NEW YORK CITY—Because surgical resection and liver transplantation are options in only about 10% to 15% of patients with liver cancer, radiologists are pursuing less invasive ways of treating the disease, including radiofrequency ablation (RFA) with liposomal doxorubicin and chemoembolization.
While using RFA on its own allows physicians to treat liver tumors up to 4 cm in size, using the technology with liposomal chemotherapy may make it possible to fully treat patients with liver tumors up to 8 cm, eradicating the cancer with very few systemic side effects, said Jonathan B. Kruskal, MD, PhD, Section Chief of Abdominal Imaging at Beth Israel Deaconess Medical Center and Associate Professor of Radiology at Harvard Medical School in Boston, speaking here at a media briefing by the Radiological Society of North America on image-guided therapies.
“This treatment offers a wonderful new opportunity,” Dr. Kruskal said, adding that it is ideal for non-surgical candidates. The combined therapy is now being used to treat patients with malignant liver tumors at Beth Israel.
An animal study of the approach is described in the July issue of Radiology (2003;228:112–118).
RFA uses heat to destroy malignant tumors. After conscious sedation of the patient, radiologists locate the tumor with computed tomography or ultrasound guidance, and then insert a 4- to 10-inch long electrode into the center of a tumor. The electrode delivers radiofrequency to heat and destroy the tumor.
“Radiofrequency ablation is essentially a way of using image guidance to put a needle into a solid tumor and deliver heat energy into this tumor to destroy tumor cells,” Dr. Kruskal said.
A liver tumor can be ablated with RFA in about 30 to 60 minutes under continuous image monitoring. “We can do up to three tumors in one [treatment session],” Dr. Kruskal said. The risks include bleeding and injury to other organs and post-ablation syndrome, which includes flu-like symptoms.
RFA has been used worldwide in the last five years to treat tumors, including those of the liver, kidney, and lung, that are up to four centimeters in size.
“This is probably the major drawback of the procedure,” said Dr. Kruskal. “Four centimeters is a pretty good size, but we need to increase the size of the tumor we can treat.”
Size limitations exist because “you can only deliver so much energy to the tumor,” explained Dr. Kruskal, adding that too much RFA therapy can damage blood vessels. Complications can also arise when inserting more than one probe, he added.
Adding doxorubicin to RFA may help improve the size of growth that can be treated because the agent leaks out into tumors, which contain naturally leaky vessels. The liposomes are then broken apart in the cancer by the heat of RFA.
Dr. Kruskal and his colleagues found that with the addition of liposomal chemotherapy in rats, large tumors could be treated with RFA and that partially destroying tumors with RFA slows tumor growth and increases survival.
RFA with doxorubicin was used to treat mammary adenocarcinoma tumors in 49 female Fischer rats. Researchers used breast cancer cells because they are very vascular and grow predictably, Dr. Kruskal explained.
The animals were divided into four treatment groups: a control group, receiving no treatment; RFA only; doxorubicin only; and RFA combined with doxorubicin. Endpoint survivals were 9.1 days for the control group; 16 days with RFA alone; 16.5 days for tumors treated with liposomal doxorubicin alone; and 26.6 days with combined treatment.
A larger tumor kill zone was apparent in the rats that received the combined therapy. Additionally, RFA appeared to increase the amount of chemotherapy that was delivered into the tumor.
“We weren't sure if this was going to happen, because often if you kill tissue, it's difficult to get a drug into it,” Dr. Kruskal said.
Another unexpected finding was that the therapy slowed down the rate of tumor growth, even when tumors were incompletely destroyed.
Treatment in Humans
Initially, a study of 10 patients with 14 focal hepatic tumors found that RFA with doxorubicin increased the size of tumor destruction and destroyed residual tumor (Am J Roentgenol 2002;179:93–101). Tumor size was about 4 cm.
Two weeks later, the residual tumor was still being destroyed because of the lingering effects of the therapy. Even after RFA, remaining tumor tissue may be destroyed with liposomal chemotherapy, partially due to an antiangiogenic effect, Dr. Kruskal explained.
Physicians at Beth Israel Deaconess have treated about 25 patients with tumors up to 8 cm in size with the combined therapy. “Our hypothesis was that if we give the chemotherapy to patients and subject them to radiofrequency ablation we could have a double effect,” he said.
So far, researchers have observed a 25% increase in the volume of tumor destruction. “This tumor destruction will continue regularly after treatment,” he said. The long-term disease stability is also promising, with one patient experiencing no growth in the treated tumor.
Based on these results, Dr. Kruskal and his colleagues are planning further studies, including a large clinical trial comparing RFA alone with RFA combined with liposomal chemotherapy. He also urges researchers to study other types of chemotherapy and antiangiogenesis therapies in combination with RFA.
In another topic described at the RSNA briefing, radiologists are also using chemoembolization, once used only for palliative care, to successfully treat patients with liver cancer.
“Chemoembolization may have a role in curative, not just palliative, therapy,” said Jeff Geschwind, MD, Section Chief of Interventional Radiology and Associate Professor of Radiology, Surgery, and Oncology at Johns Hopkins Hospital.
If the tumor is less than 4 cm in size, then the patient will more likely benefit from some form of locoregional ablative therapy, either heat or chemical, he said. However, if the cancer is more than 4 cm, is widespread or diffuse, or has multiple locations, the patient may benefit from chemoembolization.
During the procedure, an interventional radiologist directs a catheter into an artery in the groin and threads it into the hepatic artery. “Liver tumors draw nearly 100% of their blood supply from the hepatic artery,” Dr. Geschwind said. Contrast material is injected, and x-rays are taken of the vessels.
The radiologist then injects a high dose of chemotherapy suspended in an oily medium, very similar to the liposomes that are used in doxorubicin. The oil droplets carry the drugs to the target, and most of the agent stays in the tumor. Radiologists image the delivery to ensure it is successful.
Additionally, Dr. Geschwind continued, an embolizing material is then delivered to close or restrict the blood vessels leading to the tumor, trapping the chemotherapy drugs within the growth for long periods of time. Once the blood supply is cut off and the chemotherapy begins to work, the tissue breaks down and the tumor dies.
Most patients so treated can leave the hospital within 24 to 36 hours. CT or magnetic resonance imaging is performed every three months to determine how much the tumor has shrunk and if any new tumors have appeared.
The benefits of the procedure last approximately 10 to 14 months, and chemoembolization can be performed again if the cancer recurs, Dr. Geschwind said. The risks from chemoembolization are liver failure, infection, and the lodging of an embolus in the wrong place, depriving healthy tissue or blood. These risks, however, are much lower than those associated with surgery and liver transplant, he noted.
A recent review article in Hepatology (2003;37:429–442) described seven trials with a total of 545 patients with hepatocellular carcinoma and found that arterial embolization increased two-year survival compared with control patients by an odds ratio of 0.53. Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin, but none with embolization alone.
Overall, treatment induced objective responses in 35% of patients. Researchers concluded that chemoembolization increases the survival of patients with unresectable liver cancer and may become the standard treatment.
Investigators are now looking for ways to maximize the potency of chemoembolization through new drugs that target cancer cells, Dr. Geschwind concluded.