Perioperative FOLFOX4 Cuts Liver Metastases in Colon Cancer

Allison Gandey

June 26, 2007

June 26, 2007 (Chicago) — Adding chemotherapy before and after surgery to remove liver metastases significantly reduces the risk for liver tumor recurrence, researchers say. Reporting results of their new phase 3 trial here at the American Society of Clinical Oncology 43rd Annual Meeting, investigators showed that patients who received 6 cycles of FOLFOX4 — a combination of 5-fluorouracil, leucovorin, and oxaliplatin — to shrink tumors before surgery and another 6 cycles after the procedure had improved progression-free survival.

The trial, EORTC 40983 from the European Organization for Research and Treatment of Cancer group, is the first to examine this issue. "This approach may become the standard of care for patients with liver metastases from colorectal cancer that can be surgically removed," Bernard Nordlinger, MD, from Ambroise Paré, in Boulogne, France, told reporters. "The findings also support a multidisciplinary approach to care, with all members of the patient's healthcare team collaborating to determine the optimal combination of chemotherapy and surgery."

Discussing the findings at the meeting, Nicholas Petrelli, MD, medical director of the Helen Graham Cancer Center and professor of surgery at Thomas Jefferson University, in Philadelphia, Pennsylvania, congratulated the investigators for completing accrual on a difficult trial. But he disagreed with conclusions that perioperative treatment with FOLFOX4 represents a standard of care. "Chemotherapy-induced liver injury is real," he cautioned. "Patient selection, drug type, and duration of chemotherapy must be taken into consideration in the adjuvant and neoadjuvant hepatic resection clinical trial setting."

Dr. Petrelli said that while perioperative chemotherapy is not yet the first choice for resectable colorectal hepatic metastases, some oncologists will no doubt use this trial to reinforce what they have been doing anyway. He called the results "encouraging," but additional questions remain, he said, and the use of subgroup analysis weakens the results.

During his talk, Dr. Petrelli told meeting attendees that hepatic resection is still a good first option for resectable metastases. And he suggested that there is general agreement that hepatic resection is the only potentially curable treatment for colorectal liver metastases.

Do Benefits of Adding Chemotherapy Outweigh the Risks?

During an interview with Medscape, press-briefing moderator William Blackstock, MD, from the Wake Forest University School of Medicine, in Winston-Salem, North Carolina, said the positive study was very well done. "There are not many data sets like that," he said. "This trial does establish that chemotherapy can be done around resection safely. I didn't agree with Nick. I thought the benefits outweighed the risks in this trial."

The 2007 National Comprehensive Cancer Network (NCCN) guidelines exploring this issue adopt a similar approach. The guidelines say that patients with completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy. A shortened course or observation is suggested for patients who had prior neoadjuvant chemotherapy.

In the new trial, investigators looked at 364 patients with colorectal cancer that had spread to the liver. They randomly assigned half of the patients to receive perioperative chemotherapy and the remaining patients to receive surgery alone. Not all patients remained eligible for surgery. Median follow-up was 48 months.

Results From EORTC Trial
Chemotherapy (n)
Surgery (n)
Absolute Difference in 3-year Progression-Free Survival (%)
Hazard Ratio (CI)
+7.2 (28.1 – 35.4)
0.79 (0.62 – 1.02)
All eligible
+ 8.1 (28.1 – 36.2)
0.77 (0.60 – 1.00)

Response Evaluation Criteria in Solid Tumors After Pre-Operative Chemotherapy
Patients (n=182), n (%)
Complete response
7 (3.8)
Partial response
73 (40.1)
Stable disease
64 (35.2)
Progressive disease
12 (6.6)
8 progressed after 3 to 4 cycles, 3 were resected

4 progressed after 6 cycles, 1 was resected

Not evaluable
26 (14.3)
Benign lesion
<3 cycles
No follow-up measures

Tolerance to Postoperative Chemotherapy
Grade 3/4 Toxicities
Patients (n=115), n (%)
5 (4.4)
6 (5.2)
5 (4.3)
3 (2.6)
Hand-foot syndrome*
1 (0.9)
Sensory neuropathy*
11 (9.6)
Cholinergic syndrome*
1 (0.9)
5 (4.3)
6 (5.2)
1 (0.9)
Febrile neutropenia*
4 (3.5)
Infection without neutropenia*
2 (1.7)
Catheter-related infection*
5 (4.3)
14 (12.2)
40 (34.8)
8 (7.0)
1 (0.9)
*No grade 4

Critiquing the findings, Dr. Petrelli said a range of 7% to 9% in absolute difference in progression-free survival is minimal. There is little difference in the hazard ratios for the groups — especially when considering the confidence intervals, he said. "The resected group is the more homogeneous group and also more likely to show less variation in response other than that attributed to the chemotherapy."

Dr. Petrelli posed a number of questions for the planned publication of the findings. In patients who underwent hepatic resection, how many additional metastases were found on pathology, he wanted to know. And were the number of metastases resected in each group balanced after pathologic examination of the resected liver?

Dr. Petrelli also suggested that the next phase 3 trial should compare neoadjuvant with adjuvant therapy. "More chemotherapy is not necessarily better," he said, "and it's not just a matter of timing the therapy, it's a matter of maintaining a healthy non–tumor-bearing liver parenchyma prior to surgery."

American Society of Clinical Oncology 43rd Annual Meeting: Late-breaking abstract 5. Presented June 4, 2007.


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