Select Excerpts from the Interview

Track 2

DR LOVE: What was the rationale for looking at CAPOX in the AVANT trial?

DR TABERNERO: Results from a large Phase II study in metastatic disease showed that CAPOX (oxaliplatin/capecitabine) has at least the same efficacy as FOLFOX-4 (Tabernero 2002), so the next step was to further test this combination in both the metastatic and adjuvant settings.

In the metastatic setting, preliminary results of Phase III studies show that CAPOX has the same efficacy in terms of response rate and time to progression and a better safety profile than oxaliplatin and 5-fluorouracil-based combinations (Sastre 2005; Arkenau 2005).

So we want to move this chemotherapy schedule to the adjuvant setting. In addition to safety, another important issue with this schedule is patient convenience. With CAPOX patients come to the hospital or medical facility once every three weeks, and they take pills for two weeks at home.

DR LOVE: What do we know about the combination of CAPOX and bevacizumab?

DR TABERNERO: We have the results of two different studies. The first study was the TREE-2 study (Hochster 2005a, 2006), which was a randomized Phase II study with three different arms. One of the arms studied a combination of CAPOX and bevacizumab. Data from this arm were compared with those from an arm of the TREE-1 study that studied CAPOX alone.

These data showed a clear increase in response rate with a similar safety profile compared to CAPOX alone (Hochster 2005b).

The other experience we have right now is that presented by Dr Fernando this year at the ASCO meeting (Fernando 2005). It was interesting to see that the median time to progression was almost 12 months using a different schedule of CAPOX and bevacizumab. That is very relevant.

DR LOVE: Do you think the combination of CAPOX and bevacizumab is a rational first-line clinical alternative for metastatic disease?

DR TABERNERO: I would say yes. From a regulatory point of view, you definitely need the data from Phase III studies, but at this time, especially in the United States, some physicians are treating patients with the combination of CAPOX and bevacizumab.

The safety reports from patients who are treated with this regimen do not cause us to anticipate any different safety issues than those associated with FOLFOX-4.

Track 3

DR LOVE: What are the exclusion criteria for the AVANT trial in terms of prior cardiovascular disease?

DR TABERNERO: They rule out patients with what we call active ischemic arterial disease — not only cardiac disease, but also other arterial diseases (3.1). This means that patients who’ve had an arterial event must be without signs and symptoms for one year with disease control.

The same goes for arterial hypertension. Arterial hypertension must be well controlled with either diet or medical treatment.

But this is only one requirement for treating patients in the AVANT study. The other thing we stress to the patients is that they need close follow-up. I request at least three blood pressure readings per week for the first treatment cycle.

If I see that the patient has no problem with hypertension, I reduce the follow-up requirement. But at the beginning of treatment, I think this is important.

Track 4

DR LOVE: Can you talk about your decision-making approach off protocol in terms of adjuvant therapy for Stage III and Stage II disease?

DR TABERNERO: I’m convinced of the effects of oxaliplatin-based chemotherapy, especially FOLFOX-4, in the adjuvant setting.

I discuss the risks of disease recurrence with patients with a 5-fluorouracil/leucovorin-based chemotherapy or FOLFOX. Very few patients are opposed to treatment with oxaliplatin-based chemotherapy, so my standard has been to begin patients with FOLFOX-4 for 12 cycles.

DR LOVE: How do you approach Stage II disease?

DR TABERNERO: I give the same recommendations; although the recurrence risk is lower for some patients with Stage II disease, for others it’s even higher than that for Stage III disease. I believe the relative reduction in the recurrence risk is almost the same with chemotherapy.

Chemotherapy does not discriminate the tumor stage, and chemotherapy reduces the risk of relapse. You need to determine not only the absolute figures but also the relative figures.

Patients who are in very good condition, in a very healthy state, without any disease that might compromise their life in the next five to seven years usually want to have as much treatment as possible to decrease the risk of recurrence.

So my recommendation is to give FOLFOX-4 to patients with high-risk Stage II disease.

Track 5

DR LOVE: Could you summarize your take on the X-ACT trial?

DR TABERNERO: When the X-ACT trial (Twelves 2005) results were presented, they impressed us because we had expected equivalence between capecitabine and 5-fluorouracil/leucovorin. Instead, we were shown some impressive advantages in relapse-free survival and disease-free survival (3.2).

I think the good news is that capecitabine is an alternative for patients who are reluctant to receive oxaliplatin because they fear polyneuropathy or they may even fear receiving intravenous chemotherapy.

The only bad news from the X-ACT study was that patients with high-risk Stage II disease were not included in the trial.

So, unfortunately, the regulatory approval of capecitabine will include only patients with Stage III disease. In some countries, it might be difficult at times to use capecitabine in the adjuvant treatment of patients with high-risk Stage II disease.

Track 13

DR LOVE: In a clinical setting, how do you decide between capecitabine and infusional 5-FU for neoadjuvant therapy of rectal cancer?

DR TABERNERO: I give the option to the patient. I’m used to administering 5-fluorouracil as a continuous infusion, and I feel comfortable using it. But a number of patients complain about having a pump continuously for six or seven weeks, so this is an issue. If patients have concerns about the pump, I give them the opportunity to receive capecitabine as an alternative.

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