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The FDA has updated the product labeling for Xeloda and 5-FU to highlight the risks associated with dihydropyrimidine dehydrogenase deficiency.
The FDA updated labels for Xeloda and 5-FU to stress the importance of DPD deficiency testing due to risks of severe chemotherapy toxicity.
The U.S. Food and Drug Administration (FDA) has updated the product labeling for Xeloda (capecitabine) and fluorouracil (5-FU) to highlight the risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency, according to an announcement from the regulatory agency.
The announcement, which was published on the FDA website, highlighted that patients with complete or partial DPD deficiency face an increased risk of severe, potentially fatal toxicities, including mucositis, diarrhea, neutropenia and neurotoxicity, encouraging oncologists and other healthcare providers to inform patients of these risks and conduct genetic testing for DPD. Specifically, the FDA highlighted the considerations that healthcare providers should take about testing prior to starting treatment.
In an exclusive interview with CURE, Dr. Gabriel A. Brooks said, “The main takeaway message would be to encourage patients to ask their doctors about DPD deficiency, and to ask patients to open up a conversation with their doctors about getting tested for DPD deficiency before starting 5-FU and [Xeloda].”
Dihydropyrimidine dehydrogenase (DPD): an enzyme that breaks down fluoropyrimidines, such as 5-FU and Xeloda.
Mucositis: an inflammation of the mucous membranes.
Neurotoxicity: the damage or dysfunction of the nervous system caused by exposure to toxic substances, such as chemotherapy.
Neutropenia: a condition in which there is an abnormally low number of neutrophils or white blood cells in the bloodstream.
In the interview, Brooks discussed what DPD deficiency is and how it effects patients receiving chemotherapy treatment for their cancer diagnosis and encouraged patients to discuss testing for this disease with their oncologists in order to be sure they will have the best possible response to treatment.
Brooks is an associate professor of medicine and an associate professor of The Dartmouth Institute, Dartmouth Cancer Center, The Dartmouth Institute for Health Policy and Clinical Practice; as well as a member of the Cancer Population Sciences Research Program, and a member of the Gastrointestinal Clinical Oncology Group, at Dartmouth Geisel School of Medicine, in Lebanon, New Hampshire.
DPD is the abbreviation for the enzyme that metabolizes 5-FU and Xeloda. How both of those drugs are broken down by the body is regulated by that enzyme, and deficiency of that enzyme means that the enzyme that your body has, doesn't work in a fully active or fully normal way. If you have DPD deficiency, it could lead to increased side effects from the chemotherapy.
The best way to determine if you have DPD deficiency is to do a gene test that can be done on a simple blood draw. I routinely do that test for all of my patients who are going to get 5-FU or Xeloda chemotherapy. That blood test can take about a week — sometimes a little more — to turn around.
It is important to think about this ahead of time, so that once the plan is made to do chemotherapy treatment with 5-FU or Xeloda, as soon as the decision is made, [you can send for a test]. This is the time to send this test so that it doesn't delay the start of chemotherapy. It's best to have the results back before starting chemotherapy, because if you have a significant DPD deficiency that affects the dosing of the chemotherapy, you want to know that before the first dose, ideally.
When patients have partial DPD deficiency, which is the most common finding — it's rare to find complete DPD deficiency —we can reduce the chemotherapy dose, usually by about half. That makes sense because most people have two copies of the gene that makes the DPD protein, and if you lose one of those copies, or if one of those copies isn't working, then it means that your body has a 50% slower metabolism of the drug. The 50% reduction of the chemotherapy dose is logical, and it turns out, is also supported by other scientific evidence.
Symptoms of DPD deficiency are significant or severe toxicity from 5-FU or Xeloda chemotherapy or chemotherapy regimens that contain those drugs. In the worst case, it can include fatal toxicity from chemotherapy. This is of critical importance to avoid. Most people with DPD deficiency do not have fatal toxicity, but the risks of fatal toxicity, of dying from chemotherapy toxicity, are much higher in people who have DPD deficiency. That is why, in my view, it's so important that we be doing [testing] prior to starting the chemotherapy treatment.
Other symptoms that people can have include severe, low white blood cell count; severe diarrhea, which is a common side effect of 5-FU and Xeloda, but the severity could be much greater in someone who has DPD deficiency; nausea and vomiting, which are usually not severe side effects of 5-FU or Xeloda but can be severe in people who have DPD deficiency. Those symptoms and side effects are the ones that are most common with DPD deficiency.
The question is whether there are safe chemotherapy options for people who have complete DPD deficiency, and it depends on the situation, depending on what the chemotherapy is used for. This is because 5-FU and Xeloda are used for many different cancers and in many different situations. Depending on what the situation is, there might be good alternatives.
In some other situations it might be appropriate to choose not to do chemotherapy at all. If there are no good alternatives, there might be an opportunity to go to a specialized treatment center and consider very low doses of 5-FU even in the case of complete deficiency, but that would only be with supervision of someone who is an expert in that kind of treatment.
Right now, the FDA recommends that doctors discuss DPD deficiency with their patients, but we know that many doctors are not doing that. The guidelines out there have been a little mixed. In Europe, it is standard of care to offer this test before starting chemotherapy. In many centers in the United States, this is becoming standard of care before starting 5-FU and Xeloda chemotherapy; however, in other centers, this test is not uniformly used. I am a believer that it should be used before treatment, and I encourage patients to discuss it with their doctors, as advised on the FDA drug labels for 5-FU and Xeloda.
This test is not uniformly used, so it's worth bringing this up for discussion with your doctor and understanding that your doctor may not be planning to order this test unless you bring it up for discussion with them.
Editor’s note: For more information on DPD deficiency, check out https://test4dpd.org.
Transcript has been edited for clarity and conciseness.
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