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ADVERSE EFFECTS |
From the Department of Pharmacy, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (Y. S. Heo); Division of Hematology-Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (H. M. Chang, T. W. Kim, M.-H. Ryu, J.-H. Ahn, S. B. Kim, J. S. Lee, W. K. Kim, Y.-K. Kang); and the Graduate School of Clinical Health Sciences, Ewha Womans University, Seoul, Korea (Y. S. Heo, H. K. Cho).
Address for reprints: Yoon-Koo Kang, MD, Division of Hematology-Oncology, Department of Internal Medicine, Asan Medical Center, 388-1 Pungnapdong, Songpa-gu, Seoul, Korea 138-736.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Capecitabine • hand-foot syndrome • docetaxel • cisplatin • vinorelbine
Capecitabine is an oral fluoropyrimidine rationally designed to deliver 5-FU to the tumor site through a 3-step enzymatic process and to mimic the continuous infusion of 5-FU.6 Clinical studies testing the efficacy and safety of capecitabine have shown that HFS is the most common treatment-related adverse event of this drug, occurring in 45% to 68% of patients, and is more frequent than observed from continuous infusion of 5-FU.2,6-9 Because the pathogenesis of HFS has not been clarified, an effective treatment has not been determined. The reactions are usually managed symptomatically with supportive treatments, including topical wound care, elevation, cold compresses, the application of topical emollients, and the use of pyridoxine.1,2,10
Although HFS is not a life-threatening toxicity, it has a significant impact on the treatment schedule and quality of life. The increased use of capecitabine in the treatment of many solid tumors has raised concerns about the occurrence of HFS. Moreover, HFS in patients treated with a combination of capecitabine and other chemotherapeutic agents has not been well documented. We evaluated the occurrence and clinical course of HFS induced by capecitabine-containing combination chemotherapy in this study. We also investigated the factors associated with HFS in these patients.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The 3 treatment schedules are presented in Table I. Before initiation of each cycle of chemotherapy, each patient received a physical examination, a toxicity evaluation, and routine laboratory studies. Complete blood count was checked weekly during each chemotherapy cycle to assess hematologic toxicity. All toxicities were assessed using National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0, and capecitabine doses were modified according to the guidelines.11-14 Compliance was assessed by questioning patients and counting their remaining pills at each outpatient visit.
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Data Collection
Toxicity data were collected prospectively throughout the trials. Doctors and clinical research nurses assessed the toxicities at each patient visit and graded them according to NCI CTC criteria. All patients who received at least 1 dose of study drug were evaluated in the analyses of HFS. Patient baseline characteristics, treatment data, compliance of capecitabine, and adverse events were collected from medical records and from case report forms.
Statistical Analysis
Frequency, severity, clinical course, and consequence of HFS were determined by descriptive methods. To assess the differences among the treatment regimens, we compared categorical variables with the chi-square test. Analysis of variance (ANOVA) was used to compare continuous variables.
We assessed the prognostic factors affecting the occurrence of HFS during treatment with capecitabine using the inverted Kaplan-Meier method and log-rank test, with the x-axis being the cumulative dose of capecitabine. Baseline clinical factors, including age, sex, pretreatment performance status, regimen, and combined use of other drugs, were evaluated as prognostic factors. The time-dependent Cox regression method was used to analyze performance status per cycle and preceding toxicities, including hematologic toxicities, diarrhea, stomatitis, neuropathy, and hypoalbuminemia. Variables significant by univariate analysis were further tested by multivariate Cox's regression. A P value less than .05 was considered statistically significant. Statistical analyses were performed using the SPSS 10.0 package. SAS version 8.0 was used for the time-dependent analysis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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HFS Occurrence and Time Course
HFS developed in 116 of 179 (64.8%) patients and in 384 of 881 (43.6%) chemotherapy cycles. Grade 3 HFS, however, occurred only in 8 patients (4.5%) and 9 cycles (1.0%). The occurrence and severity of HFS in each treatment group are presented in Figure 1. When we compared the frequency and severity of HFS among the treatment groups, we found that the DXP group tended to have a higher occurrence of HFS than the other groups (74.6% in DXP, 63.1% in XP, and 56.8% in NX; P = .179). In addition, grade 2 or 3 HFS, which was 25.7% overall, was observed in 29.5% of the DXP-treated, 23.8% of the XP-treated, and 25.0% of the NX-treated patients (P = .765).
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The chemotherapy cycle in which any grades of HFS first occurred was determined. Of the 116 patients who developed HFS, 100 (86.2%) first developed HFS within the first 3 chemotherapy cycles—29 (25.0%) during the first cycle, 49 (42.2%) during the second cycle, and 22 (19.0%) during the third cycle. The median onset was 2 cycles in each of the 3 treatment groups, and there was no statistical difference among the groups (P = .482).
Clinical Consequences of HFS
Treatment discontinuation for any toxicity was observed in 10 (19.6%) patients in the DXP group and 5 (6.0%) patients in the XP group, whereas no patient in the NX group discontinued treatment due to toxicity. Treatment discontinuation due to HFS, however, was observed in only 1 patient in the XP group.
Dose reduction of capecitabine occurred during 31.6% of the cycles (37.3% in the DXP group, 40.0% in the XP group, and 11.1% in the NX group). Dose reduction due to HFS was required in 6.7% of the cycles (5.8% in the DXP group, 6.7% in the XP group, and 7.7% in the NX group). Administration of capecitabine was delayed in 19.4% of the cycles (10.4% in the DXP group, 12.1% in the XP group, and 41.3% in the NX group), whereas dose delay due to HFS occurred in 0.7% of the cycles (0.4% in the DXP group, 0.5% in the XP group, and 1.3% in the NX group). Although frequency of dose modification was similar among the treatment groups, dose delay in the NX group was more frequent than dose reduction due to the different dose modification schedules for this treatment regimen.
Risk Factors for HFS
Inverted Kaplan-Meier curves were constructed to show the relationship between cumulative dose of capecitabine and occurrence of HFS (Figure 2). For Kaplan-Meier estimation, the baseline was defined as the cumulative dose of capecitabine, and the event was the first development of any grade of HFS. The median cumulative dose of capecitabine for the first development of HFS was 61,250 mg/m2 in the DXP group, 105,000 mg/m2 in the XP group, and 105,000 mg/m2 in the NX group.
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We also evaluated the risk factors for the occurrence of HFS based on a cumulative dose of capecitabine (Table III). Log-rank test showed that age 
52 years (P = .024), treatment regimen (P = .000), combined use of docetaxel (P = .000), and combined use of cisplatin or vinorelbine (P = .021) were each associated with HFS. Multivariate Cox regression analysis showed that combined use of docetaxel was the only independent risk factor for capecitabine-induced HFS (P = .001) (Table IV). The association of other temporal factors with HFS was evaluated using time-dependent Cox regression. Previous occurrence of chemotherapy-related stomatitis before development of HFS was associated with occurrence of HFS (P = .029), whereas other preceding toxicities and performance status per cycle were not.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The overall frequency of HFS in our study (64.8%) was similar to that in other studies (45%-68%).2,6-8 In a randomized phase III trial comparing capecitabine plus docetaxel combination therapy with docetaxel monotherapy in patients with advanced breast cancer, the overall frequency of HFS in 255 patients receiving capecitabine was about 63%, whereas that of grade 3 HFS was 24%.9 In addition, a phase II trial of capecitabine in combination with docetaxel and epirubicin in 67 patients with advanced breast cancer resulted in overall and grade 3 HFS frequencies of 57% and 4% of patients, respectively.15 Occurrence of grades 2 and 3 HFS (25.7%) was analyzed separately in our study because these grades of HFS are clinically significant and have a different effect on the subsequent treatment dose. In our study, occurrence of grade 3 HFS (4.5%) was somewhat lower than in other studies (4%-24%).2,6-8,15
Most first occurrences of capecitabine-induced HFS have been reported to develop in either the first or second course of treatment.2,16 In a trial of capecitabine monotherapy (2500 mg/m2/day), 92.9% of HFS first developed within the first 2 cycles of treatment.2 In our study, 86.2% of HFS first developed within the first 3 cycles of chemotherapy. We found that the initial occurrence of HFS peaked during the second cycle, a slight delay compared with that observed previously. Our findings of a delayed onset and lower frequency of grade 3 HFS may be due to dose modifications of capecitabine resulting from other chemotherapy-associated toxicities. Delay and dose reduction of capecitabine were conducted in approximately half the cycles in each treatment group (47.7% in DXP, 52.1% in XP, and 52.4% in NX), indicating that combination chemotherapy resulted in more frequent capecitabine dose modifications. Neutropenia was the most frequent cause of dose modification, although myelosuppression is not a common toxicity of capecitabine. Frequent dose modification may have influenced the severity or course of HFS in our study.
Treatment interruptions and dose modifications of capecitabine due to HFS were not common in our study. Severe HFS was rare and well controlled by appropriate measures. Treatment discontinuation or modification due to HFS may have been underestimated, however, because of other concurrent and/or predominant toxicities and different dose modification schedules according to the protocols of trials.
Analysis of risk factors for capecitabine-induced HFS in combination chemotherapy is complicated because capecitabine dose, schedule, and combined drugs differ among the 3 treatment regimens. To adjust capecitabine dose, we analyzed HFS according to Kaplan-Meier curves based on the cumulative dose of capecitabine. Analysis of risk factors for HFS by logrank test and multivariate Cox regression showed that treatment regimen, especially DXP, was significantly associated with more frequent HFS.
Docetaxel is a semisynthetic taxoid that has been found to cause cutaneous reactions, including HFS, although HFS is not a common adverse event of docetaxel treatment.17,18 Docetaxel is used together with capecitabine because they have synergistic antitumor activity.19 The increased occurrence of HFS in DXP-treated patients may be due to the interaction of docetaxel and capecitabine. Upregulation of thymidine phosphorylase (TP), which is required for the conversion of capecitabine to 5-FU, may be induced by docetaxel in tumor tissue, which may increase the exposure of 5-FU.16,19 Although TP is induced after exposure to docetaxel, a pharmacokinetic analysis revealed that docetaxel did not have a significant effect on capecitabine and its metabolites.16,19,20 The mechanism of interaction could not be explained clearly; docetaxel, however, may trigger or aggravate capecitabine-induced HFS. Interestingly, 23 of 51 (45.1%) patients treated with the DXP regimen had nail toxicity, which showed a significant association with the occurrence of HFS (P = .022, chi-square test). This finding indicates that the combination of docetaxel and capecitabine increases cutaneous toxicity.11
Vinorelbine-induced HFS has also been described, particularly that associated with prolonged infusion of high-dose vinorelbine.21 In our study, vinorelbine was administered as a bolus, which is not likely to exacerbate capecitabine-induced HFS.
The risk factors for HFS have been reported to be old age, female sex, and better performance status, as well as continuous infusion of chemotherapy.2,3 In our study, however, none of these factors increased the risk of HFS. We found that the combined use of docetaxel and the previous occurrence of chemotherapy-related stomatitis were the only significant prognostic factors for the development of HFS. HFS was not associated with any other temporal factor, including hematologic toxicities, diarrhea, neuropathy, hypoalbuminemia, and performance status per cycle.
The patient population in our study was not homogeneous, which may have influenced data interpretation. Our study, however, included data from a large number of patients (n = 179), and the analysis was based on the cumulative dose of capecitabine, adjusted to different dose levels, which could decrease the limitations of our findings.
Although there is no standard therapy for the management of HFS, pyridoxine therapy has been shown to be effective for managing and delaying HFS.10,22 Much of these data, however, is anecdotal and variable, making further evaluation of pyridoxine necessary. HFS has also been considered an inflammatory phenomenon mediated by the overexpression of cyclooxygenase 2 (COX-2),23 suggesting that a COX-2 inhibitor may be useful in the prevention and treatment of HFS.
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FOOTNOTES |
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Submitted for publication February 11, 2004; Revised version accepted March 22, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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