by Katharine Hendrix
Illustrations by Emma Vought
The incidence of liver cancer has more than tripled since 1980, with death rates climbing 2.7 percent annually from 2003 to 2012.1 Intrahepatic cholangiocarcinoma (ICC), a rare but frequently fatal form of liver cancer, affects between 5,000 and 8,000 Americans a year (age-adjusted incidence 0.73 per 100,000), two-thirds of whom are older than 65.2,3 The prognosis for ICC patients is grim: The median survival after diagnosis is about 28 months for patients who undergo surgical resection and 12 months for unresectable patients.4,5
Despite ICC’s poor prognosis and rising incidence, there is no consensus regarding optimal treatment.5 Complete surgical resection is the only treatment option to offer a potential cure but two-thirds of ICC patients who undergo resection will have a recurrence, most often in the remnant liver.4 Thus, among those receiving surgical resection, reported five-year survival rates are relatively low — ranging only from 25 to 40 percent.6
Most patients present with locally advanced disease, and only a third are candidates for resection at the time of diagnosis.7 The prognosis is even worse for patients with unresectable tumors, among whom just 5 to 10 percent can expect to survive for five years after diagnosis.8
Therapeutic options are limited in cases of unresectable disease or a recurrence that is not amenable to further surgery, and the most effective strategies for chemotherapy and radiotherapy in both resectable and unresectable disease are poorly defined.4 These factors converge to make choosing treatment strategies for these patients one of an oncologist’s most challenging tasks.9
A new treatment option, currently being investigated by a collaborative team of MUSC Health Radiation Oncology and Interventional Radiology faculty, may soon provide hope for ICC patients with unresectable disease.
The phase 1 study evaluates a combination regimen of current first-line chemotherapy, gemcitabine/cisplatin (gem/cis), with trans-arterial embolization using Yttrium 90 (TARE Y90) microspheres. The primary goal of the trial is to determine safe doses for using these two therapies in combination.
“While TARE Y90 has been combined with chemotherapy to improve disease control in the liver for colorectal cancer liver metastases, this is the first time TARE Y90 has been combined with gemcitabine and cisplatin in the hope of prolonging survival in patients with ICC,” explains MUSC Health radiation oncologist S. Lewis Cooper, M.D., the principal investigator for the study.
The trial’s novelty lies not only in the combination of chemotherapy and radiotherapy, but also in the radiation delivery system that directly targets liver tumor cells from inside the liver parenchyma — in other words, radiation therapy that is delivered from the inside out.
“Our Interventional Radiology colleagues introduce a catheter into the wrist or groin and feed it to the hepatic arteries,” explains MUSC Health radiation oncologist David T. Marshall, M.D., a co-investigator on the project. “Then we inject radioactive microspheres that are drawn by the hepatic artery blood flow into the liver and to the tumors in the liver.”
This strategy for delivering radiotherapy to unresectable liver tumors has interesting advantages over traditional, external radiation treatments. Microspheres target tumor cells more accurately than traditional radiation treatments, thereby avoiding healthy liver tissue, in two ways.
First, the liver has two blood supplies — the portal vein that brings nutrients from the gastrointestinal tract and the hepatic artery that delivers blood from the aorta in the abdomen. Tumor cells obtain 70 to 80 percent of their blood supply from the hepatic artery, whereas hepatocytes (normal liver cells) obtain 70 to 80 percent of their blood supply from the portal vein.
“So, there’s a physiological advantage if we infuse the spheres through the hepatic artery,” explains Marshall. ”We’ll get more of them around the tumor than around the normal hepatocytes.”
Second, tumors typically grow their own blood supply and are more vascular than normal hepatocytes. “So the tumors get a greater proportion of the spheres because of that as well,” says Marshall.
In fact, MUSC Health has deep experience using this type of microsphere technology to embolize various tumor types.
In collaboration with their Interventional Radiology colleagues Marcelo S. Guimaraes, M.D., M. Bret Anderson, M.D., Ricardo T. B. Yamado, M.D. and Juan C. Camacho, M.D., Cooper and Marshall have been using microspheres to radioembolize tumors since 2007. ”We were the first hospital in the state to offer this option to our patients,” says Marshall. “Between 150 and 200 patients have received intra-hepatic microspheres at MUSC Health.”
The (liver tumor) study uses tiny resin microsphere beads that are coated with the radioactive isotope TARE Y90, a source of beta energy, that is permanently bound to them. Each microscopic sphere is approximately the diameter of a human hair — allowing millions to be injected into the liver during a single outpatient procedure.
“The spheres lodge in the microvasculature around the tumor and attack it in two ways, via radiation and by blocking its blood supply,” says Cooper.
An artist's depiction of radioactive microspheres being delivered to a tumor through its arterial supply.
Initially, resin microspheres were used for colorectal cancers that had metastasized to the liver, but they’ve been used successfully in other tumors since then, including primary liver tumors such as hepatocellular carcinoma.
“They’re only FDA approved for colorectal cancer metastasized to the liver but are used off-label for many other indications,” explains Marshall. “So, this is a trial of one of those uses.”
The radiation’s effective range is only 2.5 mm from each resin microsphere, helping to spare normal, adjacent liver tissue from damage. The half-life of TARE Y90 is 64 hours, and all of the effective radiation is delivered by 14 days after injection.
Patients go home the same day they are treated and, while most experience some side effects, these are typically mild to moderate and include right upper-quadrant pain and flu-like symptoms, such as fatigue and nausea, which usually clear up in one to two weeks. There is some risk for more serious side effects, such as formation of a gastric or peptic ulcer, and, rarely, liver toxicity.
Cooper and Marshall hope that combining gem/cis and TARE Y90 — each of which extends patient survival for about a year — will buy more time for their patients with ICC.
“This is a novel treatment for ICC that’s more than just chemotherapy. It combines the standard-of-care chemotherapy with a novel radiation approach. For patients with unresectable or unablatable ICCs, this is an excellent treatment option,” says Marshall. “I have some patients who are seven to eight years from treatment with Y90 who are disease free.”
The requirements for patients interested in entering the study reflect the nature of this therapeutic approach that is specifically directed to the liver. Patients should have adequate liver function, be able to tolerate a little injury from the treatment, and less than 70 percent of their liver should be replaced by tumor.
“In other words, at least 30 percent of the liver needs to be normal to make sure that, once we get rid of the cancer, patients will have enough normal, functional liver left,” explains Marshall.
Also required is good access to the hepatic artery and the arteries that go into the liver. “And, we make sure the arteries don’t branch into the GI tract because that would deliver too many spheres to the wrong place,” adds Marshall.
Potential trial participants will undergo liver function tests to ensure that they can tolerate the treatment (average bilirubin below 2, albumin 3 or higher and near-normal liver inflammatory markers). “Finally, we need patients who don’t have a lot of disease that has spread elsewhere because this will only treat disease in the liver,” says Marshall.
Optimism about the potential benefit of this novel therapeutic approach has already led to an expansion of the phase 1 trial.
“Sirtex, the device company that makes TARE Y90, has been excited enough about this trial to fund opening it at other academic medical centers to help speed enrollment and move this combination treatment forward,” explains Cooper. “We are in the process of opening the trial at three additional sites and will run those from the MUSC Hollings Cancer Center as well.”
In the bigger picture, this study takes MUSC Health another step forward as an institution offering novel treatments for rare and orphan diseases that, typically, do not attract a lot of research attention.
“Unfortunately, patients with uncommon cancers often have limited treatment options, and there are relatively few clinical trials investigating novel treatments,” says Cooper. “This is an exciting trial for patients with unresectable ICC whose treatment options are limited.”
1 American Cancer Society. What is Liver Cancer? Available at https://www.cancer.org/cancer/liver-cancer/about/what-is-liver-cancer.html Last Medical Review: 03/31/2016. Last Revised: 04/28/2016.
2 Njei B. Hepatology 2014;60(3):1107-1108.
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4 Mavros, MN, et al. JAMA Surg 2014;149(6):565-574.
5 Valle J, et al. N Engl J Med 2010;362(14):1273-1281.
6 Endo I, et al. Ann Surg 2008 Jul;248(1):84-96.
7 Maithel SK, et al. Cancer 2013 Nov 15;119(22):3929-3942.
8 Giglielmi A, et al. World J Surg 2009;33(6):1247-1254.
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