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      Hypokalemia secondary to capecitabine: a hidden toxicity?

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          Hyopkalemia is a listed toxicity in the capecitabine (Xeloda®; Roche, Nutley, NJ) package insert. However, the incidence and severity of this toxicity is not known.


          We performed a retrospective evaluation of hypokalemia in 77 patients, who received capecitabine for gastrointestinal malignancies between April 2002 and November 2004. Hypokalemia was defined as K + level <3.2 mEq/L. Patients with documented ≥grade 2 vomiting or diarrhea, diuretics, hypomagnesemia, hypokalemia, renal insufficiency, endocrine dysfunction (thyroid, adrenal, diabetic) were excluded. Hypokalemic patients were graded as: mild (grade 1: 3.0–3.2 mEq/L), moderate (grade 3: 2.5–2.9 mEq/L) and severe (grade 4: <2.5 mEq/L). We also reviewed the literature.


          Fifty-four patients met the above criteria. The most common cause of exclusion was ≥ grade 2 diarrhea (23 patients; 30%). Overall, hypokalemia was encountered in 11 patients (20.4%). Among hypokalemic patients, 8 patients (73%) presented with mild/grade 1 hypokalemia (3.0–3.2 mEq/L), 2 patients (18.18%) with moderate/grade 3 hypokalemia (2.5–2.9 mEq/L) and 1 patient (9.09%) with severe/grade 4 hypokalemia (<2.5 mEq/L) 8 (73%). Dose of capecitabine ranged between 1000–2000 mg/m 2. Hypokalemia occurred after an average of 83.7 days of capecitabine administration. No cardiac or neuromuscular complications were noticed. Replacement of K + was required in 6 patients (2 intravenous and 4 oral), while 2 patients (3.7%) required oral supplements >4 weeks. No patient had to stop capecitabine due to hypokalemia. One patient had persistent hypokalemia even after stopping capecitabine. Normalization of K + levels was achieved in 91% of patients. Four patients were on K + sparing diuretics for ascites and never presented with hypokalemia. Mean urine K + was 28 mEq/L. Only 5.5% patients had ≥grade 3 hypokalemia in our study compared with 2% and 14% in two other studies.


          Although diarrhea being the most common cause of hypokalemia in patients on capecitabine, we postulate that hypokalemia may also be related to the effect of capecitabine on renal tubules suggested by the urine K + in some patients. Due to potential complications, hypokalemia in patients on capecitabine deserves special diagnostic and therapeutic attention.

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          Most cited references 10

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          Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.

          Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.
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            Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.

            To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer. We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles. The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P =.005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P =.72), median times to treatment failure were 4.1 and 3.1 months (P =.19), and median overall survival times were 12.5 and 13.3 months (P =.974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P <.0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P <.0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P <.00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment. Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.
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              First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.

              To evaluate the safety profile of capecitabine using data from a large, well-characterized population of patients with metastatic colorectal cancer treated in two phase II studies. In these trials, capecitabine achieved significantly superior response rates, equivalent time to disease progression and equivalent survival compared with 5-fluorouracil (5-FU)/leucovorin. Patients (n = 1207) were randomized to either oral capecitabine (1250 mg/m2 twice daily, on days 1-14 every 21 days) or intravenous (i.v.) bolus 5-FU/leucovorin (Mayo Clinic regimen). Capecitabine demonstrated a safety profile superior to that of 5-FU/leucovorin, with a significantly lower incidence of diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia leading to significantly fewer neutropenic fever/sepsis cases and fewer hospitalizations. All patients in the capecitabine group received a starting dose of 1250 mg/m2 twice daily and the majority (66%) did not require dose modification for adverse events. In the 5-FU/leucovorin group, 58% of patients did not require dose reduction for toxicities. The capecitabine dose-modification scheme reduced the recurrence of key toxicities without compromising efficacy. In both treatment arms, patients with moderate renal impairment at baseline (estimated creatinine clearance 30-50 ml/min) experienced a higher incidence of grade 3 or 4 toxicities. This increase was more pronounced with 5-FU/leucovorin. Capecitabine is at least as effective, better tolerated and more convenient than i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer. Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events. The phase III data and an additional pharmacokinetic study support a lower starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30-50 ml/min) and a contra-indication in patients with severely impaired creatinine clearance at baseline (<30 ml/min). For patients with normal or mildly impaired renal function at baseline, the standard starting dose is well tolerated. The incidence and severity of adverse events in patients with moderate renal impairment at baseline who were treated with 5-FU/leucovorin was more pronounced, indicating that capecitabine provides a better-tolerated alternative.

                Author and article information

                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                March 2007
                March 2007
                : 3
                : 1
                : 177-180
                [1 ]Yale University School of Medicine New Haven, CT, USA
                [2 ]Carraway Methodist Medical Center Birmingham, AL, USA
                [3 ]University of Alabama at Birmingham AL, USA
                Presented at the Annual Meeting of ASCO, Orlando, FL in 2005
                Author notes
                Correspondence: M Wasif Saif Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street; FMP 116, New Haven, CT 06520, USA Tel +1 203 737 1875 Fax +1 203 785 3788 Email wasif.saif@ 123456yale.edu
                © 2007 Dove Medical Press Limited. All rights reserved
                Original Research


                5-fu, capecitabine (xeloda), renal loss, hypokalemia, potassium, colon cancer


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