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Perioperative chemotherapy with FOLFOX4 can improve progression-free survival in patients with liver metastases from colorectal cancer, according to phase III trial results presented in the plenary session.
Progression-free survival at 3 years was 36% in all patients assigned to perioperative chemotherapy versus 28% in all patients assigned to surgery alone (hazard ratio 0.77, P = .041), Dr. Bernard Nordlinger reported on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Intergroup study 40983.
The benefit was more pronounced in patients whose metastases were resected, as opposed to those deemed inoperable despite being seen as resectable on imaging, according to Dr. Nordlinger, who is the chair of the department of surgery and oncology at the Hôspital Ambroise Paré, Boulogne-Billancourt, France.
Progression-free survival at 3 years reached 42.4% for resected patients in the chemotherapy arm, compared with 33.2% for those in the surgery-only arm (HR 0.73, P = .025).
That translates into a nearly 30% reduction in the risk of relapse among chemotherapy patients.
"This treatment should be proposed as the new standard for these patients, and very importantly, should be delivered by a multidisciplinary team," Dr. Nordlinger said.
Between September 2000 and July 2004, the EORTC 40983 investigators randomized 364 patients with up to four liver metastases evident on their CT scans to either surgery alone or to six cycles before and six cycles after surgery of FOLFOX4 (leucovorin, 5-fluorouracil, oxaliplatin) chemotherapy.
Data were reported at a median follow-up of 48 months with a cutoff date of March 2007. The average patient age was 62 years in the chemotherapy arm and 64 years in the surgery arm.
Of the 182 patients who were randomized to chemotherapy, 143 (79%) were treated with six cycles of preoperative chemotherapy, 151 (83%) underwent resection, and 80 (44%) went on to receive six cycles of postoperative chemotherapy.
Of the 182 patients randomized to surgery, 152 (84%) were resected.
Grade 3 sensory neuropathy was reported in 2.3% of pre- and 9.6% of postoperative chemotherapy patients; grade 3 diarrhea in 8.2% and 5.2%, respectively; and grade 3-4 neutropenia in 18% and 35%, respectively.
There were no chemotherapy-related deaths.
Reversible surgery complications, usually liver insufficiency, were reported in 25% of chemotherapy patients and in 16% of surgery-only patients. There was one postoperative death in the chemotherapy arm, and two in the surgery-only arm.
"Liver metastases are observed in 40%-50% of 1 million patients diagnosed with new colorectal cancer worldwide each year. When resected, 5-year survival is close to 35%, but cancer relapse is common," he said, noting that just 15%-20% of patients are deemed suitable for surgical resection.
Progress in imaging is already reducing the number of patients who are deemed nonresectable at surgery, Dr. Nordlinger said.
In addition, the timing and duration of chemotherapy may be optimized, and chemotherapy with new agents will be tested in further studies.
One such study, the phase II EORTC 40051 trial, opened in April 2007, and will evaluate modified FOLFOX6 chemotherapy with cetuximab vs. modified FOLFOX6 with cetuximab plus bevacizumab as perioperative treatment in patients with resectable liver metastases from colorectal cancer.
In a discussion of EORTC 40983, Dr. Nicholas J. Petrelli said that perioperative chemotherapy with FOLFOX4 is not yet the first choice for resectable colorectal hepatic metastases, although some oncologists will use the findings to reinforce what they are already doing. He said the results were encouraging, but were weakened by the subgroup analysis.
Although chemotherapy offers the potential for control and improved survival, hepatic resection is the only potentially curable treatment for colorectal liver metastases, said Dr. Petrelli, a surgeon and medical director of the Helen F. Graham Cancer Center in Wilmington, Del.
Dr. Petrelli said chemotherapy-induced liver injury is a reality, and stressed the importance of maintaining healthy non-tumor-bearing liver parenchyma prior to surgery.
Nordlinger B. Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. Abstract LBA5.
Commentary |
This trial consisted of patients with potentially resectable liver metastases. Its goal was to determine whether standard chemotherapy (FOLFOX4) given preoperatively for six cycles and postoperatively for six cycles would improve disease-free survival. An important eligibility criterion for the study was that patients could not have received prior oxaliplatin therapy. All patients received chemotherapy both before and after surgery; the trial was not meant to determine the benefit of preoperative vs. postoperative therapy. It did demonstrate an almost 10% increase in progression-free survival at 3 years with perioperative chemotherapy. The data are encouraging, but issues remain regarding the role of liver injury, the increased complication rate in the chemotherapy group, whether preoperative chemotherapy in resected patients is necessary, and the true benefit of postoperative therapy. — Stuart M. Lichtman, M.D.
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