Cetuximab Boosts Chemo in Colorectal Liver Mets

Cetuximab Boosts Chemo in Colorectal Liver Mets
By Michael Smith, North American Correspondent, MedPage Today
Published: November 25, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
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Adding a biological agent to standard chemotherapy in difficult-to-treat cases of colorectal liver metastases significantly improved responses, researchers said.
In a randomized, Phase II study of patients whose tumors were initially considered inoperable, the approach also significantly increased the number of patients who were able to have surgery, according to Gunnar Folprecht, MD, of University Hospital Carl Gustav Carus in Dresden, Germany, and colleagues.

The regimen was "generally found to be tolerable," the researchers reported online in The Lancet, although 72% of patients had grade 3 or worse toxicities.
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The findings come from a study of 111 patients whose colorectal cancer had been surgically removed, but who developed liver metastases that were regarded as nonresectable.

Such patients have a poor prognosis, the researchers said, but earlier research had suggested that neoadjuvant chemotherapy based on irinotecan (Camptosar) or oxaliplatin (Eloxatin) could shrink tumors and consequently make surgery possible.

Since many colorectal liver metastases express the epidermal growth factor receptor (EGFR), the researchers decided to test the effect of adding cetuximab (Erbitux) to the chemotherapy.

Cetuximab is a monoclonal antibody, administered by intravenous infusion, that inhibits the EGFR receptor.

Patients were randomly assigned to get either irinotecan- or oxaliplatin-based chemotherapy, with the addition of cetuximab, and were followed for up to two years, with surgeons regularly re-evaluating whether surgery was possible.

While the main study was not blinded, the researchers carried out a retrospective blinded surgical review of 68 patients who had MRI and CT scans at baseline and during treatment.

Folprecht and colleagues found:

* An objective complete or partial response in 62% of patients, with no significant difference between the groups
* 36 of 106 evaluable patients were eventually able to have surgery with no margins left -- so-called R0 surgery -- while another 13 had microscopic margins and/or radiofrequency ablation

The blinded review found that treatment with cetuximab significantly increased the proportion of tumors that were amenable to surgery -- 60% were judged to be resectable after treatment compared with 32% at the start of the study.

The difference was statistically significant at P=0.0001.

Review also found that response was higher in patients with KRAS wild-type tumors than in patients whose KRAS gene was mutated, 70% versus 41%, which was significant at P=0.008

The researchers also found a significant benefit for patients whose tumors contained the wild types of KRAS and another gene, BRAF, compared with those who had either one mutated.

Of the 64 patients with both wild types, 46 responded to therapy, compared with 12 of 30 patients who had a mutation in either. The difference was significant at P=0.003.

Recent research has shown that activating mutations in either gene results in increased resistance to EGFR inhibitors, the researchers noted.

"The 70% response rate in patients with a KRAS wild-type tumor is very encouraging," said Sabine Tejpar, MD, PhD, of the Catholic Hospital of Leuven in Leuven, Belgium, and colleagues in an accompanying comment article.

The finding "consolidates" results from earlier studies, they said, and opens the door to studies that look at such clinically important endpoints as overall survival.

The study was supported by Merck-Serono, sanofi-aventis, and Pfizer. Folprecht reported financial links with Merck Serono, Pfizer, sanofi-aventis, Roche, Abbott, and Amgen. Other authors also reported potential conflicts

The comment authors declared no conflicts of interest.

Primary source: The Lancet Oncology
Source reference:
Folprecht G, et al "Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial" Lancet Oncol 2009; DOI: 10.1016/S1470-2045(09)70330-4.

Additional source: The Lancet Oncology
Source reference:
Tejpar S, et al "Improved first-line chemotherapy: a better chance for surgery?" Lancet Oncol 2009; DOI: 10.1016/S1470-2045(09)70345-6.