Preoperative 3 hand–foot syndrome at a capecitabine

Preoperative combined-modality treatment with continuous
infusion 5-Florouracil and Radiotherapy is now a well-accepted approach in the
management of patients with locally advanced rectal cancer. The more recent
availability of new effective drugs that replicate the antitumor mechanism of
5-FU, including oral fluoropyrimidines such as capecitabine, uracile and
tegafur (UFT), and a new generation of thymidylate synthase inhibitors such as
raltitrexed, have provided the opportunity to explore new chomothrapy
and radiotherapy combinations in rectal cancer. One of
the major advantages of these combinations is the avoidance of central lines.
More importantly, capecitabine is converted to 5-FU by the TP enzyme, which is
upregulated by radiation, and this mechanism may improve the likelihood of
capecitabine enhanced radiosensitization9. A phase I study combining escalating doses of capecitabine
with RT, 50.4 Gy with 1.8 Gy daily fractions, as preoperative, postoperative or
palliative treatment of patients with rectal cancer, has been reported by Dunst
et al.13. Capecitabine was increased
from 250 to 1250 mg/m2 b.i.d., 7 days/week. The doselimiting toxicity was defined by grade 3 hand–foot syndrome at a
capecitabine dose of 1000 mg/m2 b.i.d. Therefore, the recommended dose of
capecitabine for further phase II studies was 825 mg/m2 b.i.d. In a similar
phase I study by Ngan et al.14,
capecitabine, given on a 5 days/week schedule (Monday to Friday) in combination
with 50.4 Gy of RT, increased from 425 to 1000 mg/m2 b.i.d. The dose-limiting
toxicity was grade 3 skin reaction and grade 3 diarrhoea with dehydration at
the capecitabine dose of 1000 mg/m2 b.i.d. Although with a different toxicity
profile, the recommended capecitabine dose of 900 mg/m2 b.i.d. reported in this
study was comparable to the 825 mg/m2 b.i.d. reported by Dunst’s study, which
employed a 7 days/week capecitabine schedule.

In the present study, 35 patients with locally
advanced, rectal cancer were treated with preoperative RT, 50.4 Gy in 28
fractions, combined with capecitabine at the recommended dose of 825 mg/m2 twice
daily on radiotherapy days. The patients were evaluated
for tolerance to treatment. The incidence of
acute toxicity during capecitabine–RT was very low. As expected, no grade 4
toxicity was reported and grade 3 toxicity was observed in two patients (5.71%). Similarly,
low toxicity rates have been reported in other capecitabine-RT phase II trials 15.
These data compare favorably with those reported with preoperative
RT combined with continuous infusion or bolus 5-FU. In addition, they appear similar, but with a possible
improvement in the safety profile, to those reported with uracil-tegafur
and raltitrexed. The results from published series with
preoperative RT and 5-FU-based chemotherapy show
a high incidence of grade 3+ toxicity (15%–25%). In studies with uracil/tegafur
and RT16, although with a decreased
incidence, grade 3+ diarrhea was reported as the most frequent toxicity (14%)
and grade 3 leucopenia was the most frequent severe toxicity (9%) with RT and raltitrexed17.
In our study, grade 1 and 2 toxicity was common,
but very well tolerated by patients and no dose reduction was required. Therefore, these data confirm the feasibility of our
treatment programme and the high level of compliance reported in the previous
phase I study13. Capecitabine, an active and safe oral
fluoropyrimidine in combination with RT as demonstrated by our study, might
simplify chemoradiation by replacing continuous infusion 5-FU and the necessity of central lines in these newer
preoperative approaches.

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Oral capecitabine in combination with neoadjuvant radiotherapy is feasible and
well tolerated in locally advanced rectal carcinoma patients.