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.