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Niall Tebbutt, BM, Bch, PhD, MRCP, FRCP Consultant Medical Oncologist, Austin-Repatriation Medical Centre, Melbourne, Australia

Edited comments by Dr Tebbutt

Phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer

Trial background, rationale and design

This study builds upon the epirubicin/cisplatin/5-FU (ECF) regimen devised by David Cunningham's group in the GI units of the Royal Marsden Hospital. Importantly, this regimen uses a protracted venous infusion (PVI) schedule of 5-FU, which is not as myelosuppressive as bolus schedules of 5-FU.

The rationale for the ECF regimen was that, while these three agents don’t have single-agent activity in the adjuvant setting for esophagogastric cancer, by putting them together you’ve got three agents with independent activity and nonoverlapping toxicity profiles. This regimen went through initial Phase II trials, showing significant activity. There have now been two large randomized studies establishing ECF as a highly active regimen, which is a standard of care in the United Kingdom, many parts of Europe and Australia.

This study examines the role of capecitabine and oxaliplatin in bringing the ECF regimen forward. Capecitabine is an oral treatment, without the hassles and complications of lines and pumps. The other potential advantage of capecitabine is the fact that it is activated via thymidine phosphorylase, which itself is upregulated by other agents. So, there is potential for synergy by combining capecitabine with other agents, which activate thymidine phosphorylase.

Oxaliplatin has activity in a variety of cisplatin-resistant tumors, and generally has a more favorable toxicity profile than cisplatin. There is less renal toxicity, and patients do not need the same prehydration with oxaliplatin that they need with cisplatin. There is also less auditory toxicity and neurotoxicity.

The study was designed to establish the role of those two agents — capecitabine and oxaliplatin — building from the ECF regimen. It's a 2-by-2 factorial design, with essentially two randomizations: cisplatin or oxaliplatin, and PVI 5-FU or capecitabine.

Interim study results

Currently accrual stands at about 200 patients, with a targeted accrual of 600. I presented a planned interim analysis after 80 patients, but it’s difficult to make significant interpretations. All the regimens, and importantly the two experimental regimens, look active. The study is designed to compare the 5-FU treatment arms with the capecitabine treatment arms separately. Response rates and toxicity results in the two experimental arms are very promising.

The toxicity results were no worse for the capecitabine treatment arms, and they certainly looked better than the toxicity encountered with PVI 5-FU. But, this is a randomized Phase II trial, and we can’t interpret too much. When the study is completed, we will be able to very confidently define the role of capecitabine and oxaliplatin in upper GI cancer.

Select publications of clinical trial results in advanced esophagogastric cancer