January 26, 2009 (San Francisco, California) — The type of chemotherapy regimen has a greater impact on response than the duration of treatment after hepatic resection for colorectal liver metastases. In fact, extended preoperative chemotherapy increases the risk for hepatotoxicity in this population and does not improve pathologic response, according to new data presented here at the 2009 Gastrointestinal Cancers Symposium.
Researchers from the University of Texas MD Anderson Cancer Center, in Houston, reported that preoperative chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX) plus bevacizumab (Avastin, Genentech) was associated with a significantly higher frequency of complete or major pathologic responses, compared with FOLFOX alone. This was the case for both long- and short-course chemotherapy.
However, among patients who received 9 or more cycles of chemotherapy, the incidence of sinusoidal injury was higher than in those who received fewer cycles (26% vs 42%), as was as was the incidence of liver insufficiency (4% vs 11%). Extended chemotherapy was the only independent predictor of postoperative liver insufficiency upon multivariate analysis.
In colorectal cancer with liver metastasis, chemotherapy should only be given if it can cure the patient or help them live longer, said David P. Ryan, MD, from the Massachusetts General Hospital Cancer Center, in Boston. "The potentially curative situation is what we are looking at today, and there is some confusion in the oncologic community as to how to best manage these patients."
"We know that resecting liver metastases can cure patients in approximately 30% of cases, and that unresectable patients can occasionally become resectable after chemotherapy," explained Dr. Ryan, who served as a discussant during the presentation of this paper.
"Perioperative FOLFAX may be associated with improved progression-free survival," he said, "but chemotherapy is associated with various types of liver injury, including steatohepatitis, and preoperative therapy increases surgical morbidity."
The study shows that longer-term chemotherapy does not improve pathologic response, only liver injury, and the addition of bevacizumab increases the pathologic response, he pointed out.
"This MD Anderson experience, along with other experiences that have been reported, provides enough rationale to move forward with larger multi-institutional phase 3 trials in patients with resectable disease," Dr. Ryan said.
No Benefit Seen With Longer-Term Therapy
The optimal benefit, duration, and safety of preoperative chemotherapy in patients with colorectal liver metastases remain undefined. The goal of this study was to evaluate the association between the duration of preoperative chemotherapy with FOLFOX with or without bevacizumab, along with the pathologic response and the incidence of hepatotoxicity after hepatic resection, in patients with colorectal liver metastases.
Specific liver injury resulting from chemotherapy has been previously described, said lead author Daria Zorzi, MD. Steatohepatitis is associated with an increased 90 day mortality (15% vs 2% for no steatohepatitis) and an increased risk for death from liver failure (6%).
Dr. Zorzi and colleagues used a prospective hepatobiliary database and selected a cohort of 219 consecutive patients who underwent hepatic resection for colorectal liver metastases after receiving a preoperative chemotherapy regimen of FOLFOX. The patients were divided into 2 study groups, based on the duration of chemotherapy: the short course consisted of 157 patients who received from 1 to 8 cycles of treatment, and the extended course consisted of 62 patients who received 9 or more cycles.
They found that the clinical, surgical, and pathologic variables were similar in the short- and extended-course groups.
Pathologic Response to Preoperative Chemotherapy
| Response | Short course, n = 157 (%) | Extended course, n = 62 (%) |
| Complete response | 11 (7) | 7 (11) |
| Major response | 79 (50) | 27 (44) |
| <50%> | 90 (57) | 34 (55) |
Increased Response With Bevacizumab
However, patients in both study goups who received combination FOLFOX and bevacizumab had a significantly higher frequency of complete or major pathologic response than those who received FOLFOX alone. Among patients who received FOLFOX alone (n = 117), 53 (45%) experienced less than 50% residual tumor, as did 71 (70%) of those who received FOLFOX plus bevacizumab (n = 102).
"An improvement in response was seen with bevacizumab in both short- and [extended-course] chemotherapy," said Dr. Zorzi. "Extended chemotherapy resulted in increased sinusoidal injury, but when bevacizumab was added to the regimen, the incidence of sinusoidal injury was decreased in both regimens."
However, even though bevacizumab significantly reduces the incidence of sinusoidal injury, the researchers found that the rate of hepatic insufficiency was similar after correcting for duration of chemotherapy.
"Extended preoperative chemotherapy increases the risk of hepatotoxicity after hepatic resection for colorectal liver metastases, and does not improve pathologic response," Dr. Zorzi concluded, adding that the type of chemotherapy has more impact on pathologic response than duration, and the pathophysiology of liver insufficiency after FOLFOX appears to be independent of sinusoidal injury.
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