the technique. You need the infrastructure to consistently replicate it.”

The Brazilian Bottleneck

This caveat is particularly valid in Brazil. Although the country has public and private centers of excellence in oncologic liver surgery, access is unequal across regions and healthcare systems.

University hospitals, cancer hospitals, and large institutions concentrate multidisciplinary expertise, interventional radiology, specialized intensive care, and advanced anesthetic support. Outside these centers, availability can be irregular.

“When we talk about expanding surgical indications, we’re not just talking about a medical decision. We’re talking about installed capacity,” said Salvador. “Who performs the surgery, where it’s performed, with which team, and with what support — all of this affects the outcome.”

This point helps explain why percutaneous procedures remain so relevant: in many contexts, they are more feasible, can be repeated, and are less dependent on immediate high-complexity surgery.

Transplantation Remains on the Horizon

Another important aspect is that some of these patients may also be candidates for liver transplantation, a strategy that simultaneously treats both the cancer and the underlying liver disease. The problem is the shortage of organs and the waiting time. In scenarios with long waiting lists, treatments such as TACE, RFA, and, in selected cases, resection can serve as a bridge to transplantation or even as definitive treatment when transplantation is not feasible.

“In real life, the physician does not choose between perfect options,” noted Salvador. “He chooses between possible options within the time available for that patient.”

Not Every Statistical Gain Becomes a Clinical Rule

Although the results are consistent, the authors themselves acknowledge important limitations. Most of the studies included in the analysis were observational, which increases the risk for selection bias: operated patients tend to be healthier, have better liver function, and have technically more favorable tumors.

Additionally, different centers used distinct criteria to indicate surgery, ablation, or TACE, which makes an absolute comparison between groups difficult.

For Salvador, this methodological caution must accompany any practical interpretation. “The meta-analysis reinforces an important signal, but it does not replace clinical judgment or multidisciplinary discussion.”

What Might Change From Here On

Even without redefining clinical practices on its own, the study pushes future guidelines to move away from overly rigid algorithms.

Instead of “multiple nodules = no surgery,” the trend may shift toward more refined questions: What is liver function? What is the location of the tumors? What is the remaining liver volume? Does the center have expertise? Is transplantation a possibility? What is the patient’s preference?

At the end of the article, the authors advocate for a reassessment of current algorithms, at least in scenarios where transplantation is not an immediate option. For Coimbra, this is the real breakthrough. “If the study helps place surgery among the first options for suitable candidates, it will have already fulfilled an important role.”

Salvador sums it up in practical terms: “Multiple small tumors should not automatically rule out surgery. They should make room for a more thorough discussion.”

This story was translated from Medscape’s Portuguese edition.