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April 21, 2010, (Vienna, Austria) — Proton beam radiotherapy can be used to safely treat patients with unresectable hepatocellular carcinoma (HCC), including those with advanced disease, according to American researchers.
The therapy was shown to be effective in treating lesions up to 10 cm, researchers from Loma Linda University Medical Center in California reported.
Patients within the Milan criteria — having 1 lesion smaller than 5 cm or as many as 3 lesions each smaller than 3 cm — have better survival rates than those with tumors outside those criteria, according to data presented here at the European Association for the Study of the Liver (EASL) 45th Annual Meeting.
Lead investigator Zeid Kayali, MD, assistant professor of medicine and medical director of the Liver Transplantation Program at Loma Linda University Medical Center, said during his presentation that this is the largest prospective trial using proton beam therapy to treat liver tumors in patients with cirrhosis.
The median survival time for all 76 patients in the study was 20 months. The median progression-free survival time was 36 months.
Among the 18 patients whose livers were treated and who later received transplants, there was no residual tumor in 6, microscopic residual tumor in 7, and gross residual tumor in 5 of the livers.
"Proton beam therapy is safe locoregional treatment for a wide array of HCC patients," said Dr. Kayali. "In our opinion, proton beam therapy is a very promising locoregional treatment for HCC, and I strongly believe, and my team strongly believes, that it's going to play a major role [in the treatment of HCC]."
In proton beam radiotherapy, protons passing near the electrons orbiting the nuclei of cancer cells pull the electrons out of their orbits, interfering with their function, including their ability to proliferate, Dr. Kayali explained.
Champions of proton beam therapy tout its ability to control the proton beam better than standard x-ray treatment, he added.
The distribution of the proton beam's energy can be done in a 3-dimensional pattern, giving greater precision. This allows for higher doses of treatment without as much concern about adverse effects. But randomized controlled trials remain to be done to compare proton beam therapy with transarterial chemoembolization and other similar treatments.
In the study presented here, each patient received 15 fractions over 3 weeks, for a total treatment of 63 cobalt Gy-equivalent (CGE), or 4.2 CGE per session.
Patients were included regardless of their eligibility for a transplant or their Child-Pugh score.
About half of the patients (47%) had a Child-Pugh score of 7 to 9; 29% had a score of 5 or 6; and 24% had a score of 10 to 15.
Nearly half of the patients (45%) had a Model for End-Stage Liver Disease (MELD) score of 11 to 14; 38% had a MELD score of 6 to 10; 13% had a MELD score of 15 to 20; and 4% had a MELD score of greater than 20.
Roughly half the patients (46%) fell within the Milan criteria. The average tumor size was 5.5 cm.
Patients were not included in the study if they had more than 3 lesions or had only a single lesion of less than 2 cm, if the tumor had spread outside the liver, or if they had other limiting medical conditions.
The safety and toxicity of the treatment was encouraging; the average MELD scores saw only a slight up-tick, from 12 points before treatment to 14 points 3 months after treatment, Dr. Kayali said. That was not a significant change (P = .12).
The 3-year overall survival rate for patients within the Milan criteria was 48%; for patients outside the Milan criteria, it was 12%.
Results were similar for progression-free survival, with 3-year progression-free survival for those within the Milan criteria at 60%, and for those outside the criteria at 20%.
Fifteen patients (20%) had local tumor recurrence, 23 patients (30%) had intrahepatic recurrence, and 13 (17%) had extrahepatic recurrence.
"As you know, doing trials on hepatocellular carcinoma is very challenging, and this study, like any HCC [study], has limitations," Dr. Kayali told meeting attendees. "This is not [a study of] consecutive patients, and that introduced a bias in our cohort. We believe this cohort is biased toward a more heavy tumor burden."
Observers in the audience raised questions about the cost and the availability of the treatment.
Dr. Kayali acknowledged there were questions about the cost — proton beam radiotherapy is not reimbursable by Medicare or Medicaid — but he predicted wider acceptance eventually.
"I think it's going to be used more widely in the United States," he said.
Mark Thursz, MD, professor of hepatology at Imperial College London in the United Kingdom and vice-secretary of EASL, who moderated the session, told Medscape Gastroenterology that he had questions about how much the treatment could be used because of the scarcity of the proton beam accelerator machines. He also questioned this study's approach.
"I think there were some biases in the way the patients were selected in the study," he said. "They treated patients who perhaps should have been treated in other ways. It wasn't a randomized trial."
But Dr. Thursz acknowledged that there might be some potential for proton beam radiotherapy. "On the more positive side, you don't need an intervention. You don't need somebody to poke a radiofrequency probe into the tumor. . . . So it's minimally invasive, which is appealing."
The study received no commercial financial support. Dr. Kayali and Dr. Thursz have disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 45th Annual Meeting. Presented April 15, 2010.
Authors and Disclosures
Journalist Thomas R. Collins
Thomas R. Collins is a freelance writer for Medscape.
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