May 18, 2009

Radioembolization for Liver Tumors
By Joshua L. Weintraub, MD, FSIR, and Hiram Shaish, AB
Radiology Today
Vol. 10 No. 10 P. 29

Hepatic neoplasms, both primary and metastatic in origin, have traditionally been regarded as difficult tumors to treat, let alone cure. However, recent advances in radioembolization are starting to challenge these long-held beliefs.

Primary and metastatic lesions in the liver get their blood supply primarily from the hepatic artery. This led to the development of transarterial chemoembolization (TACE) in the late 1970s. Despite the success of TACE, smaller hepatic lesions often do not respond, and many believe it is due to a greater contribution of portal blood supply. TACE remains a palliative therapy, with cures unlikely.

Yttrium 90 (Y-90) is a pure beta particle emitter with an average energy of 0.9337 MeV that was first used in 1964 in medical therapy by Irving M. Ariel, MD. Y-90 has a half life of 2.67 days and decays to stable zirconium-90. In soft tissues, it penetrates 2.5 mm, with a maximum range of 11 mm. Theoretically, this helps destroy a margin around the tumor sites in addition to areas that have mixed portal vein and hepatic arterial supply. [Editor’s Note: Sirtex Medical Limited and MDS Nordion both produce Y-90 radioembolic particles. The companies’ products are approved for differing indications in liver cancer patients.]

It has taken more than 40 years of development and technology to refine the administration techniques and make Y-90 a valuable clinical tool. New technical developments and understanding of Y-90 have resulted in improved efficacy with minimal adverse effects. Initial treatment indications were for colorectal cancer metastases and hepatocellular carcinoma (HCC). Success in these areas is expanding the accepted indications to include other unresectable, metastatic liver tumors such as neuroendocrine and breast cancer.

Patients are evaluated for acceptable liver and renal function in addition to adequate performance status (ECOG performance status score of less than or equal to 2) prior to treatment with Y-90. Patients with inadequate hepatic reserve and poor performance status have been shown not to tolerate radiotherapy. All patients are required to have two angiograms performed. The patients initially undergo a visceral angiogram to evaluate their vascular anatomy. Up to 20% of patients have a variable anatomy with a replaced or an accessory right hepatic artery coming off of the superior mesenteric artery. Branches of the hepatic artery that supply the tract, such as the gastroduodenal artery and the right gastric artery, are occluded to prevent nontarget embolization at the time of Y-90 treatment. A mock study is then performed using macroaggregated alubumin tagged with technetium 99m. This permits the determination of the shunt fraction to the pulmonary circulation in addition to allowing for Y-90 dose calculations. Patients who have greater than 20% lung shunting are at an increased risk for severe complications, including radiation pneumonitis.

The Y-90 treatment is performed on an outpatient basis under conscious sedation. The patient undergoes a repeat visceral angiogram, and the dose of Y-90 is delivered to the liver. During the procedure, a targeted, high dose of radiation is delivered to the liver tumors. Based on anatomy and hepatic reserve, either segmental or whole-liver treatment can be performed. In general, patients experience some abdominal pain and a low-grade fever that may last up to one week. It is not unusual for patients to have associated fatigue.

Follow-up is routinely performed with laboratory evaluations and serial CT scanning. The vast majority of tumor necrosis is seen at one month after the procedure but continues out to six months.

Future of Targeted Treatment
Sirtex’s Y-90 is currently FDA approved for treating unresectable, metastatic liver tumors from primary colorectal cancer. In addition, on a Humanitarian Device Exemption from the FDA, Y-90 can be used in radiation treatment, as a neoadjuvant to surgery, or in transplantation for patients with unresectable HCC. It is also indicated for HCC patients with partial or branch portal vein thrombosis/occlusion when clinical evaluation warrants the treatment.

Recent research has investigated the use of Y-90 to treat unresectable liver metastases from neuroendocrine tumors. Andrew Kennedy, MD, reported that imaging response demonstrated stable lesions in 22.7%, partial response in 60.5%, complete response in 2.7%, and progressive disease in 4.9% of patients. The median survival from time of treatment was 70 months. There were few complications, with fatigue being the most prevalent complaint. No radiation-induced hepatic failure was reported despite whole-liver treatment in appropriate patients. Y-90 appears to be a safe and effective procedure in patients with metastatic neuroendocrine tumors, even with extensive hepatic involvement, according to a June 2008 article in the American Journal of Clinical Oncology by Kennedy et al.

Ongoing Research
Multiple trials are ongoing in the United States to evaluate the use of Y-90 microspheres in the treatment of both unresectable primary and metastatic disease to the liver. The University of Texas M. D. Anderson Cancer Center is planning to initiate a study utilizing Y-90 microspheres in combination with cetuximab and irinotecan in patients with advanced metastatic colorectal cancer. The National Cancer Institute is currently enrolling patients in one study to evaluate the quality of life in patients undergoing embolization and a second study looking at Y-90 in treating unresectable liver cancer. These and other studies will hopefully elucidate the potential applications and future possibilities of targeted hepatic therapy.

With a growing amount of information available about Y-90 treatment, as well as clinical trials in development, the medical community has only begun to understand all that we can offer patients with advanced liver tumors. Our goal is to continue to research and understand targeted treatments in an effort to increase the survival rate and improve the quality of life for patients with advanced liver tumors.

— Joshua L. Weintraub, MD, FSIR, is vice chairman of the radiology department, director of vascular and interventional radiology, and an associate professor of radiology and surgery at Mount Sinai Medical Center and Mount Sinai School of Medicine in New York.

— Hiram Shaish, AB, is a medical student at Mount Sinai School of Medicine in New York.


Review of Advanced Liver Tumors
Hepatocellular carcinoma (HCC) is a highly malignant primary liver neoplasm. Its epidemiology varies between ethnic background and country due to underlying risk factors such as age, sex, hepatitis B virus/hepatitis C virus status, environmental toxins, and cirrhosis from any etiology. In the United States, the overall incidence is 4.1 cases per 100,000 people per year, with those from African American and Chinese backgrounds having a higher incidence than Caucasians.1 In 2005, there were 17,550 new cases and 15,420 deaths, reflecting HCC’s high malignancy, according to the American Cancer Society. The five-year survival for stage 1 HCC is 65%, for stage 2 is 35%, for stage 3 is 18%, and for stage 4 is 0% to 3%.2

For the few patients with adequate hepatic reserve, noninvolvement of hepatic or portal veins, and limited tumors, partial hepatectomy has been the mainstay of treatment. Orthotopic liver transplantation has been shown to increase four-year survival to 75%.3 If surgery is not an option, percutaneous ethanol injection and, more recently, radiofrequency ablation (RFA) may provide similar five-year survival rates as resection for small lesions.4,5 However, most physicians would recommend surgery.6

Although systemic chemotherapy has been notoriously ineffective, transarterial chemoembolization (TACE) was shown to increase survival for unresectable tumors.7,8 In terms of external beam radiotherapy, HCC is radiosensitive, but the liver is an extremely sensitive organ, and it has been difficult to localize the beams. This has changed with stereotactic radiotherapy and radioembolization with Yttrium 90 (Y-90).9 Sirtex Medical Limited and MDS Nordion both produce Y-90 radioembolic particles. The companies’ products are approved for differing indications in liver cancer patients. Sirtex’s SIR-Spheres are the only FDA-approved microsphere therapy for colorectal liver metastases.

Approximately 148,810 Americans are diagnosed with colon adenocarcinoma each year and 49,960 die from it.10 Colorectal cancer has a tendency to metastasize to the liver via the rich portal system. Once it has reached the liver, it is considered stage 4 disease and patients have a five-year survival of 8%.11

Available chemotherapeutic agents have expanded tremendously from the days of 5-flourouracil. Options include combination therapies such as FOLFOX4 (oxaliplatin, leucovorin, and 5-flourouracil) and, more recently, monoclonal antibodies such as bevacizumab.12,13 Patients who are unresectable can now achieve survival rates double that of what was previously possible.14 While two thirds of patients with metastatic disease have extrahepatic sites, most would agree that resection offers the best chance of a cure for those with isolated liver metastases. Five-year survival rates after resection may approach 36%.15 Neoadjuvant therapy was shown to have a statistically significant improvement of three-year, progression-free survival (35% over 28%) but also a higher rate of liver failure and other complications.16

For those with isolated liver metastases who are otherwise unsuitable for resection, local ablation through RFA can improve five-year survival rates up to 18%.17 Recent studies have demonstrated the utility of TACE for colon cancer. The one-year survival rate after TACE is approximately 60%, and the two-year survival rate is greater than 25%. In patients with colon cancer, Y-90 therapy is a safe, locoregional therapy that provides an important palliative option for patients who have failed first- and second-line chemotherapy and who have adequate liver function.

Neuroendocrine tumors (NETs) that manifest themselves as liver metastases may be of the poorly differentiated type such as small-cell lung cancer or undifferentiated carcinoid or may be of the well-differentiated, slow-growing type such as carcinoid tumors. The overall annual incidence of NETs between 2000 and 2004 was reported to be 5 in 100,000, while the 29-year, limited-duration prevalence was 35 in 100,000. The most common primary site was the lung at 27%. The incidence for metastatic disease was 1.03 in 100,000. For metastatic, well-differentiated carcinoid tumors, the median survival time was 33 months, while for poorly differentiated NETs, it was five months.18 Metastatic, well-differentiated NETs present clinically based on the peptide they secrete, for example, carcinoid syndrome. Poorly differentiated disease presents with paraneoplastic syndromes and constitutional symptoms.

Treatment may also be divided according to the two broad categories of NETs. Well-differentiated NET hepatic metastases that undergo hepatic resection have demonstrated a 90% improvement in symptoms and a five-year survival rate of 61%, although the recurrence rate was 84%.19 There is also evidence that resection of the primary tumor, if localized, improves survival.20 Orthotopic liver transplantation has only been tried in a limited number of patients. Five-year survival rates approach 69% and most recur. Systemic chemotherapy has shown minimal benefit.21,22 Somatostatin analogues such as octreotide are very effective in improving the systemic symptoms of carcinoid disease but have rarely been shown to affect tumor growth.23

Liver-directed therapy has been used in patients not suitable for resection and includes locoregional therapy, RFA, TACE, and Y-90. Poorly differentiated NETs are more chemotherapy responsive. For metastatic, small-cell lung cancer, the survival benefit is low, on average an extra two months.24 For other poorly differentiated NETs, similar chemotherapy protocols are used and provide somewhat better benefit.25



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