Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases

Patients and their physicians should be careful when selecting a chemotherapy drug to treat colorectal cancer that has spread to the liver, say researchers at The University of Texas M. D. Anderson Cancer Center in Houston.

While surgery to remove liver metastases also has proven beneficial, both of the most commonly used chemotherapy drugs to treat these tumors can seriously injure the liver the researchers report in the May 1 issue of the Journal of Clinical Oncology. Furthermore the damage caused to the liver by these preoperative chemotherapy regimens can adversely affects long-term surgical outcomes.

Use of chemotherapy before surgery offers several important benefits, including reducing the size of tumors such that they are more easily removed and, potentially doubling the survival rate.

Results of their 13-year study of 406 patients, treated either at M. D. Anderson or at a hospital in Torino, Italy, found that one drug, irinotecan, produced steatohepatitis (an inflamed "fatty" liver) in 20 percent of patients who used it, and three of those patients later died.

Most of these complications were seen in patients who were overweight or who already had a fatty liver, a condition known as steatosis, says lead author Jean-Nicolas Vauthey, M.D., professor in the Department of Surgical Oncology at M. D. Anderson.

"Most patients who use preoperative chemotherapy when their colorectal cancer spreads to the liver do just fine," Vauthey says. "But this study shows us that we need to screen patients in advance and use the drug that is right for them."

The other most commonly used chemotherapy drug, oxaliplatin, produced sinusoidal dilation (swelling and leaking of blood vessels in the liver) in almost 19 percent of patients who used it, but no deaths were associated with this condition.

"Although such serious complications are comparatively rare, our finding that the choice of chemotherapy matters in outcome will become increasingly important as this surgery becomes more widespread," Vauthey says.

According to the American Cancer Society, more than 146,000 Americans will be diagnosed with cancers of the colon and rectum in 2006. Liver metastasis usually develops from colorectal cancer, and the number of surgeries now performed to remove these tumors is about 10,000 a year "and is expected to double in the near future," Vauthey says.

The study is the first to analyze the association between chemotherapy use before surgery, changes in the function of the liver and postoperative outcome in patients with liver metastases. It is also the first to monitor patient progress for 90 days post surgery. Most surgery outcome studies follow patients for only 30 days, "which is not long enough for these complications to develop," Vauthey says.

Of the 406 patients enrolled in the study, 248 were treated with preoperative chemotherapy and 158 were not. For the entire group, the perioperative complication rate was about 21 percent, and injury to the liver occurred in almost 23 percent. Steatosis was identified in almost nine percent as was high-grade sinusoidal dilation, and steatohepatitis occurred in about eight percent of patients. The investigators further found that while no specific chemotherapy regimen was linked to development of steatosis, oxaliplatin was associated with sinusoidal injury and irinotecan was connected to steatohepatitis when compared to patients who did not receive chemotherapy.

In all, 11 patients died within 90 days of surgery, and six of those deaths occurred in the 92 patients who had hepatic injuries. Five of those patients had steatohepatitis, and one had steatosis. Of the five patients who developed steatohepatitis, three had been treated with irinotecan.

Although steatohepatitis is typically a benign condition, "its presence in patients undergoing chemotherapy treatment may result in failure to regenerate new liver tissue, which can lead to liver disease and failure," Vauthey says.

Researchers further noted that irinotecan was associated with an increased risk of steatohepatitis whether or not a patient was overweight, but that the effect was more pronounced in patients with a higher body mass index (BMI).

Given these findings, researchers recommend patients be screened for BMI and for preexisting steatosis, which chemotherapy can morph into steatohepatitis. Patients in these categories should avoid irinotecan, Vauthey says. "Most patients who use preoperative chemotherapy when their colorectal cancer spreads to the liver do just fine," he says.

While both oxaliplatin and irinotecan are equally effective when combined with fluorouracil, as are other chemotherapy regimens, "this study shows us that we need to screen patients in advance and use the drug that is right for them, Vauthey says "


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