Role of adjuvant capecitabine: Implications of the X-ACT trial

The X-ACT adjuvant trial confirmed what was already known about capecitabine — it is as good as or even better than 5-FU/leucovorin (Cassidy 2004, 2005; Twelves 2005). The X-ACT adjuvant trial also informed us that we should be using capecitabine as an active chemotherapy agent. However, it’s not an oral agent that we can administer to a patient and then forget about. The adjuvant dose we start is 2.5 g/m² per day (days one to 14 of a 21-day cycle), not 2 g/m² per day as we use for metastatic disease.

In situations in which a single-agent fluoropyrimidine is being used or contemplated, capecitabine should be used. I don’t believe at this time that, if given the option, a patient will opt for intravenous treatment unless an issue arises regarding who will pay for the capecitabine. Capecitabine should be the drug of choice for patients who will receive a single-agent fluoropyrimidine, because it’s easier to administer and doesn’t interfere much with the patient’s daily routine. It has side effects, and we have to pay attention to them. But overall, it’s a treatment that patients will prefer.

In which patients should we use single-agent therapy? In patients with Stage III disease, the data on adjuvant FOLFOX have completely transformed my practice (Andre 2004). I use FOLFOX in patients with Stage III disease, except in those who refuse the combination, cannot take a neurotoxic drug or are too old for such a combination. Those patients who don’t receive adjuvant FOLFOX receive single-agent capecitabine. The next question becomes: Can we combine capecitabine with oxaliplatin? Adjuvant CAPOX is still experimental, and it should be used as part of a clinical trial. We still have to wait for the head-tohead comparison with FOLFOX.

For patients with Stage II disease, it becomes more interesting. You may still want to use adjuvant FOLFOX, although in the original European trial, less benefit was seen in patients with Stage II disease (Andre 2004). In general, our nonprotocol approach in patients with Stage II disease is to use single-agent capecitabine. We’re increasingly administering adjuvant chemotherapy in patients with Stage II disease, and capecitabine is our drug of choice.

NSABP-C-08: Phase III randomized trial of adjuvant FOLFOX with or without bevacizumab in patients with resected Stage II or III colon cancer

The specific question being asked by NSABP-C-08 (2.1) relates to the use of bevacizumab. The duration of therapy with bevacizumab is also of interest in this study because it continues after adjuvant chemotherapy for another six months. The rationale for that remains to be seen, because we don’t know whether we should use it for six months, 12 months or 24 months. Does adjuvant bevacizumab have a benefit beyond that associated with adjuvant chemotherapy? Does bevacizumab alone have any activity?

We also have to evaluate the toxicity associated with this regimen because of what we’ve seen with bevacizumab. NSABP-C-08 is a good trial because the best use of bevacizumab might be early in the natural history of the disease. This may be the way to go, but one of the concerns with the regimen is, obviously, toxicity. We’ll need to see what happens.

NSABP-R-04: Phase III randomized trial in patients with rectal cancer of neoadjuvant chemoradiation therapy with capecitabine versus intravenous 5-FU/leucovorin with or without oxaliplatin

I have mixed thoughts with respect to the first randomization in NSABP-R-04 because I already use capecitabine with radiation therapy. We started using this at our institution several years ago when there weren’t any protocols available. We reviewed and published our experience confirming the safety of this approach (Vaishampayan 2002); therefore, we have been using capecitabine routinely in these patients off protocol.

I am interested in the second randomization in the trial using oxaliplatin. I have started using that in combination with radiation therapy in some, but not all, patients. For example, I have used oxaliplatin in healthier patients with a better performance status and in patients with whom I have special concerns about not being able to preserve the sphincter, where I want to obtain a maximum pathologic response.

Clinical approach to the management of patients with metastatic disease

At our institution, we evaluated the combination of capecitabine and oxaliplatin (CAPOX). At this time, our front-line nonprotocol treatment approach includes bevacizumab and CAPOX. Granted, no Phase III trial data are available comparing CAPOX to FOLFOX.

However, in the metastatic disease setting, taking into account the convenience for patients of receiving an oral agent instead of continuous infusion 5-FU, we feel that CAPOX would be better than FOLFOX. I probably would not make the same comment for adjuvant therapy. But in the metastatic disease setting, my approach would be bevacizumab plus CAPOX.

For patients with disease that has progressed on an oxaliplatin-based treatment, we move to an irinotecan-based therapy. The question becomes: Do we use irinotecan as a single agent or in combination with a fluoropyrimidine (eg, capecitabine or 5-FU/leucovorin)? The third- or fourth-line options would be any of the above with or without cetuximab.

Select publications

Dr Philip is a Professor of Hematology and Oncology at Karmanos Cancer Institute, Wayne State University in Detroit, Michigan.