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© 2001 American Society for Clinical Oncology 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 StudyFrom The University of Texas M.D. Anderson Cancer Center, Houston; Physician Reliance Network, Inc, Dallas, TX; Michiana Hematology/Oncology, South Bend, IN; Hematology and Oncology Association of Virginia, Richmond, VA; Response Oncology, Memphis, TN; Hoffmann-La Roche Inc, Nutley, NJ; McGill University Department of Oncology, Montreal, Quebec; London Regional Cancer Centre, London; Ottawa Regional Cancer Centre, Ottawa; Group Health Center, Sault Ste Marie, Ontario; Tom Baker Cancer Center, Calgary, Alberta; H. Bliss Cancer Centre, St John’s, Newfoundland, Canada; and F. Hoffmann-La Roche Ltd, Basel, Switzerland. Address reprint requests to Paulo M. Hoff, MD, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 426, Houston, TX 77030-4009; email: phoff{at}mdanderson.org
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
COLORECTAL CANCER is the third most commonly diagnosed malignancy, accounting for 10% to 15% of newly diagnosed cancer cases in Europe and the United States. An estimated 783,000 new cases are diagnosed annually worldwide.1-4 Up to 30% of patients present with metastatic disease,4,5 and approximately 50% to 60% eventually develop metastatic or advanced disease. The prognosis for these patients is bleak, with 5-year survival rates of 5% or less.4-6 The most widely used agent in the treatment of metastatic colorectal cancer is fluorouracil (5-FU), which was developed more than 40 years ago and is included in most regimens of palliative chemotherapy for colorectal cancer.7-10 Numerous attempts have been made to improve the efficacy of 5-FU, including biomodulation and schedule modification. Protracted infusion of 5-FU and biomodulation with agents such as leucovorin (LV) have both resulted in improved response rates compared with bolus 5-FU alone, but neither approach has demonstrated a clinically meaningful survival benefit in randomized trials or meta-analyses.11-17 An alternative approach to optimizing 5-FU–based therapy has been the development of oral fluoropyrimidine derivatives designed to deliver 5-FU to target cells with predictable kinetics.18,19 Oral administration enables sustained exposure to 5-FU, avoids the technical barriers of intravenous (IV) administration and allows significant flexibility in the choice of the dosage regimen. In addition, most patients prefer oral cytotoxic therapy to IV regimens, provided that efficacy is not compromised.20-22 Capecitabine (Xeloda; Roche Laboratories, Nutley, NJ), an oral fluoropyrimidine carbamate, was rationally designed to generate 5-FU predominantly within tumor cells.23-26 After rapid and extensive absorption as an intact molecule, capecitabine is converted to 5-FU predominantly in tumor tissue by exploiting the high activity of thymidine phosphorylase in malignant tissue.24 The enzymatic conversion of capecitabine occurs in three steps. In the first stage, capecitabine is hydrolyzed by hepatic carboxylesterase to 5'-deoxy-5-fluorocytidine. This intermediate is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase in tumor cells and the liver. The third and final step involves the conversion of 5'-DFUR to 5-FU by thymidine phosphorylase (also known as platelet-derived endothelial cell growth factor or tumor-associated angiogenic factor) and occurs predominantly in tumor tissue as result of the high activity of thymidine phosphorylase.25 The increasing specificity for tumor cells occurring with each successive conversion step potentially reduces systemic 5-FU exposure while increasing the 5-FU dose within tumor tissue. The tumor selectivity of capecitabine has been confirmed in patients with colorectal cancer.26 Patients received capecitabine 1,250 mg/m2 twice daily for 5 to 7 days before surgical resection of their primary tumor and/or liver metastases. Concentrations of 5-FU in primary tumor tissue (n = 11) were 3.2-fold higher than in adjacent healthy tissue and 21-fold higher than in plasma. In a randomized phase II study designed to test three dosing schedules of capecitabine,27 an intermittent regimen (twice-daily treatment at 1,255 mg/m2 for 14 days, followed by a 7-day rest period) produced a confirmed tumor response in eight (24%) of 34 patients and a median time to disease progression of 7.7 months. This regimen was generally well tolerated and allowed administration of the highest dose-intensity among the three tested schedules. The intermittent regimen also had a shallower dose versus toxicity slope, and the inclusion of a 1-week drug-free period was considered to be more appealing to patients. In view of these promising results, we conducted one of two large randomized phase III trials28,29 with identical protocols and monitoring to determine whether the intermittent regimen of oral capecitabine was at least as active as bolus IV 5-FU/LV as first-line treatment for metastatic colorectal cancer.
Patients Patients with advanced or metastatic colorectal cancer who had not received prior chemotherapy for metastatic disease were eligible for this study. Adjuvant chemotherapy, if administered, should have been completed at least 6 months before enrollment in the trial. Histologic or cytologic confirmation of colorectal adenocarcinoma was required, as was the presence of at least one bidimensionally measurable indicator lesion that had not been treated with radiotherapy. Indicator lesions had to measure  10 mm (lung or skin) or 20 mm (liver, soft tissue masses) in one dimension. Ascites and pleural effusions were not considered measurable. Patients were required to have a Karnofsky performance status 70% and a life expectancy of at least 3 months. All patients were at least 18 years old and gave written informed consent before their inclusion in the study. Contraception was required throughout treatment for females of childbearing potential and for sexually active males. Patients were not eligible if they were pregnant or lactating, if they were hypersensitive to 5-FU or had previously experienced a severe reaction to fluoropyrimidines, if they had a history of other cancer within the previous 5 years (except for cured basal cell carcinoma of the skin or in situ cervical carcinoma), if they had received other experimental drugs or radiotherapy within 4 weeks before enrollment, or if they had not fully recovered from recent major surgery. Patients were also considered ineligible if they had organ allografts, CNS involvement of their disease, neurologic or psychiatric disorders that could interfere with treatment compliance, significant cardiac disease or a myocardial infarction within the previous 12 months, serious uncontrolled infections, or malabsorption syndrome or lack of physical integrity of the upper gastrointestinal tract. Patients were not enrolled if screening evaluations revealed significant abnormalities in neutrophils (< 1.5 x 109/L); platelets (< 100 x 109/L); serum creatinine or serum bilirubin (> 1.5 times the upper normal limit); or ALT, AST, or alkaline phosphatase (> 2.5 times the upper normal limit). However, up to five times the upper normal limits for ALT, AST, and alkaline phosphatase were allowed for patients with liver metastases, and up to 10 times the upper normal limit for alkaline phosphatase was allowed for patients with bone metastases. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by ethical committees at each participating investigative site.
Study Design and Treatment Treatment schedules. Capecitabine was administered orally at a dose of 1,250 mg/m2 twice daily (total daily dose 2,500 mg/m2) as an intermittent regimen in 3-week cycles (2 weeks of treatment followed by a 1-week rest period). For practical reasons, capecitabine doses were rounded to the nearest dose that could be administered with a combination of 500-mg and 150-mg tablets of drug. Capecitabine was given approximately 12 hours apart and taken orally with water within 30 minutes after ingestion of food (breakfast or dinner). 5-FU/LV was administered according to the Mayo Clinic regimen, consisting of a rapid IV injection of 20 mg/m2 LV followed by an IV bolus injection of 425 mg/m2 5-FU daily, days 1 to 5 every 4 weeks. Treatment with capecitabine or 5-FU/LV was continued until the development of progressive disease, unacceptable toxicity, or until the scheduled assessment at 30 weeks. Patients with a tumor response or stable disease were allowed to enter a continuation phase up to a total of 48 weeks. Treatment continuation beyond 48 weeks (postcontinuation phase) for patients without progressive disease was at the discretion of the investigator. Treatment modifications. Treatment interruption or dose reduction was not indicated for reactions unlikely to become serious or life threatening or for grade 1 toxicity (National Cancer Institute of Canada Common Toxicity Criteria [NCIC CTC], revised December 1994). Treatment was interrupted in cases of grade 2 or higher toxicity and was not resumed until the adverse effect resolved or improved to grade 1 or 0. No capecitabine dose reduction was required at the first occurrence of a grade 2 toxicity, but capecitabine doses were reduced by 25% for patients who experienced a second occurrence of a given grade 2 toxicity or any grade 3 toxicity and by 50% for patients who experienced a third occurrence of a given grade 2 toxicity, a second occurrence of a given grade 3 toxicity, or any grade 4 toxicity. Treatment was discontinued if, despite dose reduction, a given toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4. For patients assigned to receive treatment with 5-FU/LV, the dose of LV was held constant, and 5-FU doses were escalated or reduced according to toxicity. If initial treatment produced no toxicity, the 5-FU dose could be escalated by 10% for the next cycle. No change in 5-FU dose was indicated for patients who experienced grade 1 toxicity. The 5-FU dose was decreased by 20% in cases of grade 3 hematologic or grade 2 nonhematologic toxicity and by 30% in cases of grade 4 hematologic or grade 3 or 4 nonhematologic toxicity. Treatment was discontinued if a patient experienced both grade 4 hematologic and grade 4 nonhematologic toxicity.
Evaluation of Patients Safety evaluations were conducted at least monthly until 4 weeks after the end of therapy and included assessments of laboratory parameters and clinical adverse reactions. Clinical adverse events were graded according to the NCIC CTC grading system. Hand-foot syndrome (palmar-plantar erythrodysesthesia) was classified as grade 1 (numbness, dysesthesia, painless swelling, or erythema not disrupting normal activities), grade 2 (erythema with painful swelling or disrupting daily living activities), or grade 3 (moist desquamation, ulceration, blistering, or severe pain, or any symptoms leading to an inability to work or to perform daily living activities).31
Statistical Analysis Secondary efficacy end points were time to response, duration of response, time to disease progression, time to treatment failure, overall survival, and quality of life (results to be published separately). Duration of response was calculated according to the World Health Organization response criteria. Time to disease progression was calculated from the date of randomization to the first recorded observation of PD or the occurrence of death from any cause. Time to treatment failure additionally included toxicity-related premature withdrawals, failure to return, and treatment refusals as events. Overall survival time was calculated from the date of randomization to the date of death from any cause. Results for time to disease progression and overall survival time were analyzed according to Kaplan-Meier estimates and compared using the log-rank test. In addition, Cox proportional hazards models were applied to test for interactions between prognostic factors and overall survival times. The analyses of efficacy were based on all randomized patients. The IRC assessment was not designed to provide a complete clinical assessment of time-related end points, such as time to disease progression and time to treatment failure. These parameters were analyzed using the investigator assessments and, therefore, for reasons of consistency, the response data were also analyzed and reported according to the investigator assessments as well as the IRC assessments. The analyses of toxicity were based on the safety population, which included all patients who received at least one dose of study treatment. Clinical adverse events, laboratory abnormalities, hospitalizations, and treatment for adverse reactions were summarized as incidence rates. For clinically relevant, predefined grade 3 or 4 adverse reactions typically associated with fluoropyrimidines (diarrhea, stomatitis, hand-foot syndrome, alopecia, nausea, vomiting, and neutropenia), a Kaplan-Meier estimate for the time from randomization to first onset of those adverse reactions was calculated. The log-rank test was used to test for treatment differences.
Patients and Treatment A total of 605 patients were randomized to treatment with capecitabine (302 patients) or 5-FU/LV (303 patients). Patients were enrolled from 61 centers during the 17-month period from September 1996 to February 1998. Table 1 lists demographic data, baseline disease characteristics, and prior therapy for all randomized patients. As expected, most patients were elderly, and the colon was the most common site of the primary tumor. Liver, lymph nodes, and lung were the most frequent sites of metastasis. The numbers of metastatic sites were evenly distributed between the study groups. In both treatment groups, 18% to 21% of patients had tumors with poorly differentiated histology. Overall, the two treatment groups were well balanced for almost all evaluated characteristics, but serum alkaline phosphatase concentrations at baseline were significantly higher in the capecitabine group compared with the 5-FU/leucovorin group (P < .0025, Wilcoxon rank sum test).
Of the 605 patients enrolled, 593 (98%) received at least one dose of the allocated treatment drug, approximately three quarters completed 6 weeks of therapy, and approximately one quarter completed the planned treatment period of 30 weeks. The most frequent reasons for treatment discontinuation were progressive disease (188 patients in the capecitabine group and 177 in the 5-FU/LV group), adverse reactions (39 patients in the capecitabine group and 32 in the 5-FU/LV group), and treatment refusals (11 patients in the capecitabine group and 29 in the 5-FU/LV group). Both treatment groups adhered closely to the planned dosage regimens. For patients treated with capecitabine, the mean daily dose corresponded to 80% of the scheduled dose, and the mean duration of treatment was 4.3 months. For patients treated with 5-FU/LV, the mean daily dose of 5-FU corresponded to 86% of the scheduled dose, and the mean duration of treatment was 4.6 months.
Primary Efficacy End Point: Overall Response Rate
Secondary Efficacy End Points As an indicator for time to response, we grouped the responding patients into 6-week treatment intervals. In both treatment groups, most responses occurred within the first 3 months of therapy. Throughout all time periods, capecitabine treatment induced more objective responses than 5-FU/LV. The median duration of objective tumor response (CR and PR) was 9.1 months in the capecitabine group (54 events) and 9.5 months in the 5-FU/LV group (30 events) (P = .37). The median time to disease progression was 4.3 months for patients in the capecitabine group (269 events) and 4.7 months in the 5-FU/LV group (271 events) ( Fig 1). No difference was apparent between the treatment groups (P = .72, log-rank test). The hazard ratio was 1.03 (95% CI, 0.87 to 1.22), thus demonstrating at least equivalence. Times to treatment failure were similar in the treatment groups, with a median of 4.1 months in the capecitabine treatment arm (227 events) and a median of 3.1 months in the 5-FU/LV arm (280 events) (P = .19, log-rank test; hazard ratio, 0.90 [95% CI, 0.76 to 1.06]).
There was no significant difference in the median overall survival for all randomized patients, with 12.5 months for patients in the capecitabine group (260 events) and 13.3 months in the 5-FU/LV group (273 events) (P = .97, log-rank test). The hazard ratio was 1.00 (95% CI, 0.84 to 1.18), thus demonstrating at least equivalence ( Fig 2).
We conducted exploratory analyses of response rates among patient subgroups to identify demographic and/or baseline disease characteristics of potential prognostic value ( Table 3). Response rates were consistently higher for capecitabine than for 5-FU/LV in almost all subgroups, including patients with multiple metastatic sites (21% v 9% for > four metastatic sites, respectively), patients with liver metastases (25% v 17%, respectively), patients with lung metastases (30% v 8%, respectively), and patients who had received prior 5-FU–based adjuvant chemotherapy (21% v 8%, respectively).
A multivariate Cox regression analysis identified the following four significant prognostic factors: elevated alkaline phosphatase at baseline (P = .0001), poor Karnofsky performance status (70% or 80% v 100%) (P = .0001), multiple versus single sites of metastasis (P = .0001), and liver as the predominant site of metastases (P = .0035). These factors correlated with reduced overall survival times in both treatment groups, regardless of assigned treatment.
Toxicity Profile
Table 4 lists the number of patients with grade 4 adverse reactions (all) and grade 3 adverse reactions reported for 5% of patients in at least one of the treatment groups. Overall, patients in the capecitabine group were less likely to experience clinical grade 4 toxicity than patients receiving 5-FU/LV (2.7% v 4.8% of patients who experienced an adverse reaction, respectively). The incidences of grade 3 or 4 diarrhea were similar in the two treatment groups (14% v 15%, respectively). Treatment with 5-FU/LV led to a higher incidence of grade 3 and 4 stomatitis (16% for 5-FU/LV group v 3% for capecitabine group, P < .00001), whereas capecitabine led to higher incidences of grade 3 hand-foot syndrome (18% for capecitabine group v 1% for 5-FU/LV group, P < .00001) and grade 2 hand-foot syndrome (26% for capecitabine group v 1% for 5-FU/LV group, P < .0001).
Severe cardiotoxicity and neurotoxicity were infrequent in both treatment groups. Treatment-related grade 3 or 4 cardiotoxicity occurred in two patients (0.7%) in the capecitabine group (angina pectoris [grade 3] and myocarditis [grade 3]) and in three patients (1.0%) in the 5-FU/LV group (angina pectoris [grade 3], chest pain [grade 3], and myocardial infarction [grade 4]). There was no treatment-related grade 4 neurotoxicity in both arms and grade 3 toxicity occurred in six patients (2.0%) in the capecitabine group (taste disturbance, headache, ataxia, and peroneal nerve palsy) and in three (1.0%) patients in the 5-FU/LV group (taste disturbance and vasovagal attack). As described earlier, a protocol-prespecified safety analysis of the time to onset and the incidence of treatment-related grade 3 and 4 diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, and neutropenic episodes was performed. The analysis demonstrated a statistically significant difference favoring capecitabine, with a lower overall incidence and later onset of these grade 3 or 4 adverse reactions with capecitabine throughout the entire treatment period (P = .0037, log-rank test). This difference was particularly pronounced during the first 4 to 5 months ( Fig 4).
Fewer patients in the capecitabine group required hospitalization for adverse reactions than in the 5-FU/LV group (P = .003) ( Table 5). Hospitalizations for diarrhea or dehydration occurred with similar frequency in the treatment groups, whereas hospitalizations for neutropenia (with or without fever) and stomatitis occurred only in the 5-FU/LV group. No patients were hospitalized for hand-foot syndrome. Patients in the capecitabine group were also less likely than those in the 5-FU/LV group to require symptomatic treatment for adverse reactions including stomatitis (51% v 72% of affected patients, respectively), diarrhea (63% v 70% of affected patients, respectively) and nausea (60% v 75% of affected patients, respectively). Patients receiving capecitabine required treatment for hand-foot syndrome more frequently than patients in the 5-FU/leucovorin group (57% v 13%, respectively).
Table 6 lists the incidence of grade 3 or 4 abnormalities in laboratory parameters. Myelosuppression was rare with capecitabine, whereas the incidence of grade 3 or 4 neutropenia was 26% with 5-FU/LV. Increases in transaminases or alkaline phosphatase levels were rare in both arms. Using the NCIC CTC criteria, we noted reversible grade 4 hyperbilirubinemia ( 3.0 x upper limit of normal) in 4.7% of patients in the capecitabine arm and in 1.7% of patients in the 5-FU/LV arm. More cases of grade 3 hyperbilirubinemia (1.5 to 3.0 x upper limit of normal) were observed with capecitabine than with 5-FU/LV (13% v 3.7% of patients, respectively). Analyses for total and direct bilirubin were available for 53% of patients with grade 3 or 4 hyperbilirubinemia. Indirect bilirubin accounted for the bilirubin elevations in 78% of cases. Of the 52 patients with elevated bilirubin in the capecitabine group only seven had concomitant grade 3 abnormalities in alkaline phosphatase or liver transaminases (ALT or AST). By comparison, of the 16 patients with elevated bilirubin in the 5-FU/LV group, three had concomitant grade 3 or 4 abnormalities in both bilirubin plus alkaline phosphatase or liver transaminases.
Dose reduction for adverse reactions was required in 40.5% of patients in the capecitabine group (most commonly for hand-foot syndrome or diarrhea) and in 49.3% of patients in the 5-FU/LV group (most commonly for stomatitis or diarrhea). Dose reductions for adverse reactions were required earlier in the 5-FU/LV group (median, 34 days) than in the capecitabine group (median, 65 days). Adverse reactions led to treatment discontinuation in 9.0% of patients in the capecitabine group and 6.5% of patients treated with 5-FU/LV. The most frequent adverse events leading to discontinuation, either alone or in combination, were diarrhea (3.3%), hand-foot syndrome (1.7%), vomiting (1.7%), stomatitis (1.3%), nausea (1.0%), and dehydration (0.7%) in the capecitabine group, and stomatitis (2.7%), diarrhea (1.4%), dehydration (1.0%), and vomiting (0.7%) in patients treated with 5-FU/LV. Treatment-related adverse reactions were fatal for two patients treated with 5-FU/LV (one case each of sepsis and upper respiratory tract infection) and for three patients in the capecitabine group (one case each of gastrointestinal hemorrhage, pneumonia, and death of unknown cause).
This randomized phase III study compared the efficacy and toxicity profiles of oral capecitabine with those of IV bolus 5-FU/LV as first-line treatment for metastatic colorectal cancer. We found that capecitabine was more active than 5-FU/LV in the induction of tumor responses and that the two treatment groups showed similar duration of response and time to response. Time to disease progression and overall survival were at least equivalent for capecitabine compared with IV bolus 5-FU/LV. In addition, capecitabine offers clinically meaningful advantages over 5-FU/LV in terms of tolerability. We conclude that oral capecitabine provides a favorable benefit:risk ratio compared with bolus IV 5-FU/LV. Baseline disease characteristics, demographic features, and prognostic factors were generally similar between the two treatment groups and seemed to be consistent with those described in other studies of colorectal cancer patients treated with first-line fluoropyrimidine-based chemotherapy.11,12 The major exception to this observation was the significantly higher baseline concentrations of alkaline phosphatase in patients receiving capecitabine. Despite this imbalance, the overall survival in the capecitabine group was at least equivalent to the IV 5-FU/LV group. The response rate achieved with capecitabine was significantly higher than that observed in patients receiving 5-FU/LV. Furthermore, subgroup analysis indicated that response rates in most subgroups were consistently higher with capecitabine than with 5-FU/LV (Table 3). Capecitabine was more active than IV bolus 5-FU/LV in patients with multiple metastatic sites and was especially effective in patients with liver metastases (25% v 17% with 5-FU/LV) and lung metastases (30% response rate v 8% with 5-FU/LV), and in patients who had received prior adjuvant chemotherapy (21% v 8% with 5-FU/LV). There were also marked differences in response rates in certain racial subgroups (for example, 21% v 8% with capecitabine and 5-FU/LV, respectively, in black patients). However, the small patient numbers involved in the racial subgroups make it difficult to draw any firm conclusions. The types of adverse reactions reported for capecitabine are consistent with the known profiles of fluoropyrimidines in general and of continuous infusion regimens of fluoropyrimidines in particular.34 However, the toxicity profile of capecitabine differed in several important respects from that of IV bolus 5-FU/LV. Capecitabine was associated with a substantially lower incidence of diarrhea, stomatitis, nausea, and alopecia. In addition, grade 3 or 4 stomatitis and neutropenic fever/sepsis, as a consequence of rare neutropenia, were significantly less frequent among patients treated with capecitabine. There were significantly fewer hospitalizations for the treatment of adverse events with capecitabine. There was a significantly lower overall incidence and later onset of grade 3 or 4 adverse reactions typical of fluoropyrimidine therapy in the capecitabine group throughout the treatment period. This difference was particularly pronounced during the first 4 to 5 months of therapy. Consequently, dose reductions occurred less often and later in the capecitabine group than in the 5-FU/LV group; 41% of the patients receiving capecitabine and 49% of the patients receiving 5-FU/LV required dose reduction, with median times to dose reduction of 2.1 months and 1.1 months, respectively. This analysis indicates that, compared with patients receiving 5-FU/LV, patients treated with capecitabine are significantly less likely to experience clinically relevant toxicities, particularly during the initial treatment period. Treatment with capecitabine led to a higher incidence of cutaneous hand-foot syndrome compared with 5-FU/LV. Patients who developed hand-foot syndrome responded to dose interruption and/or reduction according to the protocol, with subsequent improvement and resolution of symptoms. Although 18% of patients developed grade 3 hand-foot syndrome at the planned dose-intensity of capecitabine, this reaction caused fewer than 2% of patients to withdraw from treatment, indicating that most patients tolerated continued treatment at an adjusted dose. None of the patients who developed hand-foot syndrome required hospitalization. Patients in the capecitabine group also experienced a higher incidence of NCIC CTC grade 3 or 4 hyperbilirubinemia, corresponding to grade 2 or 3 bilirubin under the new NCI CTC criteria. In most cases this was due to the indirect fraction. Hyperbilirubinemia was only rarely accompanied by abnormalities in liver transaminases or alkaline phosphatase, and all cases were reversible. The results of this trial were supported by data from an identical trial conducted in Europe, Australia, New Zealand, Taiwan, and Israel, which included 602 patients receiving first-line therapy for metastatic colorectal cancer.28 Capecitabine resulted in a significantly superior response rate and at least equivalent time to disease progression and survival compared with 5-FU/LV. In addition, the results of the European trial and the present American trial have been combined, and a prospective analysis of the integrated data has been conducted.35 The integrated analysis confirmed the results of the individual trials in terms of both efficacy and safety. Capecitabine demonstrated a significantly superior response rate (25.5% v 16.7% with 5-FU/LV, P < .00002) and at least equivalent time to disease progression and survival. The toxicity profile of capecitabine was similar to that observed in the present study, with a significantly lower incidence of key adverse events (diarrhea, stomatitis, nausea, and alopecia). Hand-foot syndrome was significantly more common with capecitabine but rarely led to treatment withdrawal and resulted in only two hospitalizations, both of which lasted for less than 24 hours. 5-FU/LV regimens have been considered the standard therapy for patients with advanced colorectal cancer.10,36 The LV-modulated IV bolus regimen used in this study is widely used because of its convenience and documented efficacy compared with bolus 5-FU monotherapy.37 Response rates reported for the 5-FU/LV regimen used in the present study range from 9%38 to 43%,37 although in more recent studies, response rates have consistently been less than 20%. The response rate in this study was therefore consistent with the literature. Median survival also fell within the 10- to 13-month range typical of this regimen.14,15,37,39-44 Continuous infusion 5-FU leads to significantly higher response rates than bolus 5-FU, and a meta-analysis identified a statistically significant increase in overall survival.12 However, this improvement was only modest, and other trials have failed to demonstrate a significant survival benefit. Continuous infusion 5-FU is not routinely administered, partly because of its inconvenience and cost and partly because central venous access causes significant complications in 15% to 20% of patients,45 including infections, bleeding, thrombosis, and pneumothorax. Each of these complications has a negative impact on quality of life.38 As with other fluoropyrimidine regimens, the significantly superior response rates achieved with capecitabine did not translate into a significant survival benefit. However, capecitabine achieved at least equivalent survival. Moreover, capecitabine offers important advantages in terms of tolerability and convenience for patients. Since the start of this study, other therapeutic agents have shown activity in advanced colorectal cancer, either as monotherapy or in combination with 5-FU/LV. Irinotecan has produced promising results in patients with advanced colorectal cancer who failed prior 5-FU therapy46-49 and as first-line therapy in combination with 5-FU/LV.39,40 The combination of capecitabine with irinotecan is currently being investigated in several clinical trials.50-52 Other groups are exploring the combination of capecitabine plus oxaliplatin,53,54 based on trials demonstrating improved response rates and time to disease progression with the addition of oxaliplatin to 5-FU/LV regimens.55,56 Phase I trials of the combination of irinotecan, oxaliplatin, and capecitabine are in the planning phase. The use of capecitabine to replace IV bolus 5-FU/LV seems to be acceptable for the treatment of advanced colorectal cancer, based on its greater response rate, its favorable toxicity profile, and patient preference for oral, home-based therapy.20-22
APPENDIX
Supported in part by a grant from F. Hoffmann-La Roche Inc, Basel, Switzerland.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999.
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Landis SH, Murray T, Bolden S, et al: Cancer statistics 1999. CA Cancer J Clin 49: 8-31, 1999 4. Midgley R, Kerr D: Colorectal cancer. Lancet 353: 391-399, 1999[Medline] 5. Williams NS, Northover JMA, Arnott SJ, et al: Colorectal tumors, in Peckham M, Pinedo H, Veronesi U (eds): Oxford Textbook of Oncology. Oxford University Press, Oxford, United Kingdom, 1995, pp 1133-1168 6. Wingo PA, Ries LA, Parker SL, et al: Long-term cancer patient survival in the United States. Cancer Epidemiol Biomarkers Prev 7: 271-282, 1998[Abstract] 7. Blijham GH: Chemotherapy of colorectal cancer. Anticancer Drugs 2: 233-245, 1991[Medline] 8. Mayer RJ: Chemotherapy for metastatic colorectal cancer. Cancer 70: 1414-1424, 1992 (suppl 5)[Medline] 9. Benson AB III: Therapy for advanced colorectal cancer. Semin Oncol 25: 2-11, 1998 (suppl 11) 10. Conley BA, Kaplan RS, Arbuck SG: National Cancer Institute Clinical Trials Program in Colorectal Cancer. Cancer Chemother Pharmacol 42: S75-S79, 1998 (suppl) 11. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10: 896-903, 1992[Abstract]
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ABSTRACT
INTRODUCTION
2 test with Schouten correction.
