Many patients with primary liver cancer could benefit from combination therapies that include radiation, but the central location of the liver requires exceptionally precise delivery of that radiation to avoid damaging healthy liver tissue or the adjacent organs. Innovative techniques enable the safe delivery of high doses of radiation to liver tumors, and clinical trials of these techniques are now enrolling patients with primary liver cancer.
The most common primary liver cancers are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), or cancer of the bile ducts. These diseases often develop in patients with inflammation or cirrhosis resulting from viral hepatitis, autoimmune disorders, or metabolic syndrome.
"Patients with primary liver cancer often have other comorbidities while they're getting their radiation, and that often adds another layer of complexity to the management of these cases," said Eugene Koay, M.D., Ph.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center.
Dr. Koay is leading several clinical trials for patients with unresectable HCC or ICC. These trials aim to open up the option of radiation to new subpopulations of patients with liver cancer.
More precise radiation techniques
Modern conformal radiation modalities such as proton therapy or photon-based intensity-modulated radiation therapy (IMRT) help ensure the precise delivery of radiation to liver tumors. At MD Anderson, Dr. Koay and the gastrointestinal radiation oncology team are investigating the survival benefits and adverse effects of these treatments. IMRT is more commonly used but can cause collateral damage to healthy liver tissue and other organs. In contrast, proton therapy may deliver less radiation to healthy tissue surrounding the tumor, resulting in reduced liver toxicity and possibly better outcomes.
In a recent multi-institutional phase II trial, Dr. Koay and colleagues found that high-dose proton therapy can achieve high levels of tumor control and promising overall survival rates for both HCC and ICC patients. These doses were delivered safely thanks to a combination of technologies and techniques that were developed or refined in recent years and can be used with proton- or photon-based therapy.
One of these techniques is hypofractionated dosing, in which a high total radiation dose is delivered in a small to moderate number of high-dose fractions. Patients in the phase II trial received a median dose of 58 Gy in 15 fractions. This moderate number of fractions reduces the chance of dosimetric variation between fractions due to position changes or motion.
Another refinement, and one used in the phase II proton therapy trial, is motion management. Since the liver moves whenever a patient breathes, breath hold is used to keep the liver motionless while the patient receives radiation. However, Dr. Koay said, "The breath hold can vary from day to day, so we need some verification of where the tumor is in space." With the use of three-dimensional image guidance, in which a computed tomography scan is taken while the patient is holding his or her breath in the treatment position, the tumor's location can be confirmed so that adjustments can be made on a day-to-day basis.
The results of the phase II trial indicate that hypofractionated proton therapy and motion management can reduce the toxic effects of radiation therapy. Patients in the trial had a lower rate (3.6%) of worsening cirrhosis after radiation therapy compared with historical rates (23%) in trials that used photon-based stereotactic body radiation therapy.
Other innovations in radiation therapy used for primary liver cancer include simultaneous integrated boost with simultaneous integrated protection. This technique delivers an extremely high radiation dose to the tumor's center, which often is more hypoxic than the peripheral tumor tissue and therefore more resistant to lower doses of radiation.
Also used at MD Anderson is a method called functional imaging, which allows radiation oncologists to pinpoint healthy liver cells. Healthy hepatocytes are accompanied by macrophages called Kupffer cells, which take up technetium-99m sulfur colloid. This agent can be used with single-photon emission computed tomography to localize those healthy cells in three dimensions, and radiation treatment plans can then be designed to avoid regions with high proportions of healthy hepatocytes to better preserve liver function.
Phase III trial for HCC
Patients with HCC are more likely to have cirrhosis than are patients with ICC; therefore, proton therapy may be a better option to treat patients with HCC without compromising their critical remnant of healthy liver. However, it has yet to be proven that HCC patients treated with proton therapy survive longer than those treated with IMRT. To compare overall survival between HCC patients given proton therapy and those given IMRT, Dr. Koay and colleagues designed a randomized phase III trial (No. NRG-GI003).
The multi-institutional phase III trial is now enrolling patients with un-resectable or locally recurrent HCC. Dr. Koay said, "Our hypothesis is that the lower dose to the healthy liver in patients treated with proton therapy rather than photon therapy will translate to a survival advantage for the patients treated with protons." Finding a substantial survival benefit would help justify the use of proton therapy, which can cost more than IMRT.
Phase III trial for ICC
The standard of care for unresectable ICC is chemotherapy alone; however, such treatment yields very low survival rates, and many patients receiving this care die within 18 months. To address these dismal outcomes, researchers at MD Anderson examined the mechanisms within the liver that led to the deaths of ICC patients and found that ICC tumors caused complications in the liver by closing off bile ducts or "squeezing" blood vessels and depriving the liver of nutrients.
Moreover, patients with ICC who received high-dose proton therapy in the recent phase II trial showed high 2-year overall survival rates compared with historical rates. "This is why giving higher doses of radiation would be thought to improve survival rates of these patients," Dr. Koay said. "If you can control the growth of the liver tumor and prevent it from causing biliary obstruction or blood vessel disruption, then you might allow the patient to live longer."
To test the hypothesis that radiation therapy can prolong survival for patients with unresectable ICC, Dr. Koay and colleagues are conducting a phase III trial (No. NRG-GI001). Patients in this trial first receive chemotherapy and then are randomly assigned to undergo either observation, as is standard, or photon- or proton-based radiation therapy as determined by the treating physician. Demonstrating the efficacy of radiation in this trial would provide a new option to this patient group.
Phase I trial for liver cancer with impaired liver function
MD Anderson researchers also are exploring the potential use of radiation therapy in patients with liver cancer and compromised liver function due to advanced cirrhosis or previous treatment. Patients who undergo radiation therapy and have grade B or C cirrhosis (on the Child-Turcotte-Pugh scale) are at risk of developing radiation-induced liver disease, which can cause death within 6 months after irradiation.
To safely deliver radiation under these conditions, Dr. Koay and colleagues are using functional imaging to create radiation treatment plans that avoid healthy liver cells in a phase I trial (No. 2015-0052) for patients with primary or metastatic liver tumors.
"Historically, patients with impaired liver function would not come to our department because of the risk of radiation toxicity," Dr. Koay said. "But by doing this trial, we're hoping to open up another treatment option for these patients who otherwise don't have any good options left."
Hoped-for changes in standard care
Although radiation therapy to the liver carries risks, more and more indications for radiation to treat various liver cancers have been identified over time, and researchers at MD Anderson hope to continue developing strategies to safely administer powerful radiation treatments to patients with liver cancer who lacked that option in the past. For patients who cannot undergo surgery, radiation therapy could provide comparable relief, especially when precise delivery techniques are used.
Dr. Koay said, "We're hoping to establish radiation as part of the standard of care for both ICC and HCC and to substantially prolong the survival of these patients."
Crane CH, Koay EJ. Solutions that enable ablative radiotherapy for large liver tumors: fractionated dose painting, simultaneous integrated protection, motion management, and computed tomography image guidance. Cancer. 2016;122:1974-1986.
Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016; 34:460-468.
OncoLog, February 2018, Volume 63, Issue 2