Preoperative Chemotherapy With FOLFOX4 Shrinks Potentially Resectable Liver Metastases of Colorectal Ca

ATLANTA—Preoperative chemotherapy with FOLFOX4 reduces by almost one-third the sum of the diameters of potentially resectable liver metastases of colorectal cancer, according to interim results of a phase III trial presented at the 2006 American Society of Clinical Oncology Annual Meeting (abstract 3500). [See also article on page 15.]

About 70% of patients who undergo resection of liver metastases of colorectal cancer subsequently experience a recurrence, said Thomas Gruenberger, MD, of the University of Vienna. "We were unable until now to demonstrate any benefit of adjuvant chemotherapy. That's why the main aim of this study was to give preoperative chemotherapy," he said, with the primary objective of improving progression-free survival.

Patients were eligible for the trial (EORTC Intergroup 40983) if they had up to four potentially resectable liver metastases of colorectal cancer, did not have any extrahepatic disease on primary imaging, and had not previously received oxaliplatin (Eloxatin) or palliative chemotherapy. A total of 364 patients were randomly assigned to receive surgery alone to resect the metastases or six 15-day cycles of FOLFOX4, followed by surgery, followed by another six cycles of FOLFOX4. Initial safety and feasibility data, presented at the 2005 ASCO meeting, showed that perioperative morbidity and mortality were not increased by preoperative chemotherapy, he noted.

Shrinking Diameter

In the chemotherapy group, the median diameter of the largest liver metastasis on CT scans was 33 mm before preoperative chemotherapy vs 24 mm afterward, corresponding to a median absolute shrinkage of 8 mm. "These results do include patients who progressed on therapy," Dr. Gruenberger noted. Furthermore, whereas 22% of patients had a largest metastasis measuring more than 5 cm in diameter before preoperative chemotherapy, only 13% had one of this size afterward. Similarly, he said, the median value for the sum of the largest diameters of liver metastases was 45 mm before vs 30 mm after preoperative chemotherapy, corresponding to a median absolute reduction of 13 mm or a relative reduction of 30%. According to RECIST criteria, 3% of patients had a complete response to preoperative chemotherapy, 35% had a partial response, 34% had stable disease, and 8% had progressive disease, Dr. Gruenberger reported. Data are still pending for an additional 20% of patients.

Overall, 87% of patients in the chemotherapy group and 92% of those in the surgery-only group did undergo surgery as planned. Liver metastases were resected in 83% and 82% of patients in the chemotherapy and the surgery-only groups, respectively.

"We have found that CT scan measurements are consistent with measurements taken at pathology," Dr. Gruenberger said. Pathologic evaluation of the resection specimens showed that both the diameter of the largest liver metastasis and the sum of the largest diameters of liver metastases were markedly smaller in the group that received preoperative chemotherapy.

Survival Data Not Yet Available

"We were able to reduce the sum of the diameter of the lesions by giving these patients FOLFOX4 preoperatively," Dr. Gruenberger concluded. He pointed out that the size of metastases at the time of surgery is a known prognostic factor for survival. He said he hopes to be able to present data on progression-free survival and survival at the end of this year.

When asked if the chemotherapy-related delay in surgery might allow disease to progress in some, thereby losing the opportunity for resection and possible cure, Dr. Gruenberger said, "If the patient is progressing under chemotherapy, he is not a good candidate for resection because the disease recurs within a short period. With preoperative chemotherapy, you can find out if the patient is really a candidate for resection."