New clinical guidelines published by the American Society for Radiation Oncology (ASTRO) offer recommendations on the use of radiation therapy to treat adult patients with primary liver cancers using external beam radiation therapy (EBRT).

Most commonly diagnosed
The evidence-based recommendations, developed a team of radiation, medical and surgical oncologists, medical physicists, a hepatologist, a transplant surgeon, and a radiation oncology resident, in collaboration with the American Society of Clinical Oncology, the American Society of Transplant Surgeons, and the Society of Surgical Oncology, are intended as tools to promote appropriately individualized, shared decision-making between physicians and patients and are based on a systematic literature review of peer-reviewed articles published from January 2000 through February 2020.

Left: Higinia Cardenes, MD, Ph.D., chair of the guideline task force and a professor of clinical radiation oncology at Weill Cornell Medicine in New York. Right: Smith Apisarnthanarax, MD, vice-chair of the guideline task force, medical director of the Seattle Cancer Care Alliance, and professor of radiation oncology at the University of Washington in Seattle.

They outline indications and optimal EBRT dosing, techniques, and treatment planning for patients with hepatocellular carcinoma (HCC), considered the most common form of liver cancer, and intrahepatic cholangiocarcinoma (IHC), with a strong emphasis on multidisciplinary care. The guideline, ASTRO’s first for primary liver cancers, is published in Practical Radiation Oncology.[1]

Primary liver cancer is the fourth leading cause of cancer death worldwide. According to the American Cancer Society, incidence rates in the United States have more than tripled since 1980, rising approximately 2% each year in the last two decades, leading to an estimated 42,230 new cases diagnosed in 2021.[2]

Mortality rates from HCC and IHC also continue to rise despite the growing availability of screening for HCC and improved prevention and/or treatment of diseases that may lead to the development of liver cancer, including, hepatitis B, hepatitis C, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH, inflamed liver). About 30,520 people will die of these cancers.[2]

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Cirrhosis and transplantation
Roughly 90% of patients with HCC also have cirrhosis, which occurs when an underlying liver disease leads to scarring and permanent liver damage and is the strongest risk factor for liver cancer. People with unresectable HCC have tumors in their liver that cannot be safely removed with surgery, either due to the severity of underlying cirrhosis or other clinical factors.

For patients with localized liver cancer and advanced cirrhosis, liver transplantation is the best and only chance for long-term survival. However, the supply of organs available for transplant is limited, and candidates often wait months or more than a year to get a new liver. In addition, if a patient’s cancer spreads outside of transplantable size criteria or to another part of the body while they are waiting for a new liver, they are no longer eligible for transplant. Many patients, therefore, receive liver-directed bridging therapy, which is a treatment to prevent the growth or spread of tumors during the waiting period.

Liver-directed treatment options for patients awaiting transplant include:

  • Thermal ablation procedures, which use advanced imaging technology to guide probes through the skin and into the liver, to burn or freeze tumors at the site; catheter-based treatments including
  • Transarterial chemoembolization (TACE) and
  • Y-90 radioembolization, where small particles are injected selectively into an artery directly supplying the tumor that cut off a tumor’s blood supply and trap chemotherapy drugs or radioactive substances within the tumor; and
  • External-beam radiation therapy (EBRT), which aims high doses of targeted radiation at tumor sites from outside the body using non-invasive techniques.
Figure 1.0 ASTRO Treatment algorithm.

A multidisciplinary approach
Multidisciplinary involvement is particularly important for primary liver cancer treatment, due to complexities in diagnosis and staging, the availability of a wide range of treatment options, and a need to consider medical comorbidities such as underlying cirrhosis, which is present in roughly 90% of patients with HCC.

Common treatment options for primary HCC include liver transplantation, surgical removal of the tumor, thermal ablation and catheter-based therapies for patients whose disease is confined to the liver, and systemic therapy (targeted therapy and/or immunotherapy) for those whose disease is more advanced. For IHC, standard treatment includes a combination of surgery and chemotherapy, with or without radiation.

EBRT, which aims high doses of targeted radiation at tumor sites from outside the body with non-invasive techniques, has historically been used less frequently than other approaches.

For example, finding from a recent study presented during the 2021 annual meeting of the American Society for Radiation Oncology (ASTRO) found that less than 4% of eligible patients received EBRT as a bridging therapy before liver transplant.

Figure 2.0: ASTRO Treatment algorithm.

The data presented was based on an analysis of data from the United Network for Organ Sharing (UNOS), a non-profit organization that operates the United States transplant system under contract with the federal government, to see which bridging therapies were prescribed most often. Of the 18,477 patients with HCC awaiting transplant since 2013, 85.4% received some type of bridging therapy. However, just 3.6% of those patients were treated with EBRT, either alone (1.2%) or in combination with another type of therapy (2.4%).

“Historically, low utilization rates for external beam radiation were due to technological limitations that made it challenging to avoid healthy liver tissue,” explained Higinia Cardenes, MD, Ph.D., chair of the guideline task force and a professor of clinical radiation oncology at Weill Cornell Medicine in New York.

“However, with significant advances in imaging and radiation treatment delivery over the past 15 years and improved understanding of how the liver responds to radiation, we now have an increasing amount of clinical data on the role that EBRT can play for patients with these diseases,” Cardenes added.

Figure 3.0: ASTRO Treatment algorithm.

“Patients diagnosed with liver cancer often have a number of treatment options available to them, and they should be presented with each of them before a treatment course is decided,” said Smith Apisarnthanarax, MD, vice-chair of the guideline task force, medical director of the Seattle Cancer Care Alliance and professor of radiation oncology at the University of Washington in Seattle.

“The different disciplines — hepatology, surgical oncology, interventional radiology, and radiation oncology — should all be involved in multidisciplinary treatment discussions to determine what might be best for each patient,” Apisarnthanarax, further noted.

“We feel that this guideline is an important milestone in the management of primary liver cancers, as we hope to provide practitioners and the public with a systematic and evidence-based foundation of where EBRT might fit into the overall complex picture of treating these challenging cases,” he concluded.

Figure 4.0: ASTRO Treatment algorithm.

What do the guidelines recommend?
Recommendations in the guideline address patient selection, as well as planning and delivery techniques for EBRT in a range of clinical situations, including definitive/non-transplant, consolidative, salvage, pre-operative (including bridge-to-transplant), post-operative, and palliative treatment settings. With an emphasis on multidisciplinary discussion and planning, key recommendations are as follows:

  • EBRT is strongly recommended (a) as a potential first-line treatment for patients with HCC confined to the liver who are not candidates for curative therapy; (b) as a consolidative therapy for patients with incomplete responses to other liver-directed treatments; and (c) as a salvage therapy option for patients with local recurrences after other treatment.
  • EBRT is conditionally recommended for (a) patients with multifocal or unresectable HCC confined to the liver, or (b) patients with macrovascular invasion when sequenced with systemic or catheter-based therapies. The guideline includes treatment algorithms for the management of HCC that is confined to the liver (Figure 1.0) and HCC with macrovascular invasion (Figure 2.0).
  • EBRT is conditionally recommended in the palliative setting for symptomatic primary HCC and/or HCC that has invaded a blood vessel. It also is conditionally recommended as a bridging therapy prior to liver transplant or before surgery in carefully selected patients.
  • For patients with unresectable IHC, EBRT with or without chemotherapy should be considered, typically after systemic therapy. For patients with resected IHC and high-risk features, adjuvant EBRT is conditionally recommended. The guideline includes treatment algorithms for unresectable (Figure 3.0) and resectable (Figure 4.0) IHC.
  • The guideline also addresses optimal dosing, fractionation, treatment planning and delivery techniques for EBRT, emphasizing that therapy should be based on individual factors including the extent and location of cancer, underlying liver function, and available treatment technologies.

[1] Apisarnthanarax S, Barry A, Cao M, Czito B, DeMatteo R, Drinane M, Hallemeier CL, Koay EJ, Lasley F, Meyer J, Owen D, Pursley J, Schaub SK, Smith G, Venepalli NK, Zibari G, Cardenes H. External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2022 Jan-Feb;12(1):28-51. doi: 10.1016/j.prro.2021.09.004. Epub 2021 Oct 21. PMID: 34688956.
[2] About liver cancer. Key Statistics About Liver Cancer. American Cancer Society. Online. Last accessed on January 12, 2022.

Featured image: Low magnification micrograph of hepatocellular carcinoma the most common form of primary liver cancer. Features on image: End-stage cirrhosis – blue collagen (fibrosis); Mallory bodies; Loss of normal liver architecture; Nuclear atypia.

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