Frontline Treatment for KRAS Wild-Type mCRC

Michael Cusnir, MD:The current recommendations for wild-type colorectal cancer patients with metastasis to the liver is really open. Based on the European studies, you would say that you would be better off treating patients with left-sided tumors with epidermal growth factor receptor inhibitors. If you base your decisions on the American studies, the data are less convincing but still show that left-sided tumors might benefit from the frontline use of epidermal growth factor inhibitors while the right-sided tumors appear to have very little benefit with the use of epidermal growth factor receptor inhibitors.

Nowadays, we have seen studies that show that intervening in the liver of patients who would have a worse prognosis in a much more aggressive fashion may be beneficial as well. Using certain technologies in those patients, such as liver-directed therapies, would be of benefit and may change the prognosis in those patients.

The use of FOLFOX [folinic acid, fluorouracil, and oxaliplatin] as a mainstream therapy has also been something that has almost become an American tradition. But if you look at the European studies, they tend to favor FOLFIRI [folinic acid, fluorouracil, and irinotecan]. Honestly, there might be a lot to say about that. It might be that FOLFOX doesn’t necessarily need to be our frontline therapy, and that we could use some other therapy, such as FOLFIRI, instead. Obviously, the problem here is the side effects and the toxicity profile that patients are facing. We’re seeing an increased incidence of alopecia in patients who are being treated with FOLFIRI. That’s part of the reason why a lot of our patients may end up choosing a therapy with FOLFOX. There’s also a lot to be said of the maintenance studies that have been done and the rationale behind using one backbone of chemotherapy versus the other.

The biologics that we are using nowadays for colorectal cancer are really divided between the epidermal growth factor receptor inhibitors and the vascular endothelial growth factor inhibitors. The main discussion here is to determine whether we should favor using the epidermal growth factor inhibitors on the left side and vascular endothelial growth factor inhibitors on the right side. I don’t think that question is completely settled. Overall, we have seen that there is a possibility of a 4-month improvement in survival when using the epidermal growth factor inhibitors on the left side. Again, this includes quality of life. There are studies that have been done looking at quality of life secondary to skin issues on the left side. A lot of patients end up choosing not to go that route, even if there was a 4-month improvement in survival in the phase III studies.

Tumor sidedness affects the progression-free survival and the overall survival regardless of the therapy that is given. We’ve seen a lot of panels and heard a lot of discussions that say that FOLFOX will do better in patients who are treated with tumors on the left side versus right side. The data on prognosis is so strong that even in between best supportive care, right-sided tumors (versus left-sided tumors) will do worse. If you look at historical data from the 1990s, when our only drug was fluorouracil, the difference in overall survival between right-sided and left-sided tumors in meta-analyses could be measured in 6 months. So we’ve seen this coming. The new data are now stronger to separate the 2 groups, and we’re starting to understand why.

Transcript edited for clarity.