Debating Issues in Frontline Treatment Approach for Advanced HCC

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WITH AN ESTIMATED 41,210 new cases and 29,380 deaths in the United States in 2023, hepatocellular carcinoma (HCC) is an uncommon but challenging tumor type to manage. Outcomes are significantly less favorable for distant-stage disease, which makes up 19% of cases and has a 3.5% 5-year relative survival compared with 37.3% for localized disease.¹

In localized disease, treatment includes surgical or locoregional therapies performed by surgeons and interventional radiologists. Medical oncologists only become involved when systemic therapies are needed for patients with advanced disease. Part of the challenge in effective management of the disease depends on multidisciplinary cooperation on decisions that are right for the patient. In the past several years, multiple effective systemic therapy regimens have been approved.

When patients present with suspected HCC, imaging and high α-fetoprotein (AFP) levels can lead to definite determination of HCC without need for a tissue biopsy of the liver, particularly in advanced disease where patients can be started on systemic therapy. However, there are considerations that can make a biopsy valuable. Other determinations such as esophagogastroduodenoscopy (EGD) can also inform treatment decisions.

In 2 separate Case-Based Roundtable events, oncologists discussed the case of a patient with a past medical history of hepatitis B infection who had an AFP level of 375 IU/mL, grade 1 hepatic encephalopathy, and mild ascites. Imaging revealed 2 lesions in the left hepatic lobe (1.8 cm and 5.2 cm) with clear vascular involvement but no extrahepatic disease and no portal hypertension. The physicians discussed whether a liver biopsy would beappropriate and what factors would influence their choice of frontline HCC therapy.

IS A BIOPSY NEEDED?

A liver biopsy can serve a diagnostic purpose in patients with HCC if imaging is inconclusive. It could also be important in cases where patients have mixed histology of HCC and intrahepatic cholangiocarcinoma. However, patients at high risk for HCC whose imaging reveals definite lesions of LI-RADS [Liver Imaging Reporting & Data System] category 5 can receive a diagnosis of HCC without need for a diagnostic biopsy.

Biopsy tissue serves another role because it can be used for molecular testing. Actionable mutations that could influence choice of frontline HCC management are very rare, primarily supporting tumor-agnostic treatments such as targeted inhibitors for NTRK alterations and immune checkpoint inhibitors for mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) disease. NTRK fusions can be found in 2% or fewer patients and dMMR/MSI-H in 0% to 2.9% of patients with HCC.^2,3 Furthermore, treatments based on molecular testing would only be recommended after progression on frontline therapy, so testing would not be needed immediately.

In the event moderated by Pierre Gholam, MD, some physicians supported performing a biopsy for patients with HCC, saying that it was valuable to rule out other histology in cases where imaging was unclear and that next-generation sequencing (NGS) might guide later lines of treatment and access to clinical trials. Gholam, an associate professor at Case Western Reserve University School of Medicine in Cleveland, Ohio, was skeptical of recommending a biopsy up front for the hypothetical patient in the case.

“If we do find a [patient with] MSI-H HCC, that is going to be [an] occurrence that happens rarely. It’s happened to me once in my entire career,” Gholam said. Other participants agreed, saying that if the radiologist was confident that the patient had malignant HCC based on LI-RADS, performing NGS wouldn’t be needed yet because treatment remains the same regardless of the findings.

The moderator of the other event, Angela T. Alistair, MD, said she has seen debates in tumor boards on this issue, because NGS for targeted mutations is useful at some point but biopsy is not mandatory in the front line. She noted that biopsy plays a larger role in patients without cirrhosis and atypical radiological observations.

Alistair, medical director of gastrointestinal medical oncology at Morristown Medical Center in New Jersey, acknowledged the low probability of actionable NGS results but stressed their increasing role. “NTRK [fusion] is only present in 2% of solid tumors, but as you can see, we keep coming up with new, small slices of molecular subtypes for all tumor types,” she pointed out. “Especially for clinical trials, I feel strongly about understanding the genomic profile of a patient.” Although not relevant to the case patient with advanced disease, Alistair reminded participants that a biopsy is also inappropriate for very early-stage disease because it could make patients ineligible for liver transplant.

STARTING AN HCC MANAGEMENT PLAN

Recommended frontline systemic HCC regimens include the combinations of atezolizumab (Tecentriq) and bevacizumab (Avastin), durvalumab (Imfinzi) and tremelimumab (Imjudo), sorafenib (Nexavar), and lenvatinib (Lenvima).⁴ The participants discussed the use of these therapies and how they are affected by factors such as tumor burden and Child-Pugh status as well as comorbidities. Marc Braunstein, MD, PhD, of New York University Langone Healthcare in New York, said in Alistair’s event that because patients with Child-Pugh class B and C were excluded from clinical trials, predicting beneficial outcomes when treating these patients is more challenging.

The National Comprehensive Cancer Network (NCCN) recommends these regimens primarily for those with Child-Pugh class A. Alistair said that in her experience, fewer patients qualify as Child-Pugh class A at their first oncologist appointment because of characteristics such as elevated albumin levels. Treatment and supportive care can improve a patient’s Child-Pugh classification.

“If they don’t have overwhelming tumor burden in the liver and they don’t have overwhelming liver cirrhosis, I will choose to sometimes treat a patient with Child-Pugh [class] B with immunotherapy with either of the combinations,” Alistair explained. She suggested she would favor the dual immunotherapy combination of durvalumab/tremelimumab if they have cirrhosis because of the likelihood of main portal vein invasion or varices. Alistair said she would “draw the line” at treating a patient with Child-Pugh class C because these patients are unlikely to improve to Child-Pugh class B even with best supportive care. However, she acknowledged that she would have a difficult time deciding not to treat a younger fit patient with Child-Pugh class C.

Participants in both events discussed the potential for resection or locoregional therapies being an option in patients with advanced disease. Bruce I. Kappel, MD, of Northwell Health in New York, said in Alistair’s event that he would continue to receive input from a surgical oncologist when deciding on how to treat a patient. Alistair agreed that this is a multidisciplinary disease and if a particular lesion does not respond to systemic therapy, presenting at a tumor board to discuss locoregional treatment would be a valid decision.

CONTRAINDICATIONS INFLUENCE SYSTEMIC THERAPY CHOICE

Atezolizumab plus bevacizumab demonstrated superior efficacy vs sorafenib in the IMbrave150 trial (NCT03434379) and is a preferred frontline regimen by the NCCN.⁴ However, bevacizumab comes with a risk of hemorrhage, and trials excluded patients with recent variceal bleeding, leading to a recommendation that patients be evaluated for varices within 6 months before treatment.⁵ It may also lead to arterial and venous thromboembolic events.

Gholam clarified that based on the IMbrave150 data, which included patients with main portal vein invasion, bevacizumab is safe to use in patients with vascular involvement. “In most patients, you’re not really worried about a venous thromboembolic event. This is progression of the tumor into the vasculature, so it’s not the same as the patient who has a significant deep vein thrombosis, pulmonary embolism, etc,” Michael R. Costello, MD, medical director of The Abramson Cancer Center at Chester County Hospital in Pennsylvania, said. “I wouldn’t see a contraindication to the use of bevacizumab.”

In Gholam’s event, Ike Onwere, MD, of the Armes Family Cancer Care Center in Ohio, said he would require an EGD out of concern for variceal bleeding before using atezolizumab plus bevacizumab but not before using the tyrosine kinase inhibitors (TKIs) sorafenib or lenvatinib.

Alistair asked her group about referring patients to a gastroenterologist for an EGD before starting treatment. Kevin Sing, MD, of New York Cancer & Blood Specialists, said he consults right away and would prefer an EGD to be done within 2 to 3 weeks, although this time frame is challenging. “I know this is pushing quite a bit, but we have worked with gastroenterologist groups who have been able to get [patients] in, because this is an urgent thing that they can accomplish in that short time frame,” he said. If an EGD could not be done quickly enough, he said he would consider the immunotherapy combination of durvalumab and tremelimumab instead of waiting.

Aqeel A. Gillani, MD, of Glens Falls Hospital in New York, also said he tries to get a gastroenterologist consultation immediately for this reason, and if a patient does not have other comorbidities, he would use atezolizumab/bevacizumab. Alistair agreed it is valuable to have the EGD results available up front, even if varices are not expected, to give patients an informed choice of frontline options.

In Gholam’s event, Baidehi Maiti, MD, PhD, of the Cleveland Clinic in Ohio, said she would consider the patient’s logistics such as difficulty traveling. In patients with this challenge, she would lean toward an all-oral regimen such as lenvatinib or sorafenib. She said she would probably choose lenvatinib over sorafenib. Timothy D. Moore, MD, of the Zangmeister Cancer Center in Ohio, concurred, describing lenvatinib as a “cleaner” TKI in terms of its VEGF targeting. Jose S. Silva, MD, of WellSpan Chambersburg Hospital in Pennsylvania, noted that he would avoid a TKI in a patient with congestive heart failure.

Gholam asked his group about using immunotherapy for patients with autoimmune conditions. Gabor Varadi, MD, of Einstein Medical Center Philadelphia in Pennsylvania, said he has treated a patient with psoriasis successfully in cooperation with a dermatologist. Alexander Barsouk, MD, of Allegheny Valley Hospital in Pennsylvania, said he would be concerned about skin toxicities in such a patient; he and others agreed they would not use immunotherapy in a patient with autoimmune hepatitis or another disease such as lupus. Moore said he would not use durvalumab/tremelimumab in a patient with a serious autoimmune disease but might consider atezolizumab/bevacizumab in a patient with a less challenging condition.

“We all have become more comfortable with using immunotherapy even for patients who have autoimmune diseases,” Alistair said. “Obviously, those have to be well controlled and not expected to have a severe flair. As a clinician, I moved from ruling out patients with rheumatoid arthritis 5 to 10 years ago to including them and collaborating closely with the rheumatologist, for example.”

CONCLUSION

The growing selection of frontline agents means physicians can tailor treatment to the appropriate patient with advanced HCC. Because outcomes are still poor for these patients, new regimens are a major unmet need, as are effective treatments in recurrent disease. Although molecular testing has yielded actionable results for only a fraction of patients, continued clinical trials could give options to more patients as new targets are developed.

Multidisciplinary coordination is vital in HCC because different specialties need to be aware of emerging options. As an example, Alistair said that surgical oncologists are consulting her more as they grow more aware of the potential to use systemic therapy to shrink larger liver tumors to resectable status. “We have to continue to educate our partners on the response rates and our experiences with the patients on systemic treatments,” she observed.

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