1 Vienna University Medical School, Vienna, Austria; 2 Box Hill Hospital, Melbourne; 3 Port Macquarie Hospital, Port Macquarie, Australia; 4 Institute of Medical Oncology, Berne, Switzerland; 5 St Vincents Hospital, Melbourne, Australia; 6 Sarah Cannon Cancer Center, Nashville, TN, USA; 7 University of Aberdeen, Aberdeen; 8 University of Edinburgh, Western General Hospital, Edinburgh, UK; 9 Rydygier Memorial Hospital, Krakow, Poland; 10 The Christie Hospital and Holt Radium Institute, Manchester, UK; 11 Outpatient Cancer Centre, Freiburg, Germany; 12 Ottawa Regional Cancer Centre, Ottawa, Canada; 13 Hospital Gregorio Marañón, Madrid, Spain; 14 Regional Center of Oncology, Bydgoszcz, Poland; 15 The Mount Hospital, Perth, and Sir Charles Gairdner Hospital, Nedlands, Australia; 16 Tom Baker Cancer Centre, Calgary, Canada; 17 Great Poland Cancer Center, Poznan, Poland; 18 Beatson Oncology Centre, Glasgow; 19 University of Leeds, Leeds, UK
Received 23 September 2003; accepted 26 September 2003
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Abstract |
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Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracilleucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes C colon cancer.
Patients and methods:
Patients aged 1875 years with resected Dukes C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m2 twice daily, days 114 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m2 with i.v. leucovorin 20 mg/m2 on days 15, repeated every 28 days (n = 974).
Results:
Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more handfoot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 handfoot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or 65 years old.
Conclusions:
Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in 2004.
Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer
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Introduction |
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Despite the advances afforded by the use of 5-FU/LV, evidence suggests that there is considerable discrepancy between consensus recommendations advocating the routine use of adjuvant treatment and its use in the community [6]. In particular, older patients are less likely to receive chemotherapy, possibly due to physicians concerns about increased toxicity in this group. In a German randomized trial comparing 5-FU/LV with 5-FU/levamisole as adjuvant treatment for resected stage III colon cancer, treatment was prematurely discontinued in 24% of patients, primarily due to toxicity and lack of compliance [7]. Better-tolerated, more convenient and more active chemotherapy is required for the adjuvant treatment of colon cancer.
In the metastatic setting both a questionnaire-based study [8] and a randomized, treatment cross-over study [9] indicated that the majority of patients (8489%) prefer oral chemotherapy, as long as efficacy is not compromised. Patients indicated that the principal reasons for this preference were the avoidance of problematic i.v. access and the improved convenience of home-based treatment. In addition, Payne [10] demonstrated that patients quality of life was significantly improved with home-based compared with hospital-based therapy.
Capecitabine (Xeloda®; F. Hoffmann-La Roche, Basel, Switzerland) is an oral fluoropyrimidine that generates 5-FU preferentially in tumor tissue via a three-step enzymatic cascade. The final step is catalyzed by thymidine phosphorylase, an enzyme with significantly higher activity in tumor compared with healthy tissue [11]. Oral capecitabine is effective in the treatment of metastatic colorectal cancer, offering improved convenience and patient acceptability compared with i.v. 5-FU/LV. Two large phase III trials have shown that, as first-line therapy for metastatic colorectal cancer, capecitabine achieves a superior response rate and at least equivalent time to disease progression (TTP) and overall survival compared with 5-FU/LV (Mayo Clinic regimen) [12]. Capecitabine also demonstrated an improved safety profile compared with 5-FU/LV [13], with significantly less diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia, leading to less febrile neutropenia and fewer associated hospitalizations (P <0.001). Handfoot syndrome occurred more frequently in the capecitabine arm than in the 5-FU/LV arm (P <0.001), but this cutaneous side-effect is never life threatening and can be managed effectively by treatment interruption and/or dose modification [13].
Considering the documented high activity, good tolerability and improved convenience in patients with metastatic disease, capecitabine has been further evaluated as adjuvant therapy for colon cancer. This international, multicenter, randomized, open-label phase III study evaluated capecitabine versus i.v. 5-FU/LV (Mayo Clinic regimen) as adjuvant therapy for patients with Dukes C colon cancer. The primary objective of the study was to demonstrate that disease-free survival with capecitabine is at least equivalent to that achieved with 5-FU/LV (Mayo Clinic regimen). Secondary end points included overall survival, quality of life, medical resource utilization and safety. The trial has completed recruitment of 1987 patients and efficacy results are expected in 2004. We report here the results of the planned safety analysis, conducted 19 months after the enrollment of the last patient.
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Patients and methods |
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Eligibility criteria
Eligible patients were aged 1875 years (although some 75 years were given waivers to participate in the study) and had histologically confirmed Dukes C colon carcinoma (with at least one positive lymph node) after surgery with curative intent. Carcinoembryonic antigen (CEA) concentrations were to be within the normal range. Patients were required to have fully recovered following surgery and have an Eastern Cooperative Oncology Group (ECOG) performance status of
1 and a life expectancy of at least 5 years.
Patients with evidence of metastatic disease, including tumor cells in ascites at study entry, were ineligible. Those who had received cytotoxic chemotherapy or who had organ allografts, clinically significant cardiac disease, severe renal impairment or central nervous system disorders were also excluded. Pregnant or lactating women and sexually active patients unwilling to practice contraception were excluded.
Study design and treatment
This international, multicenter, randomized, open-label, parallel-group phase III study was designed to demonstrate that capecitabine achieves at least equivalent disease-free survival to 5-FU/LV (the Mayo Clinic regimen) when administered as adjuvant treatment following surgery for Dukes stage C colon cancer. Secondary end points were overall survival, quality of life, medical resource utilization and safety profile.
Patients were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m2 twice daily, given on days 114 every 21 days, or i.v. leucovorin 20 mg/m2 by rapid infusion followed immediately by i.v. bolus 5-FU 425 mg/m2, days 15 every 28 days.
After inclusion of 1363 patients, an amendment reduced the capecitabine starting dose by 25% in patients with moderate renal impairment (estimated creatinine clearance 3050 ml/min [14]) based on newly available data [13, 15].
Screening/baseline assessments
Assessments included medical history, a general physical examination, vital signs, physical measurements, performance status, laboratory tests (hematology, blood chemistry, pregnancy test, urinalysis and CEA determination) and ECG. The presence of metastatic disease was excluded by computed tomography (CT) scan or magnetic resonance imaging (MRI) of abdomen and pelvis and chest X-ray. A baseline quality of life assessment (QLQ-C30) was also performed.
Evaluation of safety
This prospectively planned safety analysis was conducted 19 months after enrollment of the last patient. Adverse events were recorded and graded according to National Cancer Institute of Canada common toxicity criteria (NCIC CTC), revised in May 1991. Handfoot syndrome was graded 1 to 3, as described previously [16, 17]. Laboratory analyses performed at the beginning of each cycle included: hemoglobin, white blood and platelet cell counts, total bilirubin, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase, serum creatinine, potassium, sodium, phosphate, uric acid and calcium.
Dose modification
The capecitabine and 5-FU/LV (Mayo Clinic regimen) dose modification schemes have been published in detail [13]. In the 5-FU/LV treatment group, the dose of leucovorin was not modified, but the 5-FU dose was reduced (to 80% or 70% of the preceding dose) or escalated (to 110% of the preceding dose) depending upon the occurrence and severity of either clinical adverse events or hematological/laboratory abnormalities, or their absence in the preceding treatment cycles. In the capecitabine group, treatment was continued at the same dose (without interruption or dose reduction) if patients experienced toxicities no greater than grade 1 or other toxicities unlikely to become severe or life threatening (e.g. alopecia). All patients were instructed to interrupt capecitabine treatment upon the development of moderate or severe toxicity (grade 2), and to immediately contact the clinic for further directions. At a second occurrence of grade 2 toxicity, or after appearance of grade 3 or 4 toxicity, the capecitabine dose was to be reduced by 25%. In the event of further toxicity, a second-step dose reduction to 50% of the starting dose was allowed. Treatment was not resumed until symptoms had resolved to grade 0 or 1. Once the capecitabine or 5-FU/LV dose had been reduced, it was not to be increased at a later time.
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Results |
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Dose modification and premature withdrawal
Dose reduction was required in 42% of patients receiving capecitabine compared with 44% of patients receiving 5-FU/LV. Median time to first dose reduction was longer for patients receiving capecitabine compared with 5-FU/LV (78 versus 41 days). Second-level dose reductions (to <60% of the capecitabine starting dose and <75% of the 5-FU/LV starting dose) were also more common in the 5-FU/LV arm than the capecitabine arm (26% versus 13%); median time to second-level dose reduction was longer for patients receiving capecitabine (113 versus 57 days with 5-FU/LV).
The adverse events most commonly leading to dose modification (including treatment interruption and dose reduction) were handfoot syndrome (31%) and diarrhea (15%) in the capecitabine arm, and stomatitis (23%) and diarrhea (19%) in the 5-FU/LV arm (Table 7).
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Resource use: treatments for adverse events
Fewer patients receiving capecitabine required medications for the treatment of adverse events (703 patients versus 768 patients with 5-FU/LV). The most commonly prescribed treatments for adverse events were loperamide, antibiotics and metoclopramide (Table 9). Fewer patients receiving capecitabine required loperamide (231 versus 372 with 5-FU/LV) and metoclopramide (141 versus 243 with 5-FU/LV), reflecting the significantly lower incidences of diarrhea and nausea/vomiting in the capecitabine group. Fewer patients receiving capecitabine required treatment with antibiotics (217 versus 289 with 5-FU/LV). The lower incidence of neutropenia with capecitabine was reflected by less frequent need for granulocyte colony-stimulating factor (G-CSF). Seven patients receiving capecitabine required G-CSF compared with 27 in the 5-FU/LV group.
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Discussion |
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As first-line treatment for metastatic colorectal cancer, capecitabine was associated with significantly lower incidences of diarrhea, stomatitis, nausea, alopecia, neutropenia (including grade 3 or 4) and febrile neutropenia/sepsis compared with 5-FU/LV (Mayo Clinic regimen). Handfoot syndrome occurred more frequently with capecitabine. The improved safety profile of adjuvant capecitabine versus 5-FU/LV is demonstrated by significantly lower incidences of diarrhea, nausea/vomiting, stomatitis (including grade 3 or 4), alopecia, neutropenia (including grade 3 or 4) and febrile neutropenia/sepsis. The most common treatment-related adverse event with adjuvant capecitabine is a cutaneous side effect, handfoot syndrome. Experience in the metastatic setting shows that handfoot syndrome is effectively managed by adequate patient education, treatment interruption and, if necessary, dose reduction, and rarely leads to treatment discontinuation or hospitalization [13]. Hyperbilirubinemia is a known side effect of oral fluoropyrimidines and rarely associated with clinical abnormalities [13]. Grade 3 or 4 hyperbilirubinemia was more common in patients receiving capecitabine than in those receiving 5-FU/LV. But elevated ASAT and ALAT concentrations were uncommon in both treatment arms, suggesting that hyperbilirubinemia is not associated with hepatobiliary dysfunction.
A low level of early severe toxicities, potentially leading to treatment discontinuation or even death, is particularly important in the adjuvant setting. In this study, patients receiving capecitabine were three times less likely to experience severe early gastrointestinal toxicities, infections, neutropenia and thrombocytopenia compared with those patients receiving 5-FU/LV. These data further confirm the favorable safety profile of capecitabine.
Colorectal cancer is more common in older patients so it is important to note that capecitabine was equally well tolerated by older and younger patients. In both subgroups, capecitabine was associated with less diarrhea, nausea, vomiting, stomatitis and neutropenia than 5-FU/LV. Patients aged 65 years in the capecitabine arm experienced a similar incidence of early severe toxicities (gastrointestinal toxicities, infections, neutropenia and thrombocytopenia) to the younger patients (aged <65 years), but in the 5-FU/LV arm, patients aged
65 years experienced a higher incidence of early severe toxicities compared with patients aged <65 years.
As previously demonstrated in the metastatic setting [18], capecitabine improves medical-resource use compared with 5-FU/LV. Oral capecitabine is administered at home and patients require fewer hospital visits compared with patients receiving i.v. treatment. Administration of 5-FU/LV (Mayo Clinic regimen) requires patients to attend the clinic/hospital for five consecutive days during every 28-day treatment cycle. In addition, the improved safety profile of capecitabine, particularly the significantly lower incidences of diarrhea, nausea/vomiting and neutropenia, leads to a reduced need for medications to manage adverse events.
Good tolerability is a particularly important consideration when chemotherapy is administered in the adjuvant setting. A number of ongoing trials are evaluating 5-FU/LV in combination with irinotecan or oxaliplatin in the adjuvant setting. Recently, results from the MOSAIC study evaluating bolus/infusional 5-FU/LV and oxaliplatin (FOLFOX4) versus infusional 5-FU/LV (the de Gramont regimen) as adjuvant treatment for patients with stage II or III colon cancer were presented [19]. Although FOLFOX4 achieved a significant improvement in 3-year disease-free survival, this was at the expense of a higher incidence of grade 3 or 4 neutropenia, and 29% of patients experienced long-term (>1 year), low-grade neurotoxicity. Therefore, with FOLFOX4 there is a trade-off between improved outcomes and potential for short- and long-term side effects. In addition, recent preliminary data from the CALGB C89803 trial comparing weekly bolus irinotecan/ 5-FU/LV with weekly 5-FU/LV (Roswell Park schedule) in the adjuvant setting failed to show any failure-free (P = 0.88) or overall survival (P = 0.92) benefit associated with the combination arm (letter from principal investigator to National Cancer Institute Cooperative Group Investigators, 26 August 2003). Thus, further studies are needed to establish the benefit of combination chemotherapy over fluoropyrimidine monotherapy.
The improved safety profile of capecitabine versus 5-FU/LV observed in the current trial suggests that capecitabine is an attractive agent to replace 5-FU/LV as the backbone of adjuvant combination treatment for further studies. A large international study has shown that capecitabine in combination with oxaliplatin (XELOX) is a highly active, first-line treatment for metastatic colorectal cancer [20], achieving efficacy similar to that reported for FOLFOX4 with a substantially lower incidence of neutropenia (7% with XELOX versus 4247% with FOLFOX4 [21, 22]). XELOX is currently being evaluated versus bolus 5-FU/LV (Mayo Clinic or Roswell Park regimen) as adjuvant treatment for chemotherapy-naïve patients with Dukes C colon cancer. Recruitment of 1850 patients for this trial has begun.
In summary, this analysis shows that from a safety perspective, capecitabine can replace 5-FU/LV as the standard adjuvant treatment for patients with colon cancer. The efficacy results from this study are expected in 2004.
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Acknowledgements |
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The following additional investigators participated in this trial: E. Roca, Buenos Aires; E. Mickiewicz, Buenos Aires; R. C. Wainstein, Buenos Aires; M. G. Palotta, Buenos Aires; M. S. Varela, Buenos Aires, Argentina; K. Pittman, Woodville South; D. Wyld, Herston; P. de Souza, Kogarah; C. Underhill, Wodonga; A. Barling, Bendigo; J. Levi, St Leonards; D. Bell, St Leonards; M. Schwarz, Prahran; D. Kotasek, Ashford; D. Öfner, Innsbruck; J. Schuller, Vienna; M. Baur, Vienna; D. Geissler, Klagenfurt; H. Ludwig, Vienna; P. Balcke, St Pölten; S. Brugger, St Pölten; H. Steiner, Hall in Tirol; K. Mach, Oberwart; D. Lutz, Linz; P. Kier, Vienna, Austria; J. de Greve, Brussels; D. Vanstraelen, Hasselt, Belgium; A. Malzyner, Sao Paolo; G. Delgado, Sorocaba; C. Rotstein, Rio de Janeiro; S. Lago, Porto Alegre, Brazil; R. Rajan, Montreal; A. Sami, Saskatoon; R. Wong, Winnipeg; K. Khoo, Kelowna, Canada; E. Vrdoljak, Split; M. Duvnjak, Zagreb; R. Ostojic, Zagreb, Croatia; J. Dvorak, Hradec Kralove; P. Vodvarka, Ostrava; I. Bustova, Budejovice; I. Kocakova, Brno; M. Kta, Chomutov; J. Finek, Plze
, Czech Republic; M. Giovannini, Marseille; F. X. Caroli-Bosc, Nice; H. Gouerou, Brest; P. Dufour, Strasbourg; N. Gaudin, Lyon; J. Y. Douillard, Nantes; C. Lombard-Bohas, Lyon; E. Gamelin, Angers; M. Ychou, Montpellier; B. Audhuy, Colmar; F. Husseini, Colmar; G. Dabouis, Nantes; J. F. Seitz, Marseille, France; R. Behrens, Halle; B. Tschechne, Lehrle; B. Otremba, Oldenburg; S. Fuxius, Freiburg; W. Abenhardt, Munich; A. Beham, Regensburg; R. Heinze, Wuppertal; H. Kröning, Magdeburg; S. Bauer, Magdeburg; W. B. Hirschmann, Kassel; H. Riess, Berlin; K. Weber, Lübeck; H. J. Wanger, Lübeck; W. Brugger, Villingen-Schwenningen, Germany; V. Georgoulias, Crete; G. Fountzilas, Thessaloniki; I. Katsos, Thessaloniki; G. Panagos, Ilion, Greece; A. Benni, Haifa; A. Figer, Tel-Aviv; A. Shani, Rehovot; S. Stemmer, Petach-Tikva; B. Klein, Petach-Tikva, Israel; R. Riccardo, Genova; B. Cesare, Torino; B. Oscar, Torino; S. Franco, Mantova; L. Roberto, Bergamo; M. Marco, Cuneo; S. Alberto, Milan; V. Orazio, Venezia; P. Adriano, Venezia; B. Maurizio, Livorno; F. Vinicio, Vicenza; F. Sergio, Aviano; C. Pierfranco, Pisa; B. Guido, Bologna; S. Vittorio, Modena; A. Dino, Forli; L. Masimo, Rome; G. Gasparini, Rome; B. Carlo, Rome; A. Mauro, Rome; F. di Costanzo, Terni; B. Franco, Terni; C. Giuseppe, Napoli, Italy; A. Brize, Riga, Latvia; M. P. Nowacki, Warsaw; M. Pawlicki, Krakow; M. Foszczynska-Kloda, Szczecin; H. Karnicka-Mlodkowska, Gdynia, Poland; B. da Costa, Lisbon; N. Costa, Colmbra; M. J. Neto, Colmbra; L. Horta, Vila Nova de Gaia; S. Ferreira, Porto; G. Moura, Porto; J. Mauricio, Porto; E. Sanches, Porto; E. Santo, Barreiro, Portugal; B. Stabuc, Ljubljana, Slovenia; E. Díaz-Rubio, Madrid; G. Perez-Manga, Madrid; A. Carrato, Alicante; A. Lozano, Jaen; P. Martinez del Prado, Bilbao; A. Velasco, Madrid; E. Aranda, Cordoba; A. Cervantes, Valencia; H. Manzano, Palma de Mallorca; J. J. Valerdi, Pamplona; R. Cubedo, Madrid; J. J. Valverde, Murcia, Spain; H. Starkhammar, Linköping; B. Norberg, Jönköping; B. Löden, Karlstad; H. Grönberg, Urnea; B. Gustavson, Göteborg; J.-H. Svensson, Boras, Sweden; R. Herrmann, Basel; R. Stahel, Zurich; D. Köberle, St Gallen; C. Sessa, Bellinzona, Switzerland; S. Chakrapee-Sirisuk, Bangkok, Thailand; D. Dunlop, Glasgow; F. Coxon, Newcastle upon Tyne; P. Johnston, Belfast; T. Maughan, Cardiff; T. Iveson, Salisbury and Southampton; W. Steward, Leicester; A. Makris, Luton and Northwood; C. Topham, Guildford; T. Iverson, Salisbury; F. Daniel, Plymouth, UK; I. M. Muse, Montevideo, Uruguay; R. Siegel, Hartford, CT; J. Eckhardt, St Louis, MO; G. Gross, Tyler, TX; G. Justice, Fountain Valley, CA; J. Salvatore, Phoenix, AZ; R. Kerr, Austin, TX; E. Levine, Buffalo, NY; H.-J. Lenz, Los Angeles, CA; G. Lyman, Albany, NY; P. ODwyer, Philadelphia, PA; R. Pelley, Cleveland, OH; J. Posey, Birmingham, AL; M. Salah, Marietta, GA; J. Wooldridge, Columbia, MO; S. Rao, Seattle, WA; L. Kalman, Miami, FL, USA; and S. Jelic, Belgrade, Yugoslavia.
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Footnotes |
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