A Phase III trial from China has found that adding the monoclonal antibody cetuximab to chemotherapy converted some previously inoperable colorectal liver-specific metastases into those that could be resected, shrinking tumors and significantly increasing survival.
It is the first randomized study designed specifically to test that drug and chemotherapy against inoperable liver-specific metastases.
For patients with colorectal cancer who develop liver metastases, the prognosis is poor, with survival only about 20 months. However, so-called “conversion therapy” of isolated but initially unresectable liver metastases is possible, and studies have shown that between 12 and 33 percent of patients with initially inoperable liver metastases have a sufficient response to drugs to permit subsequent resection.
The new study, now available online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2012.44.8308), involved 138 patients with KRAS wild-type synchronous liver-specific metastases, including 70 who underwent combination therapy with cetuximab. The study included only patients with a KRAS gene because cetuximab is known to be ineffective against tumors with KRAS mutations. About 60 percent of all people with colorectal cancer have a normal KRAS gene.
In the trial, patients with stage IV colorectal cancer that had spread only to the liver were randomly assigned to receive chemotherapy plus cetuximab, or chemotherapy alone—either FOLFIRI (leucovorin, fluorouracil, and irinotecan) or mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin).
Following combination therapy, 18 of 70 patients, or 26 percent, became eligible for surgery, compared with just seven percent of those who received chemotherapy alone. The mean survival time for cetuximab-treated patients who underwent successful liver surgery was 46.4 months compared with 25.7 months in those in the chemotherapy-alone group, and the overall prolonged median survival time was 30.9 months for the former versus 21 months for the latter.
Combination treatment also significantly increased objective liver tumor shrinkage over chemotherapy-alone (57 versus 29 percent), and increased predicted three-year overall survival (41 percent versus 18 percent).
“The main findings of our study may be relevant for patients in Europe and North America, but we do also realize the study's limitations,” the lead author, Jianmin Xu, MD, PhD, a surgeon at Zhongshan Hospital and Fudan University, Shanghai, People's Republic of China, said in an interview.
“First, the number of patients analyzed was limited and follow-up time was short, so some findings from subgroup analyses should be interpreted with caution, especially which chemotherapy-regimen patients underwent FOLFOX or FOLFIRI. Second, the population in this study was from just one Chinese center.”
In addition, he said, cetuximab is expensive and not approved for reimbursement in China, so some patients discontinued treatment while others who may have wanted to receive cetuximab were discouraged. “This may have resulted in some minimal bias in study results, he said.
Cetuximab is a monoclonal antibody that acts as an epidermal growth factor receptor (EGFR) inhibitor. It was approved by the Food and Drug Administration last year for use in combination with FOLFIRI for first-line treatment of patients with KRAS mutation-negative wild-type EGFR-expressing metastatic colorectal cancer.
National Comprehensive Cancer Network (NCCN) practice guidelines recommend “downsizing” chemotherapy or use of chemotherapy-targeted combination regimens to convert initially unresectable metastases to operable tumors.
“According to NCCN, surgical removal of metastases is the only potentially curative therapy for patients with colorectal liver metastases,” Xu said. “The drawback is that only 10 to 12 percent of patients with liver metastases are candidates for surgery. Fortunately, the appearance of target drugs such as cetuximab offers such patients a beacon of hope.”
Asked for his opinion for this article, Bert H. O'Neil, MD, Co-director of the GI Oncology Program at the University of North Carolina Lineberger Comprehensive Cancer Center, said that while the results are interesting, it remains uncertain whether cetuximab offers better results than use of combination therapy with the angiogenesis-inhibitor bevacizumab in terms of conversion to resectability.
“This study involved a relatively small sample size, but is interesting because it confirms other research findings—notably subgroup analyses of similar patients in the CRYSTAL and OPUS studies. It is not a novel observation, but it is the first study that I am aware of from Asia, so it does suggest consistency across ethnic groups.”
He noted that there is an ongoing debate over whether such patients do better with chemotherapy combined with a vascular endothelial growth factor (VEGF)-inhibitor such as bevacizumab or an EGFR-inhibitor such as cetuximab.
“Several studies have suggested that the response rate with cetuximab is better, but it will take a study like the Cancer and Leukemia Group B and SWOG CALGB80405 trial comparing the two drugs head-to-head to provide direct evidence of the front-line efficacy of bevacizumab versus cetuximab. This study compared cetuximab with no biologic therapy.”
He said that although cetuximab has been approved for use with chemotherapy in colorectal cancer metastases, “relatively few” patients with inoperable liver tumors are being treated with front-line cetuximab in the U.S., even though the rate in Europe is closer to 50 percent.
“This paper certainly adds to our understanding and confirms other research, but I feel we need more confirmation before routinely using cetuximab for this purpose.”
Better Definition Needed
Nancy E. Kemeny, MD, a medical oncologist in the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center and the author of an accompanying editorial, told OT that the definitions of resectable and unresectable liver metastases need to be clarified.
“Right now the definition of unresectable is subjective and based in part on the aggressiveness of the liver surgeon. Some surgical oncologists believe that having six metastases makes a patient unresectable while others do not,” she said. “For the oncology community, it is important to understand which type of patient can become resectable, and to do this we need more randomized studies. The good news is that in some patients with unresectable disease, shrinking the tumor can allow the patient to get to resection as this study demonstrated.”
She cautioned that although in the current study patients did much better with the addition of cetuximab, there are also several randomized studies that have not found an increase in resection rates with the addition of cetuximab to chemotherapy, and that the frequency of converting a patient with truly unresectable disease to the point of resectability by chemotherapy is about 15 percent.
“In this study, 25 percent of patients were able to undergo resection, but 66 percent of the patients had recurrence in the liver on follow-up. Future studies need to focus on decreasing liver recurrences.”
Another question is how many patients were truly unresectable. “Surgeons should look at all patients prior to study entry to determine that they are truly resectable,” she said.
Kemeny specializes in treating liver metastases using regional chemotherapy—administering drugs into an artery that feeds liver tumors. Hepatic arterial infusion (HAI) chemotherapy delivers high concentrations of cytotoxic agents directly to liver metastases with minimal systemic toxicities and decreases hepatic reoccurrence after resection.
She noted that when she began treating cancer patients 30 years ago survival was only about 12 months, but today patients are surviving five and even 10 years, even with multiple liver metastases.
“A lot of people do not realize that even when told they are initially unresectable, they can become resectable, which is what this article from China demonstrates.”