May 8, 2012

Intensive Follow-up Reduces Mortality from Hepatocellular Cancer

By: NEIL OSTERWEIL, Family Practice News Digital Network


ORLANDO – Intensive follow-up of patients who have undergone surgery for hepatocellular carcinoma reduces deaths from tumor recurrence and metastases, Dr. Timothy M. Pawlik said at a symposium sponsored by the Society of Surgical Oncology.

Data from surveillance programs for hepatocellular carcinoma (HCC) and empiric data from centers treating colorectal liver metastases (CRLM) suggest that HCC tends to recur locally, and that recurrent HCC and CRLM, if caught early, can be successfully controlled with a variety of therapeutic options, said Dr. Pawlik, associate professor of surgery and oncology, and hepatobiliary surgery program director at Johns Hopkins Medical Center, Baltimore.

"I would favor high-intensity surveillance for patients with hepatocellular carcinoma. This argument is based on level 1 data showing that high-intensity primary surveillance decreases mortality for patients who have cirrhosis," he said.

Although there is a high HCC recurrence rate following surgery, most recurrences will be contained within the liver, and may be successfully treated with salvage transplantation, ablation, or intra-arterial therapy.

"But if we miss that opportunity and patients recur with advanced disease, all those options are off the table, and their prognosis is abysmal," Dr. Pawlik said.

According to National Cancer Institute data, liver cancer holds the dubious distinction of being the fastest growing cancer in terms of death rate in the United States, outpacing lung cancer in women, esophageal cancer, and thyroid cancer.

Risk factors for HCC include cirrhosis from any cause (hepatitis B and C viruses, alcoholism, nonalcoholic fatty liver disease), hepatitis B primary infection (with or without cirrhosis), and inherited metabolic diseases such as hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease, or tyrosinemia.

"Most patients who have HCC don’t simply have a cancer; they also have significant underlying cirrhosis, so when thinking about the approach to HCC, we have to be thinking about all of the tumor-specific factors such as tumor size, location, and number, and we also have to be thinking about all of the liver-specific factors," Dr. Pawlik said.

Surgical treatment options include resection for HCCs of all sizes; transplantation, for single lesions 5 cm or smaller, or up to three lesions of 3 cm or less or advanced cirrhosis; and ablation for small lesions or inoperable or unresectable tumors as a bridge to transplant.

In various series, overall 5-year survival following resection ranges from 42% to 62%, and following transplantation from 57% to 75%.

But as Dr. Pawlik and colleagues noted in a 2008 study, disease-free survival following resection for HCC is only half of the percentage after transplantation (40% vs. 82%, P less than .01). (J. Gastrointest. Surg. 2008;12:1699-1708).

Intrahepatic recurrence is most frequent among patients with hepatitis C infection, but also occurs with hepatitis B and C coinfection, and hepatitis B alone. A subset of patients who have undergone transplantation (about 20%) will also have recurrence, Dr. Pawlik said.

National Comprehensive Cancer Network guidelines for follow-up of patients with HCC after resection or transplantation include imaging every 3-6 months for 2 years, then every 6-12 months thereafter, and testing of alpha-fetoprotein (AFP) level, if initially elevated, on the same schedule, he noted.

For example, a trial that included 18,816 hepatitis B carriers in China randomized to either intensive surveillance with AFP level and twice-yearly ultrasound versus no screening showed that the intensive surveillance was associated with a significantly lower rate ratio for mortality compared with no screening (RR 0.63) (J. Cancer Res. Clin. Oncol. 2004;130:417-22).

Similar evidence has been found to support intensive follow-up for colorectal cancers, for which there is effective therapy for recurrent disease, Dr. Pawlik noted.

Unlike pancreatic cancer or melanoma, where recurrences tend to be distant metastases, hepatocellular carcinoma is more frequently locally recurrent. It was found that 64%-80% of patients with cirrhosis had an intrahepatic recurrence within 5 years of HCC resection.

In one study, investigators found that 60%-70% of tumors recurred within 2 years, and 30%-40% of patients with recurrences had de novo tumors (J. Hepatol. 2003;38:200-7).

"For patients who have hepatocellular carcinoma, there are two reasons to [monitor] these patients closely. One is that they may truly have recurrence, and two is that a subset of these patients will develop new de novo disease in the cirrhotic liver," Dr. Pawlik said.

Treatment options for late recurrences are very limited and not very effective, he added. Sorafenib (Nexavar) is approved for unresectable HCC, but in the phase III SHARP trial was associated with an improvement in median overall survival of only 2.8 months vs. placebo (P = .00058) (N. Engl. J. Med. 2008;359:378-90).

In contrast, early recurrences generally respond to repeat resection, salvage transplantation, radiofrequency ablation, or transarterial chemoembolization, Dr. Pawlik noted.

Dr. Pawlik said he has no relevant disclosures.


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