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Adding docetaxel to cisplatin and 5-FU in gastric cancer: too toxic?
Impressive activity, but cannot be given to all patients
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Docetaxel with CF is superior to CF but not in a huge way. The median survival with the addition of docetaxel is only marginally better than CF alone. Part of our research effort is to try to improve on the DCF regimen with modifications to reduce toxicity.
There is a lot of evidence that docetaxel is active in the treatment of gastric and GEJ carcinoma. There are many different combinations that have similar activity with median survivals of nine to 11 months, although the DCF and ECF [epirubicin/cisplatin/5-FU] regimens (or similar regimens to ECF) have the most patient data, in terms of clinical trials to support their use.
I am definitely impressed with the activity of docetaxel in gastric cancer. I think the FDA was right to approve it in the firstline setting for the disease with CF. But I think that the concern about the toxicity is a real one. It cannot be given to everybody. Patient selection is very important when choosing this regimen. For example, many clinicians may not realize that docetaxel clearance is reduced in patients with elevated liver function tests at onset. The adverse effects of the drug are thus increased in patients with elevated liver enzymes that receive a full treatment dose of docetaxel.
For most drugs we use bilirubin as the indicator for hepatic dysfunction, but for docetaxel we should also use AST [aspartate transaminase], ALT [alanine transaminase] and ALP [alkaline phosphatase]. Many physicians may adjust a dose based on bilirubin alone (as is true, for example, for irinotecan), but may not realize they must adjust the dose of docetaxel based on the AST, ALT or ALP even when the bilirubin is normal.
Part of our research focus is to identify how best to administer docetaxel with CF so that we can add targeted agents safely. We are definitely encouraged by our preliminary results.
Manish A. Shah, MD, is a Medical Oncologist at Memorial Sloan-Kettering Cancer Center in New York and Assistant Professor of Medicine at the Weill-Cornell Medical College in New York.
Benefit is short, toxicity is significant
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With docetaxel, the duration of benefit is pretty short, about 10 months, and the toxicity is significant.
The findings of the V-325 trial included a formal quality-of-life analysis, which is unusual in that they followed the people after they went off-trial. They did find a quality-of-life benefit in the docetaxel arm. But they compared docetaxel with people who were getting cisplatin, which already shows a poor quality of life.
Similarly, in comparing the toxicities, there was a high rate of toxicity in the experimental and control arms. So if you’re telling somebody it’s only a little more toxic than the standard of care and the standard of care is cisplatin, then you’re not being completely upfront about how severe the toxicity is. The toxicity was more than 80% in the docetaxel arm.
If you look at the number needed to treat on the docetaxel arm, more than 11 patients need to receive the potential additional toxicity of docetaxel for one patient to get benefit, and the absolute risk reduction is only 8.6%, not so impressive in terms of overall survival. There is also a question of the choice of CF as the control arm, and we should keep in mind that there are other regimens such as EOX that may have better OS.
I am excited about a phase-1 trial here — a study of patupilone and RAD001 [everolimus] in patients with refractory solid tumors. Patupilone has a similar mechanism of action to a taxane, but it’s soluble in water so it potentially doesn’t cause as much toxicity as docetaxel, which is in a cremophore vehicle.
Rebecca A. Moss, MD, is a Medical Oncologist at the Cancer Institute of New Jersey and is Assistant Professor of Medicine of UMDNJ-Robert Wood Johnson Medical School in New Jersey.