A panel of experts at the 2009 Gastrointestinal Cancers Symposium tackles two challenging cases of hepatocellular carcinoma.
SAN FRANCISCO—A number of viable treatments are available for unresectable hepatocellular carcinoma, so a multidisciplinary approach is a must. The panelists at the ASCO GI Cancer Symposium were:
• Moderator Jorge Marrero, MD, Keith S. Henley, MD, Collegiate Professor in Gastroenterology and director of the Multidisciplinary Liver Tumor Program at the University of Michigan in Ann Arbor.
• Surgeon Myron E. Schwartz, MD, professor of surgery and surgical oncology at Mt. Sinai Medical Center in New York.
• Interventional radiologist Riad Salem, MD, MBA, associate professor in the department of radiology, Chicago’s Feinberg School of Medicine at Northwestern University.
• Radiation oncologist Laura Dawson, MD, associate professor, department of radiation oncology, Princess Margaret Hospital in Toronto.
• Medical oncologist Jennifer Knox, MD, Princess Margaret Hospital and assistant professor of medicine, University of Toronto, Canada.
Treatment options for HCC are surgery, transarterial chemoembolization (TACE), yttrium-90 radioembolization (yttrium-90), radiotherapy, radiofrequency ablation (RFA), or systemic therapy with sorafenib (Nexavar), emphasizing the need for a multidisciplinary team for HCC management decisions.
Case 1: Focal lesions
Dr. Marrero: The patient is a mildly obese 55-year-old male with abdominal pain. He has chronic hepatitis C, cirrhosis, preserved liver function, and grade 1 esophageal varices. He is classified Child-Pugh A. He had no response to antiviral therapy, has diabetes, and drinks one or two glasses of wine a day.
Examination reveals no ascites and no palpable mass. Laboratory values are as follows: INR 1.2; bilirubin 1.5 mg/dL; albumin 3.6 g/dL; platelets 65,000; creatinine 1.0 mg/dL; AFP 261.6 ng/mL. Dynamic imaging studies reveal a 6-cm mass with a typical vascular pattern in the medial segment left lobe with satellite lesions. This is considered diagnostic for HCC, and biopsy confirmation is not required.
Dr. Schwartz: The presence of portal hypertension means this patient is not a perfect candidate for resection. Transplant would be his best chance for survival, but the risk of recurrence is too high with a tumor this size. The approach should be nonsurgical, with an eye toward downstaging and achieving resectability and possibly transplant later.
Dr. Marrero: Yes, liver transplantation in patients with early-stage HCC and a single lesion < 5 cm or no more than three lesions < 3 cm (Milan criteria) has been shown to result in a four-year survival of 75%.
Dr. Salem: There are level 1 data to support TACE in this patient. But if such a patient cannot, for some reason, receive TACE, he is a candidate for localized therapy with yttrium-90, which is FDA-approved for use in patients with HCC and branch/partial portal vein thrombosis. We have treated many like this with yttrium-90.
Dr. Dawson: If this patient is not eligible for TACE, then he would be an ideal candidate for external-beam conformal radiotherapy, because he has focal lesions where high doses can be delivered safely. In Toronto, conformal RT was studied in 31 patients with Child-Pugh A disease unsuitable for surgery, TACE, or radiofrequency ablation in a phase I study. The one-year local control rate was 65%, and median survival of patients without portal vein thrombosis was 17.2 months. The caveat is that this treatment is confined to specialized centers, mostly within clinical trials (J Clin Oncol 26:657-664, 2008).
Dr. Knox: There is no role for systemic therapy in this patient. Based on survival data, TACE fits this scenario best.
Dr. Marrero: The panel’s recommendation of TACE has strong support. In a meta-analysis, TACE afforded an overall two-year survival advantage vs controls (60% vs 20%) for patients with tumors of 5 to 7 cm (J Hepatology 37:429-442, 2003).
But for small tumors, RFA is the method of choice, based on the survival benefit observed in randomized trials. And a provocative paper published last year showed that TACE followed by RFA was even more effective than either alone in patients with three or fewer lesions of ≤ 7.5 cm. Median survival with RFA-TACE was 37 months, compared with 22 months for RFA and 24 months for TACE (JAMA 299:1669-1677, 2008).
TACE was indeed performed in this patient, and his AFP dropped from 261 to 78. However, six weeks later, an MRI showed residual tumor. The best treatment for the patient’s residual disease was considered to be another round of TACE. In the future, we might add RFA or radiotherapy to targeted areas when there is residual tumor.
Case 2: HCC and vascular involvement
Dr. Marrero: The patient is a 59-year-old female with alcohol cirrhosis with preserved liver function and grade 1 esophageal varices. She experienced a 5-pound weight loss in the past 2 months, and imaging reveals a 9-cm tumor in the left lobe of the liver with a portal vein tumor thrombus. The patient has not consumed alcohol for 3 years and has never been treated with antiviral therapy. She has no encephalopathy but does have hypertension. On examination, she has mild abdominal pain and no ascites. Her laboratory values are INR 1.2; bilirubin 1.7 mg/dL; albumin 3.5 g/dL; platelets 112,000; creatinine 0.8 mg/dL; and AFP 32,992 ng/mL.
Dr. Schwartz: This patient is not a candidate for resection, because she has tumor in both lobes and her liver function is not good enough. For patients with normal liver function and with portal invasion by HCC, we often advocate surgery, because we are convinced such patients are better off vs a nonsurgical approach, but not this patient. And her risk for recurrence is too high to consider liver transplant.
Dr. Salem: A substantial proportion of HCC patients develop portal vein thrombosis, and this represents a challenging treatment dilemma. For a patient with Child-Pugh A classification and vascular invasion, chemoembolization would be difficult, and there is a chance of ischemic hepatitis causing infarction and necrosis. At our center, we would consider first-line yttrium-90 on a clinical trial protocol.
Dr. Knox: Unfortunately, this patient is typical of many with advanced HCC and is the type of patient who would have been eligible for the SHARP trial. Chemoembolization or yttrium-90 might be possible, but this approach lacks survival data. I might also seek the opinion of a radiation oncologist for this patient. Sorafenib offers a couple of months’ benefit in terms of delayed progression and increased survival, though obviously that’s a modest impact. Clinical trials will be looking at combining sorafenib with other modalities, but there are important safety questions to be answered with a combined approach. Other trials are evaluating bevacizumab [Avastin] and other combinations of targeted agents. With so many promising clinical trials in HCC now, we should attempt to enroll patients like this one.
Dr. Dawson: Patients with portal vein thrombosis have poor prognosis from their tumor biology and are also challenging to treat with radiotherapy. They are more challenging than patients with focal lesions and no vascular involvement as in the first case. Several strategies of using radiation therapy with or without other therapies have been investigated in the setting of portal vein thrombosis. In the Toronto experience, following six fractions of conformal radiation therapy in patients with portal vein tumor thrombus, recanalization was seen in 25% of patients, with stability in 38% of additional patients. As with other therapies, survival is largely dependent on tumor stage, baseline liver function, and performance status. In terms of combining this with medical therapy, sorafenib is a very strong radiosensitizer, so although there is substantial rationale for combining sorafenib and radiation therapy, there may be increased risks. We are studying this combination in clinical trials, and I would not advocate the concurrent use of sorafenib and radiation therapy outside of a clinical trial at present. Dr. Marrero: Would the recommendation be different if the patient were Child-Pugh Class B?
Dr. Knox: It is tempting to extrapolate from the proven clinical scenarios for a drug, but there are not much data to suggest that sorafenib will benefit Class B patients. While it is likely to be relatively well tolerated, a survival advantage has not been shown; it has fairly modest clinical benefit in the first place, plus it is expensive. You are stretching the indication too far. This is a group of patients who are not uncommon, however, and we need to bring them into studies of the targeted agents.
Dr. Salem: In our five-year experience in 285 patients at Northwestern, more than half were Class B, so we do need to do something for this group. A lot have good performance status, but mathematically are Class B. We use yttrium-90 on these patients.
Dr. Marrero: The patient was started on sorafenib at 400 mg BID. After she developed diarrhea, the dose was reduced and she continued on treatment for four months. Repeat MRI revealed an increased tumor burden and new lymph node involvement of 3 to 4 cm. Sorafenib was discontinued. This patient would be a candidate for a clinical trial of one of many new promising agents, depending upon maintenance of good performance status. However, considering the patient’s limited life expectancy, we need to remember that best supportive care may be the best option.