Five people died after fluorouracil chemotherapy!

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5-Fu (5-Fluorouracil, 5-fluorouracil) is a chemotherapeutic drug widely used in a variety of malignant tumors including head and neck tumors, breast tumors, and digestive tract tumors. In 2019, five cases occurred in France and the United Kingdom.Deaths caused by fluorouracil drugs after systemic chemotherapy.The cause of death in these patients is related to an enzyme related to the metabolism of the drug-DPD (dihydropyrimidine dehydrogenase, dihydropyrimidine dehydrogenase).DPD is the initial enzyme and rate-limiting enzyme of 5-Fu metabolism in the body. 80% -90% of 5-Fu is excreted in the liver after being metabolized by DPD to produce dihydrofluorouracil.And toxic reactions are closely related.The patients who died after chemotherapy as described above are suspected of having DPD enzyme deficiency in their bodies, which causes 5-Fu to accumulate in the body and eventually die due to drug toxicity.Afterwards, the families of these patients condemned the hospital for not testing the drug sensitivity before chemotherapy.These events also raise some questions: Should DPD enzyme testing be included in routine cancer chemotherapy practice?Today, let’s talk about these things about fluorouracil drugs and DPD.01 The latest announcement of the European Medicines Agency: DPD testing is required before chemotherapy with fluorouracil drugs. On March 13 this year, the European Medicines Agency (European medicines agency, EMA) issued a new announcement that cancer patients are receiving systemic fluorouracil(Including drugs that can produce fluorouracil after being metabolized in the body, such as capecitabine, tegio, etc.) Before chemotherapy drugs, DPD testing is required to ensure the safety and effectiveness of chemotherapy, which is conducive to the formulation of reasonable individualizationChemotherapy regimen, and for patients who need topical fluorouracil drugs, DPD testing is not necessary.The European Pharmacovigilance risk assessment committee (PRAC) pointed out that the level of individual DPD can be assessed by detecting the concentration of uracil in the blood or detecting mutations in DPD-related genes.For patients with DPD dysfunction, a reasonable reduction in the dose of fluorouracil chemotherapeutic drugs can effectively avoid serious and potentially life-threatening toxic effects, but specific standard guidelines for dose reduction have not been established.Regarding the drug fluorocytosine, which is a serious fungal infection, PRAC pointed out that although fluorocytosine can be metabolized in the body to produce fluorouracil, in order to avoid the delay of the disease, DPD testing before medication is not required.For patients who are known to have complete DPD dysfunction, it is necessary to avoid the use of flucytosine, and for patients who are known to have partial DPD dysfunction, if flucytosine is used, if there are serious toxic and side effects, the drug should be stopped in time.02 Whether DPD testing should be routinely conducted is still controversial. However, academics have different opinions on whether DPD testing is required before the use of fluorouracil chemotherapy drugs.Professor David Kerr of the Cancer and Hematology Center of Oxford University believes that patients who have been found to have obvious DPD defects in germline genetic testing should reduce the dose of chemotherapy drugs by 50% and follow up closely.Another British expert, Professor Karol Sikora of Buckingham Cancer Medical Center, opposed the routine DPD test. He believes that DPD polymorphism is not the only factor affecting drug sensitivity, and there are many other factors that check and balance each other.Even if there is evidence of genomics testing, it cannot be assumed that all abnormal DPD genes will cause high drug toxicity.Professor Karol Sikora pointed out that less than 10% of patients may have serious problems, and only about 1% of patients need treatment, dose reduction or other treatment measures (such as the use of antidote uridine triacetate) are neededYes, but there is no need to monitor all patients.In addition, some oncology experts in the United States also pointed out that there is no need for routine DPD testing.03 Is DPD functional defects common in Chinese patients?How to detect it?The incidence of DPD functional deficiencies varies among different races. In Caucasian races, the partial incidence of DPD function abnormalities is about 3% -5%, while in Asian races only 0-0.7%.A study on the peripheral blood DPD activity of the Han population in China found that peripheral blood DPD activity was negatively correlated with age and has nothing to do with gender; when the individual liver and kidney function abnormality, peripheral blood DPD activity decreased, pregnancy will cause increased DPD activity.Clinically, the efficacy and toxicity of pyrimidine chemotherapeutics can be predicted by measuring DPD activity, but it is difficult to objectively and accurately measure enzyme activity due to the influence of factors such as timing and treatment.At this time, genetic testing is the preferred testing method.DPYD is a gene encoding DPD, located on chromosome 1p22, with a total length of about 950kb, including a total of 23 exons.DPYD gene polymorphism includes duplication, deletion, insertion and single nucleotide polymorphism (SNP), among which SNP is the most common.A 2015 meta-analysis of DPYD mutations in Asia showed that the frequency of DPYD * 5 mutations in the Chinese population can reach more than 20%, and the frequency of DPYD * 9A mutations in the Chinese population is 7.04% without detectionA common DPYD * 2A mutation in the West.These detected polymorphic sites are all related to the chemotherapy toxicity of fluorouracil drugs.04 Clinical significance of DPD detection At present, Chinese scholars generally believe that the clinical significance of DPD detection before 5-Fu chemotherapy mainly includes the following points: ① Predict the sensitivity of 5-Fu chemotherapy: the activity of DPD in tumor tissue and 5-FU chemotherapyThe sensitivity is negatively correlated. The detection of DPD helps to judge the sensitivity of patients to 5-Fu chemotherapy; ②Predict the toxicity of 5-Fu chemotherapy: DPD detection helps to determine the dosage of medication and avoid the toxicity of chemotherapy caused by overdose; ③ as a basis for combination therapy: 5-Fu combined with DPD inhibitors (eg, Jimepyridine, 5-ethynyluracil) can improve the efficacy of chemotherapy, and some compound preparations (eg, Tigio) have achieved significant clinical efficacy;④ Chronic chemotherapy using circadian rhythm: DPD activity has circadian rhythm. Generally, it is highest at 1 am and lowest at 13 pm. Chemotherapy at a low DPD period can improve the efficacy;
⑤ Study the activity of DPD in different tissues: A related study found that the activity of DPD differs greatly between tumor tissues and normal tissues, and there is no correlation between the two.Too low DPD activity in normal tissues will cause 5-Fu to accumulate in the body and increase the toxicity of 5-Fu, while too high DPD activity in tumors will accelerate 5-Fu metabolism in the body and reduce the efficacy of chemotherapy.Regarding whether DPD testing should be routinely performed before systemic chemotherapy with fluorouracil drugs, there is no clear conclusion in the clinical diagnosis and treatment guidelines for various types of tumors in China, but patients with known DPD dysfunction should be treated with caution and follow-up to avoid serious chemotherapyThe occurrence of toxic side effects.The above content is only authorized for exclusive use by, please do not reprint without the authorization of the copyright party.


The author ouyangshaoxia