Select Excerpts from the Interview

Track 2

DR LOVE: Would you discuss the NSABP-C-07 and MOSAIC trials?

DR ENZINGER: Unlike the MOSAIC study (de Gramont 2003; André 2004), the FLOX — or NSABP-C-07 — study (Wolmark 2005) specifically looked at a bolus regimen of 5-FU and leucovorin with or without oxaliplatin. In a sense, it was the traditional Roswell Park regimen with oxaliplatin added to every other treatment.

The accrual for the trial took a little bit longer than that of the MOSAIC study, and the results were reported at a later date. NSABP-C-07 investigators ultimately came to the conclusion that oxaliplatin adds a 4.9 percent absolute benefit when added to 5-FU and leucovorin therapy, almost the same absolute three-year benefit that was found in the MOSAIC study (3.1).

The question is whether we need to give infusional 5-FU or whether we can continue with bolus dosing of 5-FU. Ultimately, I think the infusional 5-FU schedules have lower overall toxicity, but the dose of oxaliplatin in the MOSAIC study was higher, so patients had a higher incidence of neuropathy.

In NSABP-C-07 (Wolmark 2005), a 10 percent difference in Grade III and Grade IV toxicities was evident between the Roswell Park regimen (FU/LV) and the same regimen plus oxaliplatin (FLOX). Seven percent of that difference is due to neuropathy. So the difference in overall toxicity is really only three percent.

The ultimate conclusion is that NSABP-C-07 is a confirmatory trial. It confirms the benefit of oxaliplatin, and it offers oncologists an alternative way of administering this agent in combination with 5-FU and leucovorin, which is reassuring.

I would like to see the overall survival advantage for both trials, and that will probably become evident as deaths increase. When we look at the number of patients who are dying and the patients who are having recurrences, we see that the number of patients with recurrences is increasing.

We’re beginning to see a trend in that direction. My suspicion is that it’s going to take some time before we actually see an overall survival advantage in either one of these trials.

Track 5

DR LOVE: In what situation would you discontinue oxaliplatin due to neurotoxicity? I hear people talk about discontinuation prior to the development of functional impairment. Is that your approach?

DR ENZINGER: Yes, although I think the more interesting question is when to start attenuating the dose. Do you push the patient to functional impairment using the full dose, or do you start attenuating early or drop the oxaliplatin as in the OPTIMOX trial (de Gramont 2004)?

There are many ways of doing this in metastatic disease, and I don’t think there’s one right or wrong way. With many other therapies available, giving treatment for a certain period of time and then switching to something else before these neuropathies arise may be the better approach.

Colleagues who treat lung and breast cancer utilize a set number of cycles, or they treat for a set period of time. It’s really only with the GI malignancies, because our patients have such a poor prognosis, that we treat continuously.

We probably should begin to consider adopting more of a breast or lung cancer type of approach. In part, I believe that patients will have a better quality of life using that kind of approach.

DR LOVE: FOLFOX in the metastatic setting is very different from using it in the adjuvant setting. In the adjuvant setting, how many patients discontinue the drug? Generally, when is it stopped?

DR ENZINGER: I almost always have to attenuate the oxaliplatin toward the end of the treatment. I need to attenuate oxaliplatin starting around the eighth or ninth treatment in 80 or 90 percent of all patients. I’ve had to drop oxaliplatin completely in 10 percent.

Track 6

DR LOVE: When patients are about to start receiving FOLFOX for the first time and they ask you about the chances of having some type of residual neuropathy, how do you respond?

DR ENZINGER: I tell them that we don’t know whether or not this will occur. The data right now are out to 18 months. But I try to reassure the patient in the sense that the neuropathy — at least according to the MOSAIC study — is very mild. So I tell them that about 24 percent of patients have some residual neuropathy, but only 0.5 percent have debilitating neuropathy. I think those odds are pretty good.

Most patients have experienced some tingling or mild tingling, and that’s what I tell my patients to expect. I don’t believe that they’re going to be left with any debilitating neuropathies. I think the risk for another adverse event is much higher than for long-term debilitating neuropathy.

Track 7

DR LOVE: Another major trial that’s had a big impact on clinical decision-making is the X-ACT study, which evaluated capecitabine versus 5-FU (Cassidy 2004; Twelves 2005a, 2005b). Can you summarize that study and discuss your interpretation of the findings?

DR ENZINGER: The X-ACT study evaluated the FDA-approved dose of capecitabine, which is 2,500 mg/m² daily for 14 days straight every three weeks for six months. The standard treatment arm in that trial received the Mayo Clinic 5-FU regimen.

The study was powered to detect relatively small differences in survival and also to look at equivalence between the arms. The three-year results evaluated relapse-free survival, disease-free survival and overall survival.

At the three-year analysis, we saw that the regimen of capecitabine was at least equivalent to the Mayo Clinic 5-FU regimen (3.2). In fact, there was a statistically significant improvement in relapse-free survival, and disease-free survival was right on the edge of significant improvement.

I think overall survival will also show an improvement with further follow-up. We’re seeing the same thing here that we’re seeing in the metastatic disease setting — that capecitabine is probably slightly better than what we’ve observed with bolus 5-FU.

Track 8

DR LOVE: How do you determine which patients are candidates for capecitabine in the adjuvant setting?

DR ENZINGER: The goalpost for adjuvant treatment has been changed since X-ACT was initiated. Most doctors are now recommending FOLFOX, particularly for patients who are at higher risk for recurrence. So the question now is where capecitabine fits into this whole category.

We know capecitabine had a very nice toxicity profile in the head-to-head comparison with the Mayo Clinic regimen (Twelves 2005b). Toxicities across the board were less than those associated with the Mayo Clinic regimen, except for hand-foot syndrome, with which 17 percent of patients had severe Grade III to Grade IV toxicity.

But the reality is that this will occur during the first cycle. Then you attenuate treatment, and typically, patients will do fine for the rest of the adjuvant course.

Looking at the X-ACT data, a subgroup analysis suggests that patients with N1 disease did better than those with N2 disease, which makes sense to me and would actually fit in nicely with the FOLFOX paradigm.

In my mind, I would say that patients with N2 disease, the patients who have higher risk for recurrence, really should not even be given an option. Those patients should be pushed towards FOLFOX.

Patients who have a lower risk for recurrence, perhaps those with N1 disease, and patients who wish to avoid the neuropathies may actually be good candidates for capecitabine. So perhaps the patients with Stage IIIA disease would do well with capecitabine.

In my own practice, patients with high-risk Stage III disease receive FOLFOX. With low-risk patients, I have an intensive conversation about the risks and benefits of FOLFOX versus the Roswell Park 5-FU regimen versus capecitabine.

DR LOVE: What are the situations in which you’d use the Roswell Park regimen instead of capecitabine?

DR ENZINGER: In my opinion, the Roswell Park regimen is well suited for an elderly patient who needs the social support associated with coming to the office and seeing the nurses. Often, they enjoy the stimulation of coming for a visit.

Capecitabine is a therapy for a business professional, for somebody who believes that adjuvant therapy gets in their way and who wants to have the least number of interruptions possible.

Now we really haven’t seen any direct comparisons between Roswell Park and capecitabine. Capecitabine has always been measured against the Mayo Clinic regimen, so I don’t know how a toxicity analysis between these other two would work out.

I suspect that Roswell Park would be associated with more diarrhea, more hematologic toxicity and stomatitis, but the difference would be less than when compared with the Mayo Clinic regimen.

DR LOVE: What about patients with Stage II disease?

DR ENZINGER: I think patients with Stage II disease sometimes have a higher risk for recurrence than those with Stage III disease. A patient with Stage IIB colorectal cancer, in my opinion, may have a higher risk for recurrence than someone with Stage IIIA disease, and again, that’s where I’d consider all three options.

I tend to push patients towards FOLFOX if they have tumors that have perforated.

Track 16

DR LOVE: The design of randomized trials, both in the metastatic and the adjuvant setting, is becoming a lot more complicated because of all the new agents. What are some of the current research questions that you think are most interesting?

DR ENZINGER: One of the most interesting questions in the adjuvant setting is the role of bevacizumab. It is now shown to be of significant benefit in the metastatic disease setting. Can we duplicate that in the adjuvant setting?

People have argued that we’re destroying isolated cancer cells in the adjuvant setting, and isolated cancer cells don’t need vasculature — they don’t need to recruit oxygen. However, I believe our imaging capabilities are suboptimal.

We’re able to detect cancer nodules that are approximately one centimeter in size — it’s quite clear that we’re not able to detect a cancer nodule less than 0.5 centimeters in size, even in the best-case scenarios. A one-centimeter nodule is significantly larger than the one- to two-millimeter nodule that is the size at which we think the angiogenic switch is being thrown.

If a patient has a tumor nodule between one and 10 millimeters, I believe that’s where bevacizumab will probably have its greatest impact. Not only will it have an anti-angiogenic effect, but it’ll also promote drug delivery into these fairly large conglomerates of tumor cells. We’re talking about many millions of cells in these small tumor nodules.

In designing these trials, I would stratify and look at patients who have poor-risk Stage III disease — the patients who probably have residual tumor nodules, because I think bevacizumab may actually exert its greatest impact or activity in patients with macroscopic residual disease that we just can’t see — not in microscopic residual disease.

Track 17

DR LOVE: Can you discuss the upcoming Intergroup trial that will evaluate combined biologic therapy in metastatic disease?

DR ENZINGER: In the upcoming Intergroup study, patients will be randomly assigned to standard chemotherapy (FOLFOX or FOLFIRI) with standard treatment (bevacizumab) or with experimental treatment that includes cetuximab or cetuximab with bevacizumab (3.3). Based on the data we’ve seen from the CBI trial (Saltz 2005), many of us expect the arm receiving both biologic agents to win.

The dilemma is that this will be very expensive therapy, but I think that it’s going to be very interesting. I think many of us are already tempted to throw everything at these patients — particularly the patients who are at high risk. However, use of both biologics raises financial costs and also toxicity costs.

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