Alan P. Venook, MD
FOLFOX has been the standard chemotherapy regimen for patients with stage III colon cancer, but it can cause peripheral neuropathy in almost every patient, creating a negative impact on quality of life, explains Alan P. Venook, MD.
The IDEA trial, therefore, investigated the dosage of FOLFOX by giving patients 3 months of chemotherapy versus 6 months. The trial enrolled over 12,000 patients into 6 international studies to evaluate the noninferiority of each dosing schedule and disease-free survival (DFS). With a median follow-up of 39 months, 3263 DFS events were observed. Overall, the DFS rate at 3 years was 74.6% for 3 months of FOLFOX versus 75.5% for 6 months (HR, 1.07; 95% CI, 1.00-1.15).
“What we would like to see from analyses in the future is some clarity as to the right number of doses that maintains curability and is not likely to cause neuropathy,” says Venook.
In an interview during the 2018 OncLive®
the State of the Science SummitTM
on Gastrointestinal Cancers, Venook, The Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the significance of the findings of the international IDEA study investigating doses of FOLFOX for patients with colon cancer.
OncLive: Can you provide some background on the IDEA study and the significance of it?
: The challenge in the management of colon cancer has been our inability to get beyond FOLFOX, which is the chemotherapy that was shown to be helpful in curing more patients in the adjuvant setting back in 2004. The problem with the drug is that it causes peripheral neuropathy in almost every patient. Somewhere between 7 and 8 doses into treatment is the average time of onset neuropathy.
The goal is to get 12 cycles of this treatment into patients. However, in so doing, they may end up with peripheral neuropathy for the rest of their lives. It may get worse, but usually it gets better over time. Around 20% of patients are left with peripheral neuropathy.
The IDEA trial was a pooled analysis from 6 different groups around the world investigating the question of whether you could get away with less chemotherapy. If you could use 6 cycles you might eliminate neuropathy, and if it was equally effective that would be great. Every other story of adjuvant therapy has shown that you can get away with less therapy than previously thought.
The first study to be designed like that was an Italian trial that asked whether you could give FOLFOX for 3 versus 6 months. Subsequently, there was an international agreement amongst colon cancer researchers in recognition that this was an important question to investigate. Six trials were planned around the world, similar to the Italian study which had already started, and we agreed to pool the data to increase the statistical power and answer the question clearer.
It turns out that once enough data had been accumulated and looked at, the data show almost exactly similar survival between patients who get 3 months versus 6 months around the world. This is over 12,000 patients with stage III colon cancer. The issue, though, is how they designed the analysis. As a statistician who designed the analysis, they had a statistical endpoint. They used what is called noninferiority to make sure that patients were not jeopardizing their chance of being cured by taking less chemotherapy.
Even though the difference in DFS was less than 1% across all arms, it did not meet the criteria for being statistically noninferior so, technically, you could say that 3 months is not as good.
This is an individualized decision, but what the IDEA investigators did is look at a subset of patients who appeared to be at higher risk; these were mainly patients with many positive lymph nodes. Those patients generally needed 6 months of treatment versus 3. One thing that will come out when the paper is published, is that the authors will say that, “You could distinguish a difference between FOLFOX and CAPOX [capecitabine combined with oxaliplatin] Capecitabine was used as a substitute at the discretion of many of the doctors.
In 5 of the studies, either CAPOX or FOLFOX was permitted, but we only use FOLFOX in the United States and Canada. That was not a randomized decision; it was made by the doctors and patients. In some of these subset analyses, it looked like the patients who received capecitabine did better. That may be true, but I am hard-pressed to see how you can conclude that when it is not a randomized decision. In the United States and Canada, we did not use CAPOX in our study that contributed to the pooled analysis, since capecitabine is poorly tolerated in some patients.