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Originally published as JCO Early Release 10.1200/JCO.2003.11.122 on September 8 2003 © 2003 American Society for Clinical Oncology Randomized Phase III Study of High-Dose Fluorouracil Given As a Weekly 24-Hour Infusion With or Without Leucovorin Versus Bolus Fluorouracil Plus Leucovorin in Advanced Colorectal Cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952
From the Department of Internal Medicine I, University of Dresden, Dresden; Modizinische Hochschule Hannover, Hannover; Marien hospital Universitätsklinik, Herne; Eberhard Karls University, Tübingen; Caritasklinik St. Theresia, Saarbrücken; H.O.P.A., Hamburg; Akadem Lehrkrankenhaus der MLU Halle Wittenberg, Dessau; Allgemeines Krankenhaus Hagen GmbH, Hagen; Klinikum Lippe Lengo GmbH, Lengo; Medizinische Poliklinik der Universität, Würzberg; Martin Luther Universität Halle Wittenberg, Halle, Germany; EORTC Data Center, Brussels, Belgium; Allgeneines Krankenhaus, Vienna, Austria; N.N. Blokhin Cancer Research Center, Moscow, Russia; National Cancer Institute, Cairo, Egypt. Address reprint requests to Claus-Henning Köhne, MD, Department of Internal Medicine I, University of Dresden, Fetscherstr 74, 01307 Dresden, Germany; e-mail: claus-henning.koehne{at}uniklinikum-dresden.de.
Purpose: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. Patients and Methods: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2,600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)—all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. Results: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P = .724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P = .029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. Conclusion: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.
FLUOROURACIL (FU) is one of the major cytotoxic agents1 for the treatment of metastatic colorectal cancer. When used as an intravenous bolus application, leucovorin (LV) is usually added as a biochemical modulator to improve the efficacy of FU.2 This concept is based on the preclinical observation that 5-fluorodesoxyuridine monophosphate forms a ternary complex in the presence of reduced folates, mainly 5,10-methylenetetrahydrofolate, with thymidilate synthase, a key enzyme in DNA synthesis.3 Randomized trials and a meta-analysis have indicated a doubling of the response rate for modulated FU compared with FU alone; however, no meaningful improvement for median survival has been achieved.2 Also, according to randomized trials and a meta-analysis, administration of FU as a continuous infusion has been considered more efficacious compared with bolus application.4 Furthermore, continuous infusion of FU differs from bolus injection, with a more favorable toxicity profile. A lower incidence of gastrointestinal and hematologic toxicity is observed, but skin toxicity described as hand-and-foot syndrome may appear. Infusional FU has been used as a weekly 24-hour or 48-hour infusion, as well as an indefinite infusion continuing throughout weeks and months. Weekly or biweekly infusional regimens are gaining acceptance. The high FU dose-intensity hereby achieved may be an important factor contributing to the activity of these schedules.5 The recent results of deGramont et al6 demonstrated superior activity of a regimen given as a bolus followed by a continuous infusion on 2 consecutive days and repeated every 2 weeks. This regimen demonstrated higher response rates and prolongation of the progression-free interval, but failed to improve survival compared with the bolus Mayo Clinic regimen. In a phase I study, Ardalan et al7 defined the maximum tolerated dose (MTD) for FU as a 24-hour infusion of 2.6 g/m2 when given as weekly therapy, which was confirmed by Haas et al.8 Interestingly, when LV9 was combined with such a regimen, the MTD remained at 2.6 g/m2.
In a three-arm randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO), a weekly 24-hour infusion of FU was combined with LV (FU24h + LV), interferon alfa-2b (IFN- Encouraged by these promising results for FU24h + LV, we chose survival as the primary end point for this study. The objectives were to evaluate whether FU24h alone prolongs survival relative to the Mayo Clinic regimen, and whether biochemical modulation by high-dose LV can improve the efficacy of FU24h.
In this prospective, multicenter, randomized trial, patients were included if they had histologically verified adenocarcinoma of the colon or rectum beyond a curative option by surgery. Patients were required to have an Eastern Cooperative Oncology Group performance status of 2 or less. No previous chemotherapy for metastatic disease was allowed, with the exception of previous adjuvant treatment if it was completed at least 6 months before inclusion. In case of prior radiation, metastases had to be outside the radiation field. Patients had to have measurable and/or assessable disease according to WHO assessment methods. The initial evaluation of metastases had to be done within 2 weeks before inclusion. Patients were required to have leukocyte levels above 3,000/mm3 and platelet levels greater than 100,000/mm3. The creatinine levels were required to be below 2x the upper limit of normal (ULN). Patients 18 to 75 years of age had to give informed consent, and regular follow-up should have been possible for them. Patients were excluded in cases of CNS-metastasis or second malignancy, with the exception of adequately treated in situ carcinoma of the cervix or nonmelanoma skin cancer; patients with severe cardiac or lung failure, those with uncontrolled angina, and pregnant or nursing women were also excluded. Pretreatment evaluation consisted of a medical history, physical examination, chest x-ray, abdominal ultrasound, and computed tomography scans of abdomen and thorax according to localization of assessable lesions. Magnetic resonance imaging was recommended in case of a pelvic mass. Routine blood test and biochemistry were also performed. Before each cycle for infusional FU, or after 2 cycles for the bolus regimen, we repeated these examinations, as well as tumor evaluation for response for all measurable lesions. Before random assignment, patients were stratified by institution, Eastern Cooperative Oncology Group performance status (0, 1 v 2), tumor assessability (measurable v nonmeasurable), and prior adjuvant pretreatment (yes v no). The study was performed according to the Declaration of Helsinki and approved by the Protocol Review Committee of the European Organization of Research and Treatment of Cancer (EORTC) and the AIO, and local biomedical ethics committees. Plausibility of the data was checked for all centers by the study coordinators. Regular site visits were not performed.
Protocol Treatment Patients randomly assigned to the two experimental arms received 2,600 mg/m2 of IV FU as a 24-hour infusion on days 1, 8, 15, 22, 29, and 36 with (FU24h + LV) or without (FU24h) LV 500 mg/m2 IV as a 2-hour infusion before each FU administration. This cycle was repeated on day 50. In all arms, the treatment was given until disease progression or occurrence of unacceptable toxicity, or it was stopped on request by the patient. A minimum of one cycle for the infusional treatment or two cycles in case of the Mayo regimen was foreseen, unless this was not in the patient’s benefit. In case of complete response, the treatment was to be discontinued after 1 year.
Patients receiving the infusional regimens did not receive therapy on the scheduled day unless gastrointestinal toxicity (diarrhea, mucositis) was completely resolved, leukocyte levels were greater than 3 x 109/L, and platelet levels were greater than 100 x 109/L using the National Cancer Institute common toxicity criteria scale. FU was reduced by 20% for all succeeding administrations if patients experienced grade 4 leukopenia, or thrombocytopenia, diarrhea, mucositis, or skin toxicity greater than grade 2 at any time during therapy. If at any time during therapy with bolus FU, a patient experienced grade 4 leukopenia, thrombocytopenia Antiemetics and other symptomatic therapies were allowed. The choice of the antiemetic regimen was left to the discretion of the responsible physician. In case of severe diarrhea, the administration of loperamide or octreotide 100 µg subcutaneously three times daily in combination with rigorous fluid and electrolyte replacement was recommended until diarrhea ceased.
Criteria of Evaluation Tumor response was only assessed in patients with measurable lesions of at least 2 cm in diameter according to WHO criteria. Complete response was defined as disappearance of all known disease (measurable, assessable, and nonmeasurable) for at least 4 weeks. Partial response required a reduction of 50% or greater in the sum of the cross-product of the maximum perpendicular diameters of all measurable indicator lesions lasting for at least 4 weeks. Patients were considered to have disease progression if the measurable tumor lesions increased more than 25% according to the initial staging, or if a new lesion appeared. Patients not meeting the criteria for response or progression were considered to have stable disease. The response duration was measured from the day of random assignment until disease progression. The EORTC quality-of-life questionnaire (QLQ C30, version 2.0) was to be handed out to the patients at baseline, after each cycle, at 1 month after the end of treatment, and at 2 monthly follow-up examinations thereafter.
Statistical Methods
The duration of survival and PFS curves were estimated using the Kaplan-Meier technique. Pair-wise comparisons between the three arms were done with a two-sided unstratified log-rank test. To adjust for confounding variables, retrospective stratification and the Cox proportional hazards model were used. Comparisons of time-to-event criteria were performed using the intention-to-treat principle (ie, all randomly assigned patients are taken into account and analyzed in the treatment group to which they were assigned at random assignment). Only patients with measurable disease entered the analysis for response. Comparisons were performed using a two-sided
From December 1995 to September 1998, 497 patients from 59 institutions were randomly assigned. A total of 166 patients was allocated to the FU24h arm, 164 to the FU24h + LV arm, and 167 to the standard Mayo Clinic arm. Seventeen patients were considered ineligible (7 in the FU24h arm and 5 each in the FU24h + LV and bolus FU + LV arms). Reasons for ineligibility were as follows: no measurable or assessable cancer (8 patients), prior adjuvant treatment within 6 months of random assignment (2 patients), no informed consent (4 patients), high bilirubin levels above 2x ULN (2 patients), and non–small-cell lung cancer as prior malignant disease (1 patient).
Patient characteristics are listed in Table 1
Toxicity and Drug Administration Fourteen patients were excluded from the toxicity analysis — six had incomplete files, and eight did not get the assigned treatment. The median number of administered cycles were 2, 2, and 4 in the FU24h, FU24h, + LV, and bolus FU + LV arms, respectively. The cycle duration was different between the arms; thus, the treatment duration was in fact similar in all arms. The median cumulative FU doses were 30.9 g/m2, 30.8 g/m2, and 8.3 g/m2 in the FU24h, FU24h + LV, and bolus FU + LV arms, respectively. The median duration of all cycles for the infusional schedules was 50 days. In the bolus arm, the median duration was 28 days for the first 2 cycles and 35 days for the following cycles, as scheduled in the protocol. However, in more than one third of patients, cycles were delayed by 1 week or more in both infusional regimens, while they were shortened by 1 week ore more in more than one third of patients in the bolus arm. The relative FU dose-intensity compared with the theoretical dose to be administered was 91%, 89%, and 101% for the FU24h, FU24h + LV, and bolus FU + LV arms, respectively. However, approximately 50% of patients in the infusional FU arms received less than 90% of the relative FU dose-intensity, compared with only 12% in the FU bolus arm. A total of 19% of patients in the FU24h arm, 20% in the bolus FU + LV arm, but 34% in the FU24h + LV arm, required (at least once) an FU dose reduction at any time during the course of their treatment. The main reason for FU dose reductions was gastrointestinal toxicity in 24% of patients in the FU24h + LV arm, but in only 7.6% and 14.5% of patients receiving FU24h or bolus FU + LV, respectively. Approximately 70% of patients in the infusional FU arms, but only 40% in the bolus FU + LV arm, had at least one treatment delay. Gastrointestinal toxicity was also the reason for treatment delays in 11% and 22% of patients in the FU24h or FU24h + LV arms, and in only 4% of patients in the bolus FU + LV arm.
Toxicities observed per patient are listed in Table 2
Leukopenia and stomatitis were more frequent in patients receiving bolus FU + LV, while patients receiving FU24h + LV experienced more diarrhea and hand-and-foot syndrome. The FU24h regimen was the least toxic regarding all toxicity parameters. Cardiovascular events (grade 1 to 4) at any time during treatment, whether or not related to therapy, were observed in 7.5% and 5.7% of patients receiving FU24h or FU24h + LV, and in 4.4% of patients receiving bolus FU + LV. Chest pain at any time during treatment was reported in 4 patients receiving the bolus schedule and two and seven patients receiving FU24h or FU24h + LV, respectively. During the first four weeks of treatment angina-like chest pain occurred in one patient each in the bolus or FU24h regimen and in 2 patients in the FU24h + LV arm, suggesting a likely FU associated cardiotoxicity. Other cardiac events were arrhythmias, hypo- or hypertension, and heart failure. In total, the observed frequencies in cardiovascular side effects were not significantly different.
Quality of Life
Response Clinical response could be assessed in 409 patients with measurable disease (Table 3  ). The overall response rates were 10%, 17%, and 12% in the FU24h, FU24h + LV, and bolus FU + LV arms, respectively. The response rates did not differ significantly between treatment arms. Patients responding to the bolus regimen had a median response duration of 8.1 months (95% CI, 4.4 to 10.4 months); those responding to FU24h had a median response duration of 9.2 months (95% CI, 6.3 to 16.4 months); and responders in the FU24h + LV arm had a median response duration of 5.6 months (95% CI, 3.9 to 7.9 months). With small numbers, these differences were not statistically different.
PFS and Survival PFS was significantly different among the treatment arms, with a median of 4.0 months (95% CI, 3.4 to 4.9 months) for the bolus FU + LV arm, 4.1 months (95% CI, 3.4 to 5.0 months) for the FU24h arm, and 5.6 months (95% CI, 4.4 to 6.7 months) for the FU24h + LV arm. The PFS durations were compared between pairs of treatment arms. The corresponding P values were in favor of FU24h + LV (P = .03) when compared with bolus FU + LV, and P = .02 for the comparison with FU24h. No difference was observed between bolus FU + LV and FU24h (P = .8). The overall significance for difference between treatments was P = .03. The combination of FU24h + LV showed an approximate 22% reduction in the instantaneous progression rate compared with bolus FU + LV, and 24% compared with FU24h (Fig 2 ).
With a median follow-up of more than 3 years at the time of this analysis, 86% of patients have died. The survival did not differ significantly among treatment groups (Fig 3 ), with an overall P value of .7. Patients receiving bolus FU + LV had a median survival of 11.1 months (95% CI, 10.2 to 15.0 months). Patients receiving FU24h had a median survival of 13.0 months (95% CI, 10.4 to 15.4 months), and patients on the FU24h + LV arm a median survival of 13.7 months (95% CI, 12.0 to 16.4 months). A total of 63%, 68%, and 68% of patients received a second-line treatment that contained oxaliplatin (22%, 21%, and 22%) or irinotecan (4%, 8%, and 4%) in the FU24h, FU24h + LV, and bolus FU + LV arms, respectively. The most frequent second-line therapy was infusional FU ± LV.
This study failed to demonstrate a 6-month difference in survival for weekly high-dose infusional FU with or without LV compared with the Mayo Clinic regimen. This rather ambitious hypothesis was based on earlier findings of a randomized trial investigating the role of LV, IFN-  -2b, or both as modulators of weekly high-dose infusional FU, in which a statistically significant superior survival over infusional FU + IFN--2b (12.7 months) was observed for LV modulation (16.2 months) in this schedule.11 It is unlikely that the use of second-line treatment may have counterbalanced any potential survival difference induced by first-line treatment with infusional FU, as it was equally distributed among the treatment arms. However, this trial demonstrates that 500 mg/m2 LV, when given in combination with FU24h, significantly prolongs the median PFS compared with the Mayo regimen or FU24h alone. Single-agent FU24h seemed to have a similar efficacy, but lower toxicity relative to the modulated bolus regimen. However, the differences in the length of cycles may have potentially biased the calculation of PFS. The first two cycles of infusional regimens were expected to last for 100 days, while the first 4 cycles in the bolus arm were expected to last for 126 days, which may be equivalent to 1 month. However, more than one-third of patients had a treatment delay for at least 1 week in the infusional regimens (totaling at least 2 weeks after two cycles), while more than one third of patients in the bolus arm had a third or fourth cycle that was shorter by at least one week. At least in these patients, the length of treatment was 114 or 112 days for two infusional or four bolus cycles, respectively. Secondly, when the two infusional regimens were compared, there was a clear difference in the PFS times in the two arms, rendering it unlikely that the difference in the length of cycles was the major reason for the difference seen between the bolus FU + LV and the FU24h + LV arms. The results of our study at least indicate that LV is effective in prolonging the progession-free survival of weekly high-dose infusional FU24h, which has not been demonstrated before. It is for this reason that in the EORTC study 40986, FU24h + LV is used as the reference treatment to be compared with irinotecan12 added to this regimen, as PFS is the major study end point. The Southwest Oncology Group13 performed a large randomized phase II trial with several infusional FU regimens. Continuous infusion of 200 mg/m2 FU per day was used alone or combined with 20 mg/m2 of weekly IV LV. No difference in response rate or median survival was achieved with low-dose LV. The weekly administration of 250 mg/m2 N-phosphonacetyl-L-aspartate was also unable to increase the antineoplastic activity of high-dose FU24h in two randomized trials.13,14 Successful biochemical modulation of high-dose infusional FU was reported from an earlier EORTC trial for low-dose methotrexate.15 The results of our trial support the findings of a French study,6 in which a biweekly schedule of bolus FU followed by FU infusion in combination with LV given on 2 consecutive days was compared with the monthly (bolus FU) Mayo Clinic schedule. The infusional regimen resulted in a significantly higher response rate and longer PFS compared with the IV bolus Mayo Clinic regimen, without a difference in survival, all consistent with our findings. The results of our trial confirm a lower rate of severe leukopenia for infusional regimens compared with the IV bolus Mayo Clinic regimen. However, severe diarrhea occurred in 22% of patients receiving FU24h + LV, which was significantly higher as compared with the Mayo Clinic schedule as well as with the FU24h regimen. This was, however, expected, considering our earlier randomized trial. Rather than indicating increased gastrointestinal toxicity of the modulated infusional regimen, the difference in diarrhea probably is due more to an unusually low incidence of grade 3 or 4 diarrhea (9%) and mucositis (11%) observed in patients receiving the Mayo Clinic regimen, as we would have expected a higher rate for both diarrhea and mucositis, and more frequent treatment delays in the bolus regimen.16 Another interesting observation is that occurrence of hand-and-foot syndrome was higher in the modulated high-dose infusional arm as compared with high-dose infusional FU alone. Thus, LV is probably increasing the incidence of hand-and-foot syndrome with infusional FU. The high rate of FU dose reduction and treatment delays in the FU24h + LV arm indicates that the FU dose used in the modulated infusional regimen is probably at the upper limit of tolerance, and should be reduced17 to 2,000 mg/m2 when combined with irinotecan and/or oxaliplatin, though full-dose has been suggested by a phase I trial.18 In conclusion, FU24h seems to be as efficacious as the Mayo regimen, but it is less toxic. FU24h + LV is associated with a significantly increased PFS compared with both the Mayo regimen and FU24h, but it does not improve survival, and it increases gastrointestinal toxicity. Although reducing the disease progression rate by 22% may have important palliative implications, other treatment options may also be reasonable alternatives for first-line treatment of metastatic colorectal cancer if the use of irinotecan or oxaliplatin combination is not considered. The slightly improved antineoplastic efficacy must be weighed against higher costs associated with the use of Port-a-Caths and pumps, which are necessary to ensure outpatient treatment. However, modulated infusional regimes, either the LV5FU26 or this AIO regimen, are probably the more optimal FU schedules for combination treatment with oxaliplatin or irinotecan. In trials in which PFS is the main study end point, LV-modulated infusional FU may be the preferred mode of FU administration when new treatment options such as oral fluoropyrimidines alone or in combination with irinotecan or oxaliplatin are studied. Interestingly, some FU bolus regimes seem to be too toxic to be combined with irinotecan or oxaliplatin,19 as has been shown recently.
The authors indicated no potential conflicts of interest.
List of participating centers in alphabetical order: Abenhardt W., MOP im Liesenhof, München, Germany; Balleissen L., Ev. Krankenhaus, Hamm, Germany; Bauermeister, G. Klinikum, Quedlinburg, Germany; Behrens, R., Intern. Onkol. Gemeinschaftspraxis, Halle, Germany; Bleiberg, H. Institut J. Bordet, Brussels, Belgium; Bokemeyer, C. Eberhard Univ., Hartmann J, Tübingen, Germany; Brock, J., Gemeinschaftspraxis, Brauschweig, Germany; Brockmann, B., Oncology Clinic Humaine, Dresden, Germany; Burkhard, O., Gemeinschaftspraxis, Worms, Germany; Dahnke, A, Müritz klinikum, Waren, Germany; Daus, H., Stift Bethlehem, Ludwigslust, Germany; Dölken, G./Knoche, G. Ernst Moritz Arndt Univ., Greisfwald, Germany; Ehninger, G. Univ. Kl. Carl Gustav Carus, Dresden, Germany; El-Serafi, M., National Cancer Institute, Cairo, Egypt; Fleeth, J. Allgem. Kr. St. Georg, Hamburg, Germany; Frieling, T., Heinrich-Heine Universität, Düsseldorf, Germany; Habets, L, PZB, Aachen, Germany; Harstrick, A., Univ. Med. School, Essen, Germany; Hemeling, H., Klinikum Wuppertal, Düsseldorf, Germany; Hohaus, B, Kreiskrankenhaus, Riesa, Germany; Huntenburg, K., Kreiskrankenhaus, Neustadt, Germany; Käufer, C., Henriettenstiftung., Hannover, Germany; Keine, S, Fachkrank. Marinstift, Schwarzenberg, Germany; Kettner, E., Städtisches Kl., Magdeburg, Germany; Kirchner, H., Krankenhaus Siloah, Hannover, Germany; Kleeberg, U., H.O.P.A., Hamburg, Germany; Klinkenstein, C., Klinikum, Frankfurt (oder) Markendorf, Germany; Köhne, C.-H, R. Roessle Klinik, Berlin, Germany; Köppler, H., Hematologisch Onkol. Praxis, Koblenz, Germany; Körfer, A., Stadtkrankenhaus, Wolfsburg, Germany;Langenbuch, T., Kreiskrankenhaus, Aurich, Germany; Lichinitser, M., Cancer Research Center, Moscow, Russia; Lindenmann, H., Kath. Krankenhaus, Hagen, Germany; Lingenfelser, T., Klinik St Marien, Amberg, Germany; Lorenz, M., Klinikum der J. W. Goethe Univ., Frankfurt, Germany; Lutz, M., Univ., Ulm, Germany; Mueller, L, Hans-Susemihl Krankenhaus, Emden, Germany; Papke, J, Praxis, Neustadt in Sachsen, Germany; Pasold, R., Klinikum Ernst von Bergmann, Postdam, Germany; Pfreundschuh, M., Univ. kl. des Saarlandes, Homburg/Saar, Germany; Porcile, G., Ospedale Civile, Alba, Italy; Rapoport, B.L., Rosebank Med. Center., Johannesburg, South Africa; Respondek, M., Katharinnenhospital, Stuttgart, Germany; Ridwelski, K., Otto-von-Guericke-Univ., Magdeburg, Germany; Rückle-Lanz, H., Med. Univ. Poliklinik, Würzburg, Germany; Rudolph, R., Hamato-onkol. Gemainshaftspraxis, Essen, Germany; Scheithauer, W., 1,103, Allgemeines krankenhaus, Wiener neustdadt, Austria; Schmoll, H.-J., Martin Luther Univ., Halle, Germany; Schöffski, P., Med. Hochschule, Hannover, Germany; Souchon, R., Allgem. Krankenhaus, Hagen, Germany; Steurer, K.-T., Klinikum Nurnberg, Germany; Voigtmann, R., Marien Hosp., Herne, Germany; Weiss, U., Klinikum Lippe, Lemgo, Germany; Westerhausen, M., St. Johannes Hosp., Duisburg, Germany; Wilhelm, G., Harz-Klinikum, Wernigerode, Germany; Wilke, H-J., Ev. Huyssens Stiftung, Essen, Germany; Wils, J., St Laurentius Z., Roermond, the Netherlands; Wölfel, T., Med. Klinik I, Univ., Mainz, Germany
 Deceased. 
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4. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301–308, 1998
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12. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801–3807, 2001 13. Leichman CG, Fleming TR, Muggia FM et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303–1311, 1995[Abstract]
14. O’Dwyer PJ, Manola J, Valone FH et al: Fluorouracil modulation in colorectal cancer: Lack of improvement with N-phosphonoacetyl-L-aspartic acid. J Clin Oncol 19:2413–2421, 2001 15. Blijham G, Wagener T, Wils J et al: Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: Final results of a randomized European Organization for Research and Treatment of Cancer Study. J Clin Oncol 14:2266–2273, 1996[Abstract] 16. Tomiak A, Vincent M, Kocha W, et al: Standard dose (Mayo regimen) 5-fluorouracil and low dose folinic acid: Prohibitive toxicity? Am J Clin Oncol 23:94–98, 2000[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 3, diarrhea 
2 test. All patients who started the assigned treatment were included in the safety analysis. Comparisons of grade 3 to 4 rates between two arms were performed using a two-sided Fisher’s exact test. 
