Clinical Review of SIRT and Chemo in First-Line mCRC

Michael Cusnir, MD:The addition of selective internal radiation therapy was the scope of a major clinical trial that was actually the consolidation of many other trials. What they did in that clinical trial was add selective internal radiation to frontline therapy, which at that time was chosen as the control arm to be a FOLFOX [folinic acid, fluorouracil, oxaliplatin]/Avastin [bevacizumab] regimen. The study looked to see if frontline treatment of nonresectable disease in the liver would change the survival of these patients.

The design of that trial was done by adjusting the doses of the experimental arm. The investigators were concerned that there could be a problem giving targeted agents, such as a bevacizumab, with the selective internal radiation. They withheld that biologic until after the fourth cycle.

Furthermore, they were concerned that radiation may radiosensitize the liver too much. They decreased the dose of the oxaliplatin in the FOLFOX regimen of the experimental arm and then reescalated again after a few cycles of treatment. They intended to treat the patients concomitantly, within the first cycle or so of the chemotherapy, with the selective internal radiation therapy. The control arm was a standard FOLFOX-bevacizumab type of regimen, and the patients were treated until progression. The primary objective of the studies, individually, was progression-free survival. In all the studies that were done globally, it was overall survival.

There were 2 other caveats of the design of the study. They allowed for patients to be treated even if their disease was not liver limited. Patients with metastatic disease outside the liver were eligible to go on the study with liver dominance. The progression-free survival was taken not only on the liver but on any site of disease.

I think that it could have confused us on the analysis of the data. We decreased the doses of the systemic chemotherapy quite a bit. The biologic was probably held until the time when the first scans were done. By then, we were calling it progression of the disease, even if it was outside the liver on the experimental side.

So I find the design to be a bit flawed. We would have liked to have seen a design that would have allowed patients to be treated with much more similar chemotherapy and not at reduced doses, subsequently taking liver-only disease because the intervention was being done only in the liver.

The final results of the SIRFLOX and the FOXFIRE studies were disappointing. They did show that the progression-free survival and overall survival of the population that was treated in the study was not affected. So it is considered to be a negative study. Again, the progression-free survival could have been influenced by extrahepatic disease that showed progression. It is also possible that with the overall survival, the chemotherapy may have been insufficient in the initial stages of the treatment of the disease.

The most impressive part of the data that we can now get, of the studies with selective internal radiation with microspheres, is that the sidedness appears to have, again, a prognostic and predictive factor. The sidedness was prognostic in the sense that the patients with right-sided tumors had a worse overall survival, but the predictive factor was the opposite of everything that we had ever seen. Every tumor that we have intervened on the left side does better with our experimental treatments. If we use a biologic on the left side, such as an EGFR inhibitor or a VEGF inhibitor, patients are going to face a better prognosis.

In the selective internal radiation studies—in the SIRFLOX and FOXFIRE studies—the patients with right-sided tumors did better than those with left-sided tumors. The right side of the colon had a survival that never passed, in most of our clinical studies, the 20-month survival range. With the addition of selective internal radiation, we’ve seen that the numbers, including in some patients with extrahepatic disease, may have crossed the 22-month survival range.

More impressively, this is an unselected population of all comers, not onlyKRASwild type. In the wild-type studies, patients with right-sided colon cancer had a survival that was, again, less than 20 months. Here we have a population that may have included a lot of patients with mutated tumors. We see the trend moving toward over a 22-month survival range. So there were very impressive data in that subgroup analysis.

Transcript edited for clarity.