Tracks 1-2

DR LOVE: Howard, do you recommend preoperative chemotherapy for patients with potentially resectable hepatic metastases?

DR HOCHSTER: If a patient has a clearly resectable liver lesion or two, we have a discussion with the patient and the surgeon as to whether it makes more sense to do surgery first or to administer induction chemotherapy and then go for surgery.

I believe administering chemotherapy first is an option, and while we don’t have data showing that induction chemotherapy improves survival, we hope the EORTC-40983 trial will show that eventually.

In this Phase III trial, patients with potentially resectable liver metastases were randomly assigned to receive three months of FOLFOX before and three months of FOLFOX after surgery or to undergo surgery without chemotherapy (Gruenberger 2006b; [7.1]).

If the trial demonstrates a survival benefit for chemotherapy, then we will know to treat these patients with chemotherapy up front. However, you have to bear in mind that the systemic therapy in the trial is FOLFOX alone, not FOLFOX with bevacizumab.

DR LOVE: How do you treat the patient who has either unresectable liver disease or one or two metastases in the lung in addition to the liver metastases?

DR HOCHSTER: In those cases, I prefer FOLFOX with bevacizumab because that combination has the highest response rate. The first-line data from the somewhat abbreviated SWOG study show that cetuximab also improves the response rate when combined with chemotherapy, so we have two antibodies that increase the response rate over chemotherapy alone.

The CALGB-C80203 study, presented by Alan Venook at ASCO 2006, was supposed to accrue 2,200 patients but was stopped early after enrolling approximately 280. The design was a two-by-two randomization of FOLFOX versus FOLFIRI with or without cetuximab. The addition of cetuximab showed approximately a 10 to 20 percent increase in the response rate for both arms, so this study also suggests that the addition of cetuximab to first-line chemotherapy improves the response rate (Venook 2006; [7.2]).

Data from the large European study, the CRYSTAL trial, should also be available soon. This trial compares FOLFIRI with or without cetuximab for first-line therapy. According to the recent press release, cetuximab did increase progression-free survival, which was the primary endpoint.

Track 4

DR LOVE: Can you review the BOND-2 trial?

DR HOCHSTER: This was a Phase II, NCI consortium trial that we participated in with Leonard Saltz at Memorial. The trial evaluated patients whose disease had progressed on an irinotecan regimen but who had not received bevacizumab previously. Patients who received both bevacizumab and cetuximab had approximately a 20 percent response rate, as compared to 11 percent among patients who received cetuximab only.

The toxicities were as expected from either antibody, with no unexpected or synergistic toxicities (Saltz 2005). They saw vascular side effects and perforations from the bevacizumab and skin toxicities from the cetuximab.

DR LOVE: What other ongoing studies are evaluating the double antibody approach?

DR HOCHSTER: Two studies are examining this strategy in the front-line setting. The PACCE study is a first-line study of FOLFOX or FOLFIRI with bevacizumab in one arm versus bevacizumab and panitumumab in the second arm. It has already completed accrual, and data should be available in the next year.

The other study is the CALGB Intergroup study, C80405, which is a three-arm study powered for survival, so it is a much bigger study. The physician selects either FOLFOX or FOLFIRI, and then patients are randomly assigned to bevacizumab alone, cetuximab alone or the combination of the two (7.3).

That’s an excellent study, which, if completed, will show the merits of using an anti-VEGF antibody, an anti-EGF antibody or the combination of the two. That should give us some clear data.

Track 8

DR LOVE: Axel, what do you consider a reasonable approach to treating patients with potentially resectable metastatic disease in practice?

DR GROTHEY: I believe what we are seeking in the neoadjuvant setting is response rate, more than delaying of tumor progression, but we don’t want to get to the point where we can no longer see the metastases. I have heard the statement, “The medical oncologist’s dream is a surgeon’s nightmare.” We know that a complete response in a liver metastasis is not a complete response by the pathology criteria.

I can easily see the rationale for using EGF receptor antibodies based on Alan’s data and other data (Venook 2006). A consistent response rate benefit occurs when we add cetuximab. However, the data are limited, and we’re still waiting on the Phase III first-line trial results with cetuximab.

Whether we should also add bevacizumab is a different question. For now, I believe that in first-line, neoadjuvant therapy, response rate is our surrogate marker for resectability, but how we get there is an area of discussion.

DR LOVE: What do you currently use in clinical practice?

DR GROTHEY: Off study, I’ve used FOLFOX/bevacizumab, and I’ve used FOLFOX/cetuximab.

DR LOVE: Alan, how do you feel about double biologic therapy in this setting?

DR VENOOK: One of the endpoints of the Phase III CALGB-C80405 trial, the study of cetuximab and/or bevacizumab with FOLFOX or FOLFIRI in patients with previously untreated metastatic colorectal cancer, is to analyze the number of patients who go to surgery. However, off study, I would not use double biologics, largely due to the insurance issues.

DR LOVE: How do you feel about using FOLFOXIRI in this setting?

DR VENOOK: Data in the literature are conflicting regarding FOLFOXIRI. A paper from the Hellenic Oncology Society in Greece in the British Journal of Cancer showed more toxicity and no benefit with FOLFOXIRI when compared to FOLFIRI (Souglakos 2006).

Generally, our approach is to treat these patients with four cycles of FOLFOX/bevacizumab. If at that point the tumor is deemed resectable, we stop the bevacizumab, administer another dose of FOLFOX and then resect six weeks after the last dose of bevacizumab.

We have to be careful not to offer too much treatment to these patients preoperatively, or we may eradicate the disease and the surgeon doesn’t know where to go, believe it or not. Also, it may result in a fatty liver, and the experienced hepatic surgeon can tell you that the liver is like mush in some of these patients who have been too heavily pretreated.

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Neil Love, MD