A study published in the April 4 issue of JAMA reveals that patients who receive the drug cetuximab in addition to chemotherapy after undergoing surgery for stage III colon cancer do not have improved disease-free survival.
According to the researchers, the chance of cure among patients who undergo surgery for removal of stage III colon cancer is 50%. Several studies have demonstrated the benefit of chemotherapy following surgery in lowering the recurrence risk.
The authors write:
"Specifically, [the drugs] leucovorin, fluorouracil, and oxaliplatin (FOLFOX or slightly different method, FLOX) provides significant benefit in both disease-free and overall survival compared with the prior standard of fluorouracil and leucovorin."
For patients suffering metastatic colorectal cancer, cetuximab and panitumumab, alone or in conjunction with chemotherapy, have provided additional benefit than chemotherapy alone.
The scientists said:
"This benefit, however, is limited to patients with tumors expressing the wild-type [a strain used as a standard reference to compare any mutant derivatives] form of the gene KRAS as opposed to those with the mutated form of KRAS."
In order to evaluate the potential benefit of cetuximab, in addition to the modified sixth version of the FOLFOX regimen (mFOLFOX6), in individuals with resected stage III wild-type KRAS colon cancer, Steven R. Alberts, M.D., of the Mayo Clinic, Rochester, Minn, and team conducted a study involving 2,686 patients.
They began recruiting participants from February 2004 and permanently discontinued enrollment in November 2009, after a second examination showed that disease-free survival of the cetuximab group was unlikely to surpass that of the mFOLFOX6-only group.
In this study, 1,863 of the 2,686 patients had wild-type KRAS, 106 patients indeterminate KRAS, and 717 patients mutated KRAS. Participants were randomly assigned to receive either 12 biweekly cycles of mFOLFOX6 with or without cetuximab. Study participants received median follow-up of 28 months.
Adding cetuximab provided no benefit, according to results from the study. The researchers found that three-year disease-free survival for patients with wild-type KRAS receiving mFOLFOX6 alone was 74.6%, compared with 71.5% in patients who received mFOLFOX6 in addition to cetuximab, and 67.1% vs. 65.0% in participants with mutated KRAS. The team found no evidence of benefit in any individual subgroup. Furthermore, between treatment groups, no considerable difference was found between overall survival and time-to-recurrence.
The researchers explained:
"Among all patients, grade 3 or higher adverse events (72.5 percent vs. 52.3 percent) and failure to complete 12 cycles (33 percent vs. 23 percent) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older."
The team highlight that they are unsure as to why mFOLFOX6 in addition to cetuximab provided no additional benefit.
"In this randomized phase 3 trial for patients with resected stage III colon cancer expressing wild-type KRAS mutations, the addition of cetuximab to mFOLFOX6 did no improve disease-free or overall survival in contradistinction to the original study of cetuximab combined with FOLFOX in metastatic colorectal cancer.
New approaches are needed to identify drugs that may be of benefit in adjuvant therapy, because as shown in our trial promising activity in the metastatic setting did not translate into adjuvant therapy benefit and underscores the importance of performing clinical trials."
In an associated report, Neil H. Segal, M.D., Ph.D., and Leonard B. Saltz, M.D., of Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, state that even though results the negative results of this trial are surprising, this pattern has been seen previously.
"The inescapable conclusion is that efficacy in the metastatic setting does not reliably predict efficacy in the adjuvant setting. The role of adjuvant chemotherapy does not involve treating the tumor that the surgeon has removed, but rather attempts to eradicate whatever occult micrometastatic disease may still be present after surgery.
If there are no micrometastases, surgery is curative and adjuvant chemotherapy is unnecessary. If micrometastases are present, the long-term health of the patient will depend on whether the chemotherapy can destroy all remaining micrometastases."