Switching from 5FU to Xeloda Can Cause Significant Side Effects

An immediate switch from 5-FU treatment to Xeloda® (capecitabine) for stage III colon cancer caused so much toxicity that a trial designed to test patient preferences for treatment had to be stopped.

Patients in the Patient Preference in Adjuvant Therapy (PACT) trial who switched after 6 weeks from weekly 5-FU with leucovorin to oral capecitabine experienced excessive side effects. The trial was designed to determine which approach to treatment patients liked best.

Patients were randomized to two groups:  the first group began treatment with weekly intravenous 5-FU and leucovorin for 6 weeks (start period) and then switched to oral Xeloda for six weeks (switch period).  The second group began with Xeloda during the start period and got 5-FU during the switch period. Finally, patients would choose the treatment they preferred to complete the final 12 weeks of treatment (preference period.)

However, the trial was halted after 40 of a planned 74 patients were enrolled because of the high toxicity in the first group who made the 5-FU to Xeloda switch.  Serious grade 3 or higher side effects in those now getting Xeloda included diarrhea, hand-foot syndrome, and lethargy.  One patient had low white counts with blood infection, and one experienced angina.

During the start period:

  • The Xeloda group had moderately higher percentages of severe (grade 3 or higher) side effects than the 5-FU group (28 percent versus 0 percent)
  • 44 percent of the Xeloda group required a lower dose or postponed treatments compared to 6 percent of the 5FU group.

Durng the switch period:

  • 79 percent of the 5-FU patients who switched to Xeloda had severe grade 3 side effects compared to none of the patients who switched from Xeloda to 5FU.
  • Only 2 of 14 5-FU patients who switched to Xeloda were able to tolerate the full dose.

During the preference period:

20 patients reached the end of the twelfth week of treatment before the study was closed and were able to make a choice of which treatment they preferred.

  • 3 patients, who had taken Xeloda in the switch period, had already dropped out of treatment entirely because of severe side effects.
  • 5 patients chose to return to Xeloda.  All 5 had taken Xeloda in the start period, switched to 5-FU, and now wanted to return to Xeloda.
  • 4 of those 5 patients who returned to Xeloda after the switch period on 5-FU developed severe side effects during the preference period.
  • 2 of 12 patients (17 percent) choosing 5-FU developed severe side effects.
  • 1 patient, who had been in the original Xeloda arm during the start period and had switched to 5FU, asked to return to Xeloda.  Despite not having side effects from Xeloda during the start period, she developed serious side effects, had a heart attack, and died.

The researchers don’t know the reason that the sequence of 5-FU with leucovorin and Xeloda made such a startling difference in side effects, but they think that leucovorin (folic acid) may be at the bottom of the mystery.  It is possible that leucovorin allows folate to build up in cells and contributes to more serious side effects when Xeloda is begun.

They point out the recent studies that found more side effects from 5-FU and Xeloda in the United States where food is fortified with folic acid.

Although this study looked specifically at treatments that used 5-FU and leucovorin or Xeloda alone, the researchers believe that doctors should also take care with switching combination therapies.

This caution should also be extended to switching patients from combination regimens containing FU/LV to capecitabine-containing equivalents (eg, from infusional FU/LV with oxaliplatin to capecitabine with oxaliplatin).

The team, headed by Dr. Ivo M. Hennig, concluded,

In chemotherapy-naive patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.

SOURCE: Hennig et al., Journal of Clinical Oncology, Volume 26, Number 20, July 10, 2008.

What this means for patients

Patients need to be aware that an immediate switch from intravenous 5-FU given with leucovorin and Xeloda (capecitabine) may be dangerous.  They should discuss such switches carefully with their oncologists.

Because folate in cells may be the reason for increased serious side effects, patients should discuss all sources of supplementary folic acid with their doctors, including that in enriched foods and multivitamins.

The National Institutes of Health Office of Dietary Supplements has more information about folate in food and folic acid supplements.


  1. amir says

    hi, my father suffering from gastric cancer( signet ring type) for 1.5 yrs . he hadnt any surgery for this problem and have been treated with xeloda but because of spread of cancer to adjacent lymph nodes his oncologist switched xeloda to 5fu . after that he became ill and because of diarrhea and anorexia he isnt well . please dont hesitate to give me any advices . thanks a lot

  2. Kate Murphy says

    As a consumer you can report a serious adverse event like your mother’s to the FDA.


    Our thoughts are with your mother and with you.

    If you’d like to take action to reduce the impact of the drug shortage, ask your US Senators and members of Congress to support the Preserving Access to Life-Saving Medications Act (S 296 and HR 2245). Fight Colorectal Cancer has a simple way you can do that directly through our website.

  3. Kristin says

    My mother has been valiantly fighting stage IV colon cancer for 2 1/2 years, was tolerating chemo as well as you can and was maintaining/doing well. She was receiving 5FU and because of the shortages was switched to Xeloda. Within a week of the first round of Xeloda, her kidneys and liver failed and she spent 6 days in the hospital. She has since been released and has been enduring 3 times weekly dialysis in order to get the kidneys “going” again. Her kidneys have responded to the dialysis and it should be ending soon. Unfortunately, she had turned jaundice again and her counts are all over the place. She was readmitted to the hospital last night. Her doctor, my mother and our family are convinced it is due to the Xeloda. Obviously, I am very angry. I’ve called my representatives in Washington to express my concerns. I am willing to tell my mom’s story to anyone that will listen and help in any way I can to get the proper legislation in place to end this unnecessary shortage.

  4. Leaan says

    I had 2 5-FU treatments, the first treatment caused a heart attack, the second caused severe chest pains but had nitro so it wouldn’t turn into another heart attack (though while in the hospital on a monitor my heart stopped) they figured out it was vessel spasms & was taken off 5-FU & they gave me a month to recuperate before putting me on Xeloda. I have since been on Xeloda which had to be reduced along with the oxaliplatin for 4
    treatments & had to stop for 3-6 doses
    in the middle of each treatment due to the same chest, extreme fatigue, neck pain caused by exercising while on Xeloda and taking nitro during this period allows me to continue treatment but am wondering at what cost to my heart and body in the future. I am going in for my 7th treatment tomorrow because with aggressive stage 3 colorectal cancer I don’t see much future without aggressive treatment either. But I worry the reduced chemotherapy drugs might not be as affective & am going through all these severe reaction, nerapathy, hand & foot redness & pain, heart & vessel problems, & all the other things to have this quite possibly be my last days with such bad quality of life is it all
    worth it? I hope so – to those that came close or lost their lives I truly hope the drug companies are listening & quit treating these severe symptoms as extremely rare as they are just not reported or attributed to the drugs as they should be

  5. Nora Lopez says

    I am on 5-FU and finished the 11 out of 12 infusion. Mostly I dont have side effects but noticed that my weight is on the increased, 10 pounds in the last month. Please help, my knees hurt and dont feel ok. Thanks…

  6. Kate Murphy says

    There have been rare incidents of cardiac problems reported with Xeloda (capecitabine) similar to those related to another drug of the same type, fluorouracil or 5-FU.

    The FDA-approved label for Xeloda lists cardiotoxicity among the “Precautions”. Xeloda label.

    However, we at C3 are not physicians and cannot know if a particular drug might have caused a serious side effect for a particular patient.

    Your own doctor is the best person to ask about the situation. Definitely discuss whether or not you should continue Xeloda in light of your heart problem.

    We sincerely hope that you are recovering from your heart attack.

  7. rebecca watts says

    Have been on 3300 mgs. per day of xeloda since May. Had a heart attack 1-11-10. Could xeloda have caused this?

  8. Kate Murphy says

    Since you will be having a break in treatment between the 5-FU and Xeloda, you might not have the problems that the patients in the study had.

    BUT, we are not doctors here at C3. You need to discuss the question with your own doctor.

    Also, given the serious diarrhea and low blood counts, you might ask about being tested for Dihydropyrimidine Dehydrogenase Deficiency (DPD). This is a rare genetic change that can affect how 5-FU and Xeloda are metabolized leading to serious side effects in about 1-3 people in 100.

    Good luck with your treatment. Stick close to your doctor and report diarrhea, fever, or any other symptoms right away.

    Xeloda often has more “hand-foot” syndrome (red,sore, and sometimes peeling skin). Keeping hands and feet well moisturized helps. Talk this over with your doctor, as well.

  9. Laleen Doerrer says

    I had three treatments on FOLFOX and experienced very serious side effects- extreme neurapathy. fatigue, diarrhea, low blood counts, etc. I thought the Oxaliplatin was the the culprit for the neurapathy and fatigue. So my oncologist is plannning to put me on Xeloda (reduced dosage) once my blood count stabilizes. After reading all of this, I’m scared. Should I just continue on the 5FU infusions instead of switching to pills? Obviously, I’ll send this study to my oncologist and discuss with her. But this information is really frightening.

  10. Kate Murphy says


    We are not doctors here at C3 and can’t give you a medical answer about your reaction to Xeloda.

    You can report this reaction yourself to the FDA to help them collect evidence of bad reactions to drugs by going to the consumer page of Medwatch.

    We hope that you are recovering from your heart attack and also from colon cancer. Good luck to you in the future.

  11. jim horner says

    I was diagnosed with between stage 2 and 3 colon cancer and had 80% of my colon removed. I was put on xeloda at 2500 mg 2 times a day after 3 doses I had a major heart attack and code blued in the treatment room. I survived and am wondering if this dose was proper as I was completely healty before the cancer. and also I hear more and more of heart attacks from this drug

  12. Kate Murphy says


    We are not doctors here at C3, so can’t give medical advice, but wonder why the patient wouldn’t just continue on the 5-FU for the final two treatments.

    Xeloda is not a substitute for oxaliplatin. It is a similar drug to 5-FU, but as Dr. Hennig’s research (above) showed, an immediate switch from 5-FU to Xeloda may lead to serious side effects.

    If oxaliplatin needs to be discontinued because of neuropathy, the last few treatments can be given with 5-FU alone. This is not uncommon for adjuvant treatment for stage III colon cancer.

  13. Edward says

    A patient had allergy to oxaliplatin during 10th cycle of Folfox-4 and need to stop. If there is an option to switch to Xeloda, is this the best option for adjuvant therapy (stage 3c) in view of the increased side effect of switching from 5FU to capecitabine? If so, what can be done to keep it safe and how many cycle of Xeloda is needed?

  14. Kate Murphy says


    If you think that the chemotherapy might be related to your husband’s heart attack, you should talk to his doctor about reporting the event through the FDA Medwatch system.

    The FDA keeps track of unusual events that are connected with drugs, watching for patterns.

    You can also report the incident yourself by going to the FDA Medwatch website consumer page.

    We’re so sorry to hear about your husband’s death. Please accept our sympathy.

  15. Sara J. Kerr says

    My Husband had three treatments of Chemo therapy for colon cancer but could not tolorate it, then swiched to Xeloda. He was on his second course of treatment recently and had a heart attack and died while hunting in Colorado. Is this information relative?

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