|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Fluorouracil Modulation in Colorectal Cancer: Lack of Improvement With N -Phosphonoacetyl- l -Aspartic Acid or Oral Leucovorin or Interferon, But Enhanced Therapeutic Index With Weekly 24-Hour Infusion Schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B StudyFrom the University of Pennsylvania Cancer Center, Philadelphia, PA; Eastern Cooperative Oncology Group and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Dartmouth-Hitchcock Medical Center, Hanover, NH; Cleveland Metropolitan General Hospital, OH; Montefiore Medical Center, Bronx; Roswell Park Memorial Institute, Buffalo, NY; Fox Chase Cancer Center, Philadelphia, PA; and Northwestern University, Chicago, IL. Address reprint requests to Peter J. O’Dwyer, MD, University of Pennsylvania Cancer Center, 51 N 39th St, MAB 103, Philadelphia, PA 19104; email: podwyer{at}mail.med.upenn.edu
PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
THE CORNERSTONE for the chemotherapy of colorectal cancers for the past 30 years has been fluorouracil (5-FU).1 This antimetabolite has multiple pharmacologic effects that have been associated with cytotoxicity, including inhibition of thymidylate synthase (TS), incorporation into RNA with perturbation of its function, and incorporation of the triphosphates of both 5-FU and of uridine (which accumulates behind the TS block) into DNA.1,2 As these putative mechanisms have been elucidated, pharmacologic approaches to the selective manipulation of these pathways have been developed.2 The demonstration that (1) the reaction mechanism of TS, and (2) inhibition of TS by 5-fluorouridylate are dependent on ambient concentrations of reduced folate led to the development and testing of combinations of 5-FU and leucovorin (LV).3-5 Higher response rates in several trials and a slight survival advantage in a meta-analysis6-9 have led to the adoption of this combination as standard therapy for advanced colorectal cancer. LV, a mixture of two stereoisomers, was shown to have excellent oral bioavailability.10 Selective absorption of its active isomer supported the initiation of studies of intravenous (IV) 5-FU with oral LV.11 High response rates in early clinical trials of this regimen12 prompted a comparison with standard IV 5-FU/LV in this randomized trial. At each of its possible loci of action, the effect of 5-FU and its anabolites is opposed by the natural uridine nucleotides. Inhibitors of the de novo pyrimidine synthetic pathway (including N-phosphonoacetyl-l-aspartic acid [PALA]) depleted cells of uridine nucleotides and potentiated the activity of 5-FU in various preclinical models.13,14 A regimen of PALA and 5-FU showed promising results in a single-institution phase II trial.15 This regimen addressed another characteristic of 5-FU: the suspected dependence of its activity (and especially its therapeutic index) on its schedule of administration.16 A weekly infusion of 5-FU for 24 hours is convenient for patients and permits the administration of the highest dose-intensity of 5-FU with moderate toxicity. To isolate the contribution of PALA in modulating 5-FU, this schedule was chosen as the appropriate control.
An alternative approach to 5-FU modulation involves the coadministration of interferon alfa (IFN-
The development of these principles prompted the design of a multiarmed study ( Fig 1) to address the role of biochemical modulation of 5-FU. We wished to quantify the impact of PALA, of oral LV, and of IFN-
Originally, the study was designed to assess the efficacy of various forms of 5-FU modulation, and the expectation was that these arms would be superior to 5-FU alone. However, as the study progressed, it became clear that the continuous infusion 5-FU arm was doing as well as, if not better than, the modulation arms. Thus the accrual was modified approximately halfway through the trial to permit a full evaluation of infusion 5-FU alone.
This study was a randomized trial conducted between November 1990 and October 1995 by the ECOG, with participation from the Cancer and Leukemia Group B.
Eligibility Criteria Patients were ineligible if they were considered a poor medical or psychiatric risk or if they had an active infection or other illness that precluded chemotherapy administration. Patients with a major surgical procedure performed in the prior 3 weeks were ineligible. Patients with disease confined only to the CNS were ineligible for the study, as were patients who had received prior chemotherapy within the past 12 months or chemotherapy for metastatic disease at any time. Patients with a past history of malignancy other than colorectal cancer were ineligible, except for patients with curatively treated nonmelanoma skin cancer and carcinoma-in-situ of the cervix. Patients who were pregnant or lactating were also ineligible.
Treatment
Dose modifications were made in the case of low WBC and platelet counts on the first day of each course, and for mucositis, diarrhea, neurologic symptoms of paresthesias or muscle weakness, or other unusual toxicity. IFN- Treatment was planned to continue indefinitely until disease progression, unless there was significant treatment-related toxicity.
Measurement of Effect
Statistical Methods
A secondary objective was to compare IV LV/5-FU with PALA/5-FU. Objectives were to compare response rates within the subgroup of patients with measurable disease and progression-free survival and overall survival among the different treatments in all patients, and to compare the toxicity of the regimens. The initial accrual goal for this study was 180 patients per arm, or 900 total. The design used a one-sided overall significance level of .05, and allowed for sequential analyses at 24, 30, 36, 42, and 48 months. After 4 years, the target accrual was increased to 220 patients per arm, or 1,080 total patients, to permit two-sided instead of one-sided tests. The sample size was chosen so that there would be 85% power expected to detect an increase of 50% in median survival on the PALA/5-FU and on both LV arms. This corresponded to an increase from 9 to 13.5 months among patients with measurable disease and from 15 to 22.5 months for patients without measurable disease. Assumed monthly accrual rates were 15 patients with measurable disease and 10 patients without measurable disease. One year of follow-up was assumed. The four comparisons identified as the main objective were to be tested at a .015 level of significance. This was a compromise between the Bonferroni approach,24 which would require tests at .0125 to achieve an overall 5% level of significance, and the Dunnet approach,25 which assumes that each comparison involves a common control group. The sequential analysis initially used a constant likelihood lower bound26,27 and an O’Brien-Fleming upper bound.28 After altering the design to allow two-sided tests, interim analyses used O’Brien-Fleming boundaries on both upper and lower bounds. A data monitoring committee participated in evaluating the interim analyses. Analyses. The survival distributions for survival, time to progression, and disease-free survival were estimated according to the method of Kaplan and Meier.29 Two-sided log-rank tests for univariate comparisons of discrete characteristics were conducted using the method of Mantel.30 The proportional hazards model described by Cox31 was used to assess the association between survival data and baseline patient characteristics. A Wald test was used to test for significant covariates in the proportional hazards model. Fisher’s exact test was used to test for differences in cancellation patterns among treatment arms.32 The method described by Mehta et al33 for exact inference on ordered categorical tables was used to compare toxicity patterns among treatment arms.
The total accrual to this trial was 1,120 patients, of whom 1,098 were eligible. There were two duplicate registrations (excluded), 22 ineligible patients (2%), 19 eligible patients who did not start treatment, and one eligible patient lost to follow-up. Thus 1,120 patients were available for an intent-to-treat analysis, of whom 1,098 had complete follow-ups. The patient characteristics at study entry are described in Table 1.
The majority of patients were male (62%) and white (84%). The median age was 63 years, and the PS of these patients was excellent (47% had PS 0). Weight loss was quantified in approximately half of the patients, and almost half of those had greater than 10% loss of body weight at study entry. Fewer patients on the IFN-  /5-FU arm (33%) reported weight loss than on the other four arms (46% to 52%). A small proportion had received prior radiation or prior adjuvant chemotherapy. The primary tumor was in the right colon in 29%, the transverse colon in 9%, the left colon in 44%, and the rectum in 17%. Measurable disease was present in 57% of patients. All of these characteristics were well balanced across the five arms of the study.
Toxicity
Treatment-Related Deaths Significant differences were also observed in the levels of life-threatening or fatal toxicities thought to be treatment-related across the arms (Kruskal-Wallis asymptotic P < .001). These were lowest in the 5-FU–alone and PALA/5-FU arms (11% in each arm), although there were two fatal toxicities on the 5-FU–alone arm and seven on the PALA/5-FU arm. One patient treated with 5-FU alone died with diarrhea and pneumonia, another with a pulmonary embolism, after 3 and 2 months of therapy, respectively; the relationship to drug toxicity was probable in the first and unknown in the second. On the PALA/5-FU arm, three patients had gastrointestinal toxicity sepsis, with a clear relationship to drug administration. Another patient developed intractable cardiac failure preceded by chest pain shortly after beginning therapy; a relationship to the drug is considered likely. Three additional patients died of causes that were not clearly related to treatment: one of thrombosis, one of renal failure after a localized foot infection, and one of aspiration that followed emesis and hiccoughs. With oral LV and 5-FU, four patients died with complications of drug-induced diarrhea and one from presumed pulmonary embolism. On the IV LV arm, three patients expired in similar circumstances. Fatal diarrhea occurred in one patient on the IFN- /5-FU arm, and there was one case of sudden death within 24 hours of the initial IFN- dose in this arm.
Response
Progression-Free and Overall Survival Progression-free survival was defined as the time from randomization until documentation of progressive disease or death, whichever came first. Patients who died without evidence of disease were considered to have experienced treatment failure at the time of death. Patients whose time to progression was unknown and who had died (n = 20) were considered to have disease progression at the time they died. Patients who neither had disease that progressed nor who died were censored at the date last assessed for disease status. No significant differences were observed in progression-free survival by treatment arm ( Fig 2).
Univariate log-rank tests indicated that age  62 years, poor PS, the presence of symptomatic disease, a primary tumor on the right side (cecum, right colon/hepatic flexure, or transverse colon), liver metastases, and measurable disease, particularly in the liver, were associated with shorter time to progression.
Survival was defined as the time from randomization to death. Median survivals by arm in months were: 5-FU alone, 14.8; PALA/5-FU, 12.9; oral LV/5-FU, 13.5; IV LV/5-FU, 12.9; and IFN-
Pair-Wise Treatment Comparisons The study’s objectives identified four specific pair-wise comparisons of interest. These were examined using univariate comparisons, as well as by multivariate analysis based on the proportional hazards model. The results of these comparisons are provided in Table 4. The table also provides results of all other pair-wise comparisons. No significant differences in treatment arms were found in any univariate or multivariate pair-wise comparisons.
Prognostic Factors The most significant factors related to decreased survival when examined in a univariate analysis were poor ECOG PS; presence of symptomatic disease; right-side primary tumor site; metastases in the peritoneum, liver, or lymph nodes; the presence of measurable disease, particularly in the liver; and poor degree of tumor differentiation. To examine simultaneously the effects of multiple prognostic factors on survival, a proportional hazards model was developed. A forward selection algorithm was used, and all patient characteristics found to be significant in the univariate analysis were considered for inclusion in the model.34 A model was selected that made use of the largest possible number of observations, minimizing the effect of missing covariate values. When controlling for other variables in the model, patients with PS 1 and 2 had a higher risk of death than patients with PS 0 (hazards ratios compared with PS 0, 1.36 and 2.57, respectively; P = .0001). Patients with symptoms of disease had 1.28 times the hazards ratio of patients who were asymptomatic (P = .003). Patients with primary tumors in the right-side regions of the colon had 1.5 times the hazard of patients with primary tumors on the left side (P = .0001). Nodal metastases were associated with increased risk (hazards ratio, 1.14; P = .04). The presence of measurable disease was associated with increased risk (hazard ratio, 1.64; P = .0001). Determinants of patient survival are summarized in Table 5.
This study was designed to investigate the role of biochemical modulation by PALA, oral LV, and IFN. The results show clearly that (1) PALA at this dose and schedule fails to increase the efficacy of weekly 24 hour-infusion 5-FU; (2) oral LV provides no benefit over IV LV; and (3) IFN- does not improve the activity of 5-FU. These findings are a disappointment in that the promise of enhancing the marginal activity of 5-FU is unfulfilled. The results are consistent with a randomized phase II trial performed by the Southwest Oncology Group.35 In neither study did benefit accrue from modulating de novo pyrimidine synthesis with PALA. A recent meta-analysis further demonstrated the absence of benefit from the addition of IFN- to 5-FU,36 and this is emphasized by the results of an adjuvant study.37 Together with the meta-analysis of 5-FU/LV randomized trials, which showed benefits in response rates but not in survival,9 there would seem to be little reason to use modulation regimens in the advanced disease setting.
However, the strikingly positive result from this large trial has been the superiority of the 24-hour weekly infusion regimen. With or without PALA, this regimen was substantially less toxic than the bolus regimens of 5-FU with either LV or IFN- These findings are consistent with those of Kohne et al38 (24-hour weekly infusion with LV) and de Gramont et al39(48-hour infusion every 2 weeks with LV). Both have shown an improved therapeutic index using intermittent infusions over bolus administration. Those regimens incorporated LV, whereas the current one did not. In phase I and II studies in which LV has been added to the 24-hour infusion regimen, there was a slightly greater degree of toxicity and thus a reduced maximum-tolerated dose.40 In a randomized comparison of 24-hour weekly 5-FU with or without LV, a preliminary report suggests an advantage for the LV-containing arm.41 Together, these results imply that intermittent infusion schedules with or without LV may be the safest and most effective means of delivering 5-FU. The therapeutic index advantage for infusion 5-FU in this study might result either from an adverse contribution of the modulating agents or from a favorable schedule of 5-FU. The early studies demonstrated clearly that the addition of LV to bolus 5-FU results in increased toxicity. In a Gastrointestinal Tumor Study Group study42 of two doses of LV with weekly 5-FU 600 mg/m2, the incidence of severe or worse diarrhea, mucositis, and leukopenia was two-fold higher with 500 mg/m2 versus 25 mg/m2 of LV. In the Mayo and North Central Cancer Treatment Group study of 5-day 5-FU/LV, reasonably equivalent toxicity was obtained with 5-FU 375/LV 200 mg/m2 and 5-FU 425/LV 20 mg/m2, and 5-FU 500 mg/m2 alone.43 Thus LV can be demonstrated to add to the toxicity of 5-FU. Its addition to therapeutic response is less clear; the meta-analysis has shown higher response rates and no advantage in survival.9 Thus the contribution of the modulating agent to antitumor activity is unlikely to be adverse, and the observed superiority of 5-FU alone seems to be a consequence of the infusion schedule. If the infusion regimens have a superior therapeutic index when 5-FU is used alone, it is logical to suppose that these regimens should also optimize the administration of 5-FU in combination with irinotecan or oxaliplatin. The development of these two agents has greatly altered the therapy of colorectal cancer, and combinations of each with 5-FU have been demonstrated to be superior to the single agent in advanced disease, with adjuvant trials in progress.44-46 Infusion combination regimens have been developed, and there are important scheduling issues with both of these active drugs also.47-50 As the role of combination therapy in two- or three-drug regimens is explored, it may be expected that therapeutic gains could be maximized with optimal scheduling. The size of this trial has allowed for an exploration of prognostic factors based on pretreatment characteristics. Favorable results are associated particularly with good PS, a left colon primary tumor, a lack of involvement of liver or nodes, lack of measurable disease, and a well-differentiated tumor. These analyses suggest strategies to direct therapy based on particular features of presentation, but do not permit conclusions regarding the efficacy of therapy in these subgroups. They point, however, to a need to individualize therapy for patients with poor prognostic clinical factors. The findings are consistent with the previous studies of the Mayo and North Central Cancer Treatment Group group.43 In conclusion, this trial has demonstrated that although biochemical interventions directed to reversing 5-FU–based resistance have been minimally effective in improving results with this drug, a dose-intense intermittent infusion schedule has a profound impact on the therapeutic index of drug administration. The importance of this scheduling information will be more apparent in the context of combination regimens, with 5-FU incorporating some of the newer agents emerging for the treatment of colorectal cancer. In addition, the study identified clinical characteristics associated with shortened survival. An examination of interventions directed to these patients is warranted.
This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD) and supported in part by Public Health Service grant nos. CA15488, CA23318, CA14548, CACA14958, CA27525, CA17145, CA31946, CA37027, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1. Stevenson JP, O’Dwyer PJ: Chemotherapy of advanced colorectal cancer. Cancer Treat Res 98: 111-152, 1998[Medline] 2. Leyland-Jones B, O’Dwyer PJ: Biochemical modulation: Application of laboratory models to the clinic. Cancer Treat Rep 70: 219-229, 1986[Medline]
3.
Santi DV, McHenry CS: 5-fluoro-2'-deoxyuridylate: Covalent complex with thymidylate synthetase. Proc Natl Acad Sci USA 69: 1855-1857, 1972 4. Evans RM, Laskin JD, Hakala MT: Effect of excess folate and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 41: 3288-3295, 1981[Medline] 5. Berger SH, Hakala MT: Relationship of dUMP and free FdUMP pools to inhibition of thymidylate syntase by 5-fluorouracil. Mol Pharmacol 25: 303-309, 1984[Abstract] 6. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6: 469-475, 1988[Abstract] 7. Petrelli N, Douglass HO, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial. J Clin Oncol 7: 1419-1426, 1989[Abstract]
8.
Poon MA, O’Connell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9: 1967-1972, 1991 9. Advanced Colorectal Cancer Meta-Analysis Project (ACCNAP): 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]
10.
Schilsky RL, Ratain MJ: Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Can Inst 82: 1411-1415, 1990 11. Hines JD, Adelstein DJ, Spiess JL, et al: Efficacy of high-dose oral leucovorin and 5-fluorouracil in advanced colorectal carcinoma: Plasma and tissue pharmacokinetics. Cancer 63: 1022-1025, 1989 (suppl 6)[Medline] 12. Hines JD, Adelstein DJ, Spiess JL, et al: High-dose weekly oral leucovorin and 5-fluorouracil in previously untreated patients with advanced colorectal carcinoma: A phase I study. Adv Exp Med Bio 244: 167-172, 1988[Medline]
13.
Martin DS, Stolfi RL, Sawyer RC, et al: Therapeutic utility of utilizing low doses of N-(phosphonoacetyl)-L-aspartic acid in combination with 5-fluorouracil: A murine study with clinical relevance. Cancer Res 43: 2317-2321, 1983 14. Martin DS: Biochemical modulation of 5-fluorouracil by PALA: Mechanism of action. Adv Exp Med Biol 339: 153-163, 1993[Medline] 15. O’Dwyer PJ, Paul AR, Walczak J, et al: Phase II study of biochemical modulation of 5-fluorouracil by low-dose PALA in patients with colorectal cancer. J Clin Oncol 8: 1497-1503, 1990[Abstract]
16.
Ardalan B, Singh G, Silberman H: A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonoacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. J Clin Oncol 6: 1053-1058, 1988
17.
Wadler S, Schwartz EL: Anti-neoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: A review. Cancer Res 50: 3473-3486, 1990
18.
Wadler S, Wersto R, Weinberg V, et al: Interaction of fluorouracil and interferon in human colon cancer cell lines: Cytotoxic and cytokinetic effects. Cancer Res 50: 5735-5739, 1990 19. Schwartz EL, Hoffman M, O’Connor C, et al: Stimulation of 5-fluorouracil metabolic activation by interferon-alfa in human colon carcinoma cells. Biochem Biophys Res Commun 182: 1232-1239, 1991 20. Makower D, Wadler S, Haynes H, et al: Interferon induces thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in vivo. Clin Cancer Res 3: 923-932, 1997[Abstract] 21. Wadler S, Lembersky B, Atkins M, et al: Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 9: 1806-1810, 1991[Abstract] 22. Grem JL, Jordon E, Robson ME, et al: Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. J Clin Oncol 9: 1737-1745, 1993 23. Miller AB, Hoogstraten B, Stagnet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline]
24.
Bland JM, Altman DG: Multiple significance tests: The Bonferroni method. BMJ 310: 170, 1995 25. Dunnet CW: A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 65: 1097-1121, 1955
26.
DeMets DL, Ware JH: Group sequential methods in clinical trials with a one-sided hypothesis. Biometrika 67: 651-660, 1980
27.
DeMets DL, Ware JH: Asymmetric group sequential boundaries for monitoring clinical trials with a one-sided hypothesis. Biometrika 69: 661-663, 1982 28. O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35: 549-556, 1979[Medline] 29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 30. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 50: 163-170, 1966[Medline] 31. Cox DR: Regression models and life tables. J Roy Stat Soc B 34: 181-220, 1972 32. Cox DR: Anal Bin Data. London England, Methuen and Co, 1970 33. Mehta CR, Patel NR, Tsiatis AA: Exact significance testing for ordered categorical data. Biometrics 40: 819-825, 1984[Medline] 34. Collett D: Modeling Survival Data in Medical Research. London England, Chapman & Hall, 1994, pp 78-87 35. 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] 36. Thorion P, Cassano A, O’Dwyer PJ, et al: Meta-analysis of alpha-interferon plus 5-fluorouracil in advanced colorectal cancer. Proc Am Soc Clin Oncol 19: 244a, 2000 (abstr 945)
37.
Wolmark N, Bryant J, Smith R, et al: Adjuvant 5-fluorouracil and leucovorin: With or without interferon alfa-2a in colon carcinoma—National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90: 1810-1816, 1998 38. Kohne CH, Schoffski P, Wilke H, et al: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 16: 418-426, 1998[Abstract]
39.
de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15: 808-815, 1997 40. Haas NB, Schilder RJ, Nash S, et al: A Phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer. Invest New Drugs 13: 229-233, 1995[Medline] 41. Schmoll HJ, Koehne CH, Lorenz M, et al: Weekly 24 h infusion of high-dose 5-fluorouracil with or without folinic acid versus bolus 5-FU/FA (NCCTG/Mayo) in advanced colorectal cancer: A randomized study of the EORTC GITCCG and the AIO. Proc Am Soc Clin Oncol 19: 241a, 2000 (abstr 935) 42. Petrelli N, Douglass HO Jr, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial—Gastrointestinal Tumor Study Group. J Clin Oncol 7: 1419-1426, 1989 43. Poon MA, O’Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7: 1407-1418, 1989[Abstract] 44. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355: 1041-1047, 2000[Medline] 45. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan, leucovorin and fluorouracil is superior to daily x 5 LV/FU in patients with previously untreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 233a, 1999 (abstr 898)
46.
Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18: 136-147, 2000 47. De Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33: 214-219, 1997
48.
Levi FA, Ziadani R, Van Netzel JM, et al: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst 86: 1608-1617, 1994 49. Levi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouraracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer. Cancer 69: 893-900, 1992[Medline]
50.
Ducreux M, Ychou M, Seitz JF, et al: Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every 2 weeks (LV5FU2 regimen): A clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer. J Clin Oncol 17: 2901-2908, 1999 Submitted August 2, 2000; accepted February 7, 2001. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
4,000/mm3, platelets 
