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James L Abbruzzese, MD Professor of Medicine and Chairman, Annie Laurie Howard Research Distinguished Professor, Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center

Edited comments by Dr Abbruzzese

Capecitabine/oxaliplatin trials in patients with metastatic disease

We are involved in a Phase II trial evaluating capecitabine/oxaliplatin in patients with metastatic colon cancer. Similar to what has been found in Europe, we identified very significant activity with response rates in the 40 to 50 percent range. In fact, those results led us to propose a Phase III randomized trial through the Southwest Oncology Group, which will be a head-to-head comparison of the FOLFOX regimen (infusional 5-FU/leucovorin/oxaliplatin) to the oral regimen of capecitabine/oxaliplatin.

This Phase III trial will be a direct test of whether we can substitute capecitabine, a more convenient drug, and whether we’ll have similar or even better efficacy with the incorporation of an oral drug. We hope to have that trial up and running this year.

We’re expecting that the regimen incorporating capecitabine will have similar efficacy to the standard intravenous FOLFOX regimen. We might be pleasantly surprised and see better activity, but the expectation based on the available Phase II data is that we’ll see similar efficacy. Our goal is to demonstrate that within the context of similar efficacy, there is better overall tolerability without the central lines and pumps that are required to administer the FOLFOX regimen.

Practicing oncologists in the United States have been somewhat reluctant to adopt infusional 5-FU regimens because of the frequency of patient visits to the clinic, the unpredictability of the pumps and the complications from the central lines. Therefore, we’re hoping to see better patient acceptance and quality of life with the capecitabine regimen in patients enrolled in the Phase III trial.

Preoperative capecitabine/oxaliplatin trial

We’re just finishing a protocol to evaluate a preoperative oxaliplatin-based chemotherapy regimen in patients with potentially resectable liver metastases. We’re conducting the trial through the National Cancer Institute and hoping to interest the Southwest Oncology Group (SWOG) and possibly the Eastern Cooperative Oncology Group (ECOG). It's going to be a Phase II trial looking at preoperative capecitabine/oxaliplatin.

Our goal is to try to increase the number of margin-free resections and to render more patients without any evidence of disease at the completion of surgery. We’re anxious to see if this type of trial can be conducted in the cooperative group setting, and if the results in that setting mirror those seen in the smaller, single-institution trials that have been reported so far. We’re trying to obtain funding to look at tumor markers, but we definitely do want to try to incorporate some biology into the study.

Managing patients in a nonprotocol setting

Many patients with metastatic colon cancer are elderly and may have other significant medical problems, therefore, their performance status may not as good as that of patients enrolled on protocols. In that setting, I frequently utilize single-agent capecitabine as initial therapy. My second choice is the intravenous FOLFOX regimen, based on the N9741 trial.

I think decision-making for the elderly patient has been simplified by the availability of oral capecitabine, but I use cautious dosing.

I’ve been using other agents, such as irinotecan, more in the second-line setting. This is a very controversial area. Hopefully, the upcoming trials will begin to sort through some of the issues about sequencing and which is the best first-line agent.

Single-agent capecitabine dosing

I generally use a lower dose than is recommended in the package insert. Many patients don’t qualify for protocol therapy or have concerns about toxicity. The goal is to maintain efficacy with minimal toxicity. I usually start with a dose of 1 g/m2 administered twice a day (2 g/m2 per day), and sometimes I even use a lower dose if, in my judgment, the patient might not tolerate the drug.

I’ve also adopted a different schedule for capecitabine. I generally give patients an extra week off — I use two weeks on and two weeks off. I’ve found this regimen seems to really improve patient tolerance. My patients rarely develop severe hand-foot syndrome or severe diarrhea. If they do develop diarrhea, it's usually very easy to manage with loperamide and other antidiarrheals.

I see hand-foot syndrome very infrequently. More frequently, I am confronted by chronic dryness of the skin and scaling of the hands and feet. Patients can easily deal with this by using moisturizers. In the few cases in which we run into problems, I generally reduce the dose of capecitabine by 10 to 20 percent, or, if necessary, give the patient a short drug holiday until the skin changes reverse completely.

Usually, patients do well using those two maneuvers. With the strategies I described, I have had patients in my practice on capecitabine for up to a year and even longer in a few instances. The patients have had excellent tolerance and no cumulative problems.

Capecitabine/oxaliplatin in patients with cholangiocarcinoma and pancreatic cancer

We plan to explore the potential role of capecitabine/oxaliplatin in patients with cholangiocarcinoma or gallbladder cancer and as second-line therapy in patients with pancreatic cancer. In pancreatic cancer, there was very promising Phase II data with single-agent capecitabine published in the Journal of Clinical Oncology this past year. Capecitabine’s activity was equivalent to that of gemcitabine. I am not aware of any data with capecitabine/oxaliplatin in pancreatic cancer.

In my own practice, I frequently use capecitabine as second-line therapy in patients with pancreatic cancer who have failed gemcitabine or gemcitabine combinations and are not candidates for a clinical trial. Even though some of these patients have difficulty with gastrointestinal function, such as slow gastric emptying, it has never been a major problem with oral agents like capecitabine.

It's a very well-tolerated approach, and we see the patients’ tumors having an objective response around 10 percent of the time. A much larger percentage of patients’ tumors, an estimated 30 or 40 percent, remain stable for eight to twelve weeks and sometimes even beyond.

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