You are here: Home: CCU 1 | 2003: James Cassidy MB, ChB, MSc, MD, FRCP

James Cassidy MB, ChB, MSc, MD, FRCP Professor of Oncology and Head of Department, Cancer Research UK, Department of Medical Oncology, University of Glasgow Member, Board of Governors, Imperial Cancer Research Fund Member, New Agents Committee, UK Cancer Research Campaign

Edited comments by Dr Cassidy

XELOX versus FOLFOX in metastatic disease

I tend to give XELOX (capecitabine and oxaliplatin). It’s still early, but our own studies and others indicate that XELOX is as good as FOLFOX-4, but less toxic, much easier for the patient and without the complications of pumps and lines.

We've actually presented the Phase II data in 96 patients with a response rate greater than 50 percent, an additional 32 percent of patients with stable disease, decent progression-free survival and long overall survival. It's difficult to conceive that any two drug regimens available at the moment will be better than that.

The converse argument is: Why not irinotecan plus capecitabine? My answer is that this combination has not been examined quite as much as XELOX, so I would tend to go with that.

Reduction in neutropenia with capecitabine/oxaliplatin

There is a significant reduction in neutropenia with XELOX compared to what had been seen in other studies of FOLFOX. This may be due to patient selection, because of the small size of the study (only 96 patients). With this small number, even a handful of patients can change the rate of neutropenia. In addition, in this Phase II trial, the monitoring of neutropenia may not have been as strict. I’d like to see the raw data in order to actually be sure the events were real. However, I have no reason to suspect that the reduction in neutropenia is not real. If it is a real reduction in neutropenia, we begin to question whether a pharmacodynamic interaction could account for that.

Hand-foot syndrome with capecitabine alone and in combination with oxaliplatin

Only two percent of patients experienced grade 3 hand-foot syndrome with the XELOX combination, whereas hand-foot syndrome with single-agent capecitabine — albeit a slightly higher dose of 2500 mg/m2/day — is between 10 percent and 15 percent. This might suggest some interaction. There is probably not a pharmacokinetic interaction, because this has been studied, but there could possibly be a pharmacodynamic difference. Oxaliplatin changes the expression of tumor enzymes, so a subtle pharmacodynamic change only seen with the combination is not inconceivable.

Phase III trial of XELOX versus FOLFOX in the metastatic setting

We are in the final stages of designing a large Phase III trial, which will randomize 1,000 patients with metastatic disease to XELOX versus FOLFOX-4. This trial will be an international effort, which we hope to get up and running very soon. There's a lot of interest in both FOLFOX-4 and XELOX, so I think centers and patients will sign on quickly.

I suspect that XELOX will be superior or equivalent, but with better patient tolerance and acceptability because of the oral administration. If we can achieve as much or more with capecitabine than 5-FU, I would see that as a bonus. Capecitabine is probably equivalent to infusional 5-FU in terms of efficacy and is a much easier treatment with probably less toxicity. Removing the pumps, lines and complications is a big step forward. If we can achieve that, I think XELOX will become one of the preferred first-line regimens for metastatic disease.

Capecitabine/oxaliplatin in the adjuvant setting

There is also going to be an adjuvant study of XELOX; however, neuropathy is not as acceptable in the adjuvant setting as it is in advanced disease. So I'm not entirely convinced that it will work out.

I think XELOX should be studied in the adjuvant setting, but my reticence is that we’ll get some answers from the MOSAIC trial looking at 5-FU/folinic acid and oxaliplatin in the next two years. Perhaps we should wait to see if oxaliplatin is acceptable in terms of neurotoxicity. The disadvantage in waiting is that you delay everything by 18 months or two years.

Early evidence I have seen from an unpublished interim analysis of the MOSAIC trial is that there doesn’t seem to be a major problem with neurotoxicity with adjuvant oxaliplatin. Of course, "the devil is in the details," and we don’t know how many patients actually received all the oxaliplatin they were scheduled to receive, how many dropped out, how many got neuropathy, how many recovered from neuropathy and how many have long-term neuropathy. These details will take a while to come out. I would still be very happy to take part in the clinical trial because I think it will be an effective regimen, however, the trade-offs are important in the adjuvant setting.

Substituting capecitabine for 5-FU

I hope we don’t need to test in a randomized clinical trial every time we substitute capecitabine for 5-FU. I would like to think that we could show that conceptually this has been done in breast cancer, colon cancer and perhaps one other tumor. If you could show this phenomenon happening three times, how many more times do you really need to test it?

Select publications regarding oxaliplatin in metastatic colorectal cancer