Capecitabine

Capecitabine, an orally active, so-called pyrimidine analogue, a heterocyclic organic compound with the molecular formula C15H22FN3O6, which is to be regarded as a precursor (prodrug) of 5-fluorouracil . Capecitabine is converted into the active substance in the tumour. Capecitabine is hydrolysed in the liver to 5'-deoxy-5-fluorocytidine. This is metabolised in cells to 5'-deoxy-5-fluoruridine (doxifluridine) and further converted to the active substance 5-fluorouracil (5-FU). The effectiveness of capecitabine is therefore comparable to 5-FU. The conversion to 5-FU is effected by the enzyme thymidine phosphorylase, which occurs in particularly high concentrations in tumour tissue.

Pyrimidine analogues belong to the large group of non-selective cytotoxic chemotherapeutic agents. These are substances from different drug classes that have an antineoplastic effect. In a narrower sense, the term"cytostatic agents" refers to conventional non-selective cytostatic agents which use a broad spectrum to non-selectively inhibit the growth of proliferating cells, i.e. tumour cells, but also that of healthy cells with a high proliferation rate (see side effects, see also antineoplastic tumour therapeutics).

The effect of capecitabine is comparable to that of 5-fluorouracil. So are the effects on the tumor parenchyma. After the prodrug has been metabolized in the tumor cell to 5-FU, it is incorporated into the RNA or DNA as a false building block (antimetabolite) due to its structural similarity to the pyrimidine bases cytosine and thymine (DNA nucleotides) or uracil (RNA nucleotide). In detail, the enzyme UMP pyrophosphorylase converts 5-fluorouracil into 5-fluoro-UMP. 5-fluoro-UMP is further phosphorylated to 5-fluoro-UTP and then incorporated into the RNA. This causes the synthesis of a defective RNA. The protein biosynthesis is inhibited. Furthermore, 5-fluoro-DUMP also inhibits thymidylate synthase. These mechanisms lead to a disturbance of DNA synthesis and ultimately to an inhibition of cell division.

Like 5-fluorouracil, capecitabine is degraded by the enzyme dihydropyrimidine dehydrogenase. Therefore, it must not be taken at the same time as the nucleoside analogues Brivudine and Sorivudine. This could lead to an increase in the plasma concentration of fluorouracil and thus to an increase in toxicity

• metastatic colorectal carcinoma
• metastasized or locally advanced breast carcinoma
• further to the palliative therapy of gastric carcinoma
• in clinical trials the efficacy is being tested in other solid carcinomas, such as pancreatic carcinoma (Siddiqui NS et al. 2019.)

Like 5-fluorouracil, capecitabine can have a mutagenic effect and must not be used during pregnancy and lactation. Women of childbearing age should use effective contraception during chemotherapy and for up to 6 months afterwards.

5-Fluorouracil can have a genetically damaging effect. Men treated with 5-fluorouracil are therefore advised not to conceive a child during treatment and up to 6 months afterwards.

Breastfeeding is not allowed during the treatment.

Blood and haematopoietic system:

• Myelosuppression is a common occurrence and one of the dose-limiting side effects
• Neutropenia and thrombocytopenia of mild to severe degree, agranulocytosis, anemia and pancytopenia have been described.
• The extent (NCI grade I-IV) of myelosuppression depends on the type of application (i.v. bolus injection or i.v. continuous infusion) and dosage. Neutropenia occurs after each course of treatment with i.v. bolus injections at the appropriate dosage (nadir: 9th - 14th - 20th day of treatment.

Oro-gastrointestinal ADRs (frequent):

• Mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea and vomiting of mild to severe degree and stoneless cholecystitis have been described. Note: Mucositis can be significantly reduced by regular mouthwashing (Magic Mouthwash - Kirk LM et al. 2017)
• The severity (NCI grade I-IV) of gastrointestinal side effects depends on the dosage and the method of application. With continuous IV infusion, stomatitis rather than myelosuppression is the dose-limiting factor.
• Dehydration, sepsis as well as ulcerations and bleeding in the gastrointestinal tract are rarely observed.
• Liver cell damage is rare, in individual cases liver necrosis with lethal course.

Immunological ADRs:

• Anaphylactic reactions: Generalized allergic reactions up to anaphylactic shock may occur.

Cardiovascular ADRs:

• Cardiotoxic side effects usually occur during or a few hours after the first cycle of use. The ECG often shows changes typical of ischemia. Angina pectoris-like chest pain occurs occasionally. Rarely rhythm disturbances, myocardial infarction, myocarditis, cardiac insufficiency, dilated cardiomyopathy and cardiogenic shock have been observed, and in individual cases cardiac arrest and sudden cardiac death. Patients with pre-existing coronary heart disease or cardiomyopathy are at increased risk of developing cardiotoxic side effects.
• The occurrence of thrombophlebitisis rare

Nervous system and sensory organs:

• nystagmus, headache, dizziness
• Parkinson symptoms, pyramidal trajectory signs
• euphoric states are possible
• In individual cases, after infusion of high doses of 5-fluorouracil or in patients with dihydropyrimidine dehydrogenase (leuko)-deficiency encephalopathies with symptoms such as ataxia, speech disorders, confusion, orientation disorders, muscle weakness, aphasia, seizures or coma may occur.

Ophthalmologic ADR:

• Excessive lacrimation, blurred vision, eye motility disorders, optic neuritis,
• diplopia, visual loss, photophobia, conjunctivitis, blepharitis, scarring
• Ectropion and fibrosis of the lacrimal duct can rarely occur.

Skin and skin appendages:

• The so-called "hand-footsyndrome" with dysesthesia, redness, swelling, pain and desquamation of the skin on the palms of the hands and soles of the feet occurs significantly more frequently than with the application of 5-FU (Lou Y et al. 2016). Furthermore, other severe skin reactions may occur during therapy with capecitabine (very rarely), such as:
  • Stevens-Johnson syndrome (SJS)
  • Toxic epidermal necrolysis (TEN)

Capecitabine must not be used:

• in case of hypersensitivity to 5-fluorouracil or any of the other ingredients
• for bone marrow depression
• for severe blood count changes
• for severe liver dysfunction
• in acute infections
• for patients in poor general condition

Capecitabine must not be taken or used together with brivudine, sorivudine and analogues. Brivudine, sorivudine and analogues are potent inhibitors of the 5-FU-degrading enzyme dihydropyrimidine dehydrogenase (DPD)

Xeloda®

Cave: Patients with partial or complete dihydropyrimidine dehydrogenase (DPD) deficiency have an increased risk of severe toxicity when treated with fluoropyrimidines including 5-fluorouracil (5-FU) and its prodrugs capecitabine and tegafur. The following instructions should therefore be observed: Before starting treatment with fluoropyrimidines, the phenotype and/or genotype should be determined.

Treatment with drugs containing 5-FU, capecitabine or tegafur is contraindicated in patients with known complete DPD deficiency.

A reduced starting dose should be considered in patients with identified partial DPD deficiency.

In patients receiving continuous 5-fluorouracil infusions, therapeutic drug monitoring (TDM) of 5-fluorouracil may improve clinical outcomes.

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2. Freeman NJ et al. (1088) 5-fluorouracil-associated cardiotoxicity. Cancer 61:36-45.
3. Kirk LM et al (2017) Beyond-use dating of lidocaine alone and in two "magic mouthwash" preparations. At J Health Syst Pharm 74:e202-e210.
4. Lemaitre F et al (2018) Suivi thérapeutique pharmacologique du 5-fluorouracile: mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer [5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer]. Bull Cancer 105:790-803
5. Lou Y et al (2016) Possible Pathways of Capecitabine-Induced Hand-Foot Syndromes. Chem Res Toxicol 29:1591-1601.
6. Primrose JN et al (2019) BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 20:663-673.
7. Siddiqui NS et al (2019) Capecitabine for the treatment of pancreatic cancer. Expert Opinion Pharmacother 20:399-409.