5-Fluorouracil vs Capecitabine: Which To Choose?

When discussing the treatment options for your cancer, your oncologist may have given you the choice between 5-fluorouracil and capecitabine. Both drugs play a significant role in chemotherapy regimens, but they come with different administration methods and pharmacological profiles that can influence treatment choices.

It’s important for you to understand the similarities and differences between these two drugs to make informed decisions regarding your cancer treatment.

5-Fluorouracil and capecitabine are fluoropyrimidines

5-FU and capecitabine are both classified as fluoropyrimidines, a type of chemotherapy drug class also called anti-metabolites. Tegafur (or S-1) is another chemotherapy drug that is part of this class but it’s mostly only available in Asian countries. I’m not familiar with S-1 and won’t be including it in today’s discussion.

5-FU has been used for decades in the treatment of colorectal and other cancers. Capecitabine and S-1 are newer oral chemotherapy drugs called pro-drugs. This means they are converted to the ‘real drug’, in this case 5-FU, in the body.

Is capecitabine as effective as 5-fluorouracil?

Capecitabine and 5-fluorouracil (5-FU) has been extensively studied in various cancer types. While they share a similar mechanism of action, their efficacy can vary depending on the specific cancer type and treatment regimen.

It’s beyond the scope of this article to discuss any of the specific studies in detail but in general, oral capecitabine has been found to be at least as effective as intravenous 5-FU in certain cancer types, particularly in the treatment of colorectal cancer.

Several clinical trials have shown that capecitabine is non-inferior (as good as) to intravenous 5-FU in the treatment of stage III colon cancer when used in combination with oxaliplatin (XELOX regimen) after cancer-removing surgery to prevent your cancer from coming back.

In metastatic colorectal cancer, capecitabine is as effective as intravenous 5-FU when used in combination with other chemotherapy drugs, such as irinotecan or oxaliplatin.

Capecitabine is also widely used in replacement of 5-FU to treat other cancers like oesophageal cancer, gastro-oesophageal cancer, gastric cancer, and bile duct cancer.

5-FU and capecitabine administration

5-FU is given intravenously and is often administered as a bolus (short infusion) in the oncology day unit followed by a longer infusion (typically over 48 hours) at home. 5-FU is often given in combination with other chemotherapy drugs like oxaliplatin or irinotecan which are also given intravenously.

Capecitabine is a tablet that you take orally. The drug comes in 500 mg and 150 mg strengths and one cycle typically consists of taking the drug twice a day for 2 weeks. If you’re having capecitabine in combination with oxaliplatin or irinotecan, you’ll have intravenous chemotherapy on the first day and start oral capecitabine on the same day for 14 days.

How does 5-fluorouracil work?

The way chemotherapy drugs work is complex but I’ll try to simplify it here. The mechanism of action of fluoropyrimidines involves several steps:

1. Cell uptake – 5-FU enters cancer cells through facilitated transport mechanisms, as it is structurally similar to the natural nucleoside uracil.
2. Conversion to active metabolites: Once inside the cell, 5-FU is converted into several active metabolites through a series of enzymatic reactions. The key active metabolites are Fluorodeoxyuridine monophosphate (FdUMP), Fluorodeoxyuridine triphosphate (FdUTP), and Fluorouridine triphosphate (FUTP)
3. Thymidylate synthase inhibition: FdUMP inhibits the enzyme thymidylate synthase (TS), which is crucial for the synthesis of thymidine, a nucleotide required for DNA replication and repair. By inhibiting TS, FdUMP causes a depletion of thymidine nucleotides, leading to an imbalance in the nucleotide pool and ultimately disrupting DNA synthesis and cell division.
4. Incorporation into DNA and RNA: FdUTP and FUTP can be mistakenly incorporated into DNA and RNA, respectively, during synthesis. This incorporation leads to disruptions in the structure and function of these nucleic acids, ultimately causing cytotoxicity and cell death.
5. Induction of apoptosis: The disruption of DNA and RNA synthesis, as well as the depletion of nucleotide pools, can trigger apoptosis (programmed cell death) in cancer cells.

5-FU is cell cycle-specific, meaning it primarily targets rapidly dividing cells, such as cancer cells. However, it can also affect normal, rapidly dividing cells, leading to side effects such as myelosuppression (suppression of bone marrow function), mucositis (inflammation of the mucous membranes), and gastrointestinal toxicity (diarrhoea).

How does capecitabine work?

As we mentioned before, Capecitabine is a prodrug, which means it is an inactive compound that needs to be metabolized into its active form within the body.

Capecitabine works in much the same way as 5-FU but with a few extra steps at the beginning:

1. Absorption and activation: After oral administration, capecitabine is absorbed from the gastrointestinal tract and undergoes a series of enzymatic reactions to convert it into its active form, 5-fluorouracil (5-FU).
2. Capecitabine is first metabolized by carboxylesterase enzymes in the liver to form 5′-deoxy-5-fluorocytidine (5′-DFCR).
3. 5′-DFCR is then converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase enzymes found in various tissues, including cancer cells.
4. Finally, 5′-DFUR is converted to the active metabolite 5-FU by thymidine phosphorylase (TP) enzymes, which are often present at higher levels in tumor cells than in normal cells.

Once capecitabine is converted to 5-FU within tumor cells, it exerts its cytotoxic effects through the same mechanisms as the parent drug 5-FU (see above).

One advantage of capecitabine is that it is preferentially activated in tumor cells due to the higher levels of thymidine phosphorylase (TP) enzymes present in these cells compared to normal cells. This tumor-selective activation can potentially reduce side effects and improve the efficacy of this drug.

Like 5-FU, capecitabine is cell cycle-specific, meaning it primarily targets rapidly dividing cells, such as cancer cells. However, it can still affect normal, rapidly dividing cells, leading to side effects such as myelosuppression, hand-foot syndrome, diarrhea, and mucositis.

Toxicity profile

As 5-FU and capecitabine as very similar and are ultimately the same drug, they share quite a few side effects. Both drugs can cause:

• nausea
• mucositis (ulcers in the mouth)
• myelosuppression (suppression of bone marrow activity resulting in low red blood cells, white blood cells and platelets)
•  loss of appetite
• photosensitivity (increased skin sensitivity to sunlight)
• cardiac toxicity – irregular heart beat, chest pain, and a small but significant risk of coronary artery spasm causing reduced blood flow to the heart muscle. This mimics a heart attack and is potentially life-threatening.
• excessive tearing, sensitivity to light and blurred vision
•  fatigue
• Hand-foot Syndrome

In clinical practice, capecitabine causes more diarrhoea and tends to cause hand-foot syndrome over time.

How to choose between 5-FU and capecitabine

There’s really no right or wrong answer here. These drugs are both very effective treatment for certain cancers and which drug you go for ultimately depends on your personal circumstances.

Pros and Cons of 5-FU

Even though their side effects profile is similar, I find 5-FU slightly better tolerated than capecitabine. There is less diarrhoea and nausea.

You also don’t need to remember to take your medications twice a day for 2 weeks. If you have issues with memory or compliance, probably best to choose 5-FU instead of capecitabine.

However, as 5-FU is usually administered as a long infusion over 48 hours, you’ll require a portacath (a combination of a portal and catheter) to be inserted surgically, or at least a PICC line (a long indwelling catheter).

Plus, the chemotherapy regimens containing 5-FU is often given in 2-weekly cycles. This means you need to have more chemotherapy every 2 weeks.

Pros and cons of capecitabine

Admittedly, capecitabine has slightly more side effects compared to 5-FU. However, not needing to have a portacath or PICC line is a big plus.

You also don’t have to come back to the oncology day unit 2 days later to have your 5-FU infusion pump removed. As capecitabine is often given in 3-weekly cycles, you really only need to come for appointments every 3 weeks.

This works well if you live far away, or have other responsibilities that makes it harder for you to attend appointments often.

However, you’ll need to remember to take your drugs twice a day. If you don’t take your medications regularly, you’ll reduce the efficacy of capecitabine.