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© 2000 American Society for Clinical Oncology Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal CancerFrom the Service de Médecine Interne-Oncologie, Hôpital Saint-Antoine, Paris; Debiopharm, Charenton; Service d’Oncologie Médicale, Centre Hospitalier Lyon Sud, Pierre-Benite; and Centre Hospitalier René Dubos, Pontoise, France; Institute of Oncology, Belinson Medical Center, Petach Tikva, Israel; Imperial Cancer Research Fund Cancer Medicine Research Unit, University of Leeds; Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen; Department of Medical Oncology, St Bartholomew’s Hospital, London; and Addenbrooke’s National Health Service Trust, Cambridge, United Kingdom; Servizio di Oncologia Medica, Arcispedale S. Maria Nuova, Reggio Emilia; Instituto Europeo di Oncologia, Milan; and Clinical Oncology Centre, Service d’Oncologie Médicale, Div Oncologia Medica Azienda, Ospedaliera di Verona, Verona, Italy; Servicio de Oncología, the Hospital 12 de Octubre, Madrid; and Servicio de Onco-Hematologia, Hospital Clinico Universitario, Valencia, Spain. Address reprint requests to A. de Gramont, MD, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France; email aimery.de-gramont{at}sat.ap-hop-paris.fr
PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
COLORECTAL CANCER accounts for 10% to 15% of all cancers and is the second leading cause of cancer deaths in Western countries. Approximately one half of all patients develop metastatic disease.1 The prognosis for these patients is poor, although palliative chemotherapy has been shown to be able to prolong survival and to improve the quality of life (QoL) over best supportive care.2 To date, no other single agent has been shown to be more effective as first-line therapy than the antimetabolite fluorouracil (5FU), which has been available for more than 40 years. Leucovorin (LV) modulation of 5FU increases the response rate (RR) but has no major impact on survival.3 Although there is no internationally accepted gold-standard 5FU/LV regimen, the monthly 5-day bolus North Central Cancer Treatment Group/Mayo Clinic regimen4 is commonly used as a reference treatment in phase III trials. In a previous trial, this regimen was compared with LV5FU2, a bimonthly schedule of LV and bolus-plus-infusion 5FU. LV5FU2 proved superior in terms of RR (32.6% v 14.5%), progression-free survival (PFS; 27.6 v 22.0 weeks), and toxicity (grade 3 or 4 in 11.1% v 22.9% patients), but not overall survival (OS).5 Oxaliplatin, a new cytotoxic agent from the diaminocyclohexane platinum family, has a mechanism of action similar to that of other platinum derivatives, but its spectrum of antitumor activity against tumor models differs from those of cisplatin and carboplatin. Activity against cisplatin-resistant colon carcinoma cell lines has been demonstrated.6 In addition, experimental data showed synergistic activity of the oxaliplatin/5FU combination.6 Oxaliplatin clinical toxicity is also distinct from other platinum drugs: it has no renal toxicity and minimal hematotoxicity; it causes both a reversible acute, cold-related dysesthesia and a dose-limiting cumulative peripheral sensory neuropathy that usually rapidly regresses after treatment withdrawal. Activity as a single agent in metastatic colorectal cancer patients either previously untreated or treated with 5FU was demonstrated in phase II trials with RRs ranging between 10% and 24%.7-10 Consistent with laboratory evidence of oxaliplatin/5FU synergy, there is evidence for the clinical activity of 5FU/LV/oxaliplatin combinations, with RRs of 20% to more than 50% reported for the three-drug combination in phase II trials.11-13 To further investigate the value of oxaliplatin to the treatment of previously untreated metastatic colorectal cancer, a randomized study was designed to assess the impact of combining oxaliplatin to the bimonthly LV5FU2 schedule. The primary objective was to demonstrate whether adding oxaliplatin would prolong PFS. The secondary objectives were to compare the two treatments in terms of RR, OS, tolerability, and QoL.
Patient Eligibility The eligibility criteria were adenocarcinoma of the colon or rectum; unresectable metastases; at least one bidimensionally measurable lesion of  2 cm; adequate bone marrow, liver, and renal function; World Health Organization (WHO) performance status of 0 to 2; age 18 to 75 years; and ability to complete QoL questionnaires. Previous adjuvant chemotherapy, if given, must have been completed at least 6 months before inclusion. Patients with CNS metastases, second malignancies, or disease confined to previous radiation fields were excluded. Written informed consent was required and the study was approved by the ethics committees of all of the participating centers.
Chemotherapy
Patients were assessed before starting each 2-week cycle using the National Cancer Institute common toxicity criteria. Chemotherapy was delayed until recovery if neutrophils decreased to less than 1.5 x 109/L or platelets decreased to less than 100 x 109/L or for significant persisting nonhematologic toxicity. The 5FU dose was reduced after National Cancer Institute common toxicity criteria grade 3 diarrhea, stomatitis, or dermatitis occurred. Oxaliplatin was reduced for grade 3/4 neutropenia, and in cases of persistent ( 14 days) paresthesia or temporary (7 to 14 days) painful paresthesia or functional impairment. In cases of persistent ( 14 days) painful paraesthesia or functional impairment, oxaliplatin was omitted from the regimen until recovery.
Study Parameters WHO criteria were used to assess tumor response. Complete response was defined as the complete disappearance of all clinically assessable disease for at least 4 weeks, and partial response was defined as a decrease of at least 50% of the sum of the products of the diameters of measurable lesions for at least 4 weeks. CT or MRI scans were performed 4 weeks later to confirm a response. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% of measurable lesions, and progressive disease was defined as an increase of at least 25% of measurable lesions or the appearance of new malignant lesion(s). All CT and MRI scans were subjected to external review by at least two radiologists who were blinded to the patients’ treatment to confirm responses and the date of progression. PFS was defined as the time interval from the randomization date to the date of disease progression or, if the patient died without evidence of progression, to the date of death. When CT scans were not available or were not performed, or if there was a discrepancy between investigators and radiologists, a clinical expert blinded to the treatment received was asked to make the final decision. Poststudy second-line chemotherapy was allowed for both arms at the discretion of the investigators and prospectively monitored for exploratory survival analysis. Cross-over from arm A to arm B was allowed, provided that disease progression under LV5FU2 was documented.
Statistical Considerations Two interim analyses were scheduled for stopping rules17,18: (1) after inclusion of 41 patients on arm B with fewer than eight responses, and (2) after 100 patients had been enrolled per arm and when RR differed by at least 26% between arms. The Mantel-Haenszel test was used for population, RR, and toxicity comparisons.19 Response duration, PFS, and OS were calculated from the date of randomization using the Kaplan-Meier method.20 Stepwise analyses were undertaken to identify subsets of factors associated with response, PFS, and OS using the Cox proportional hazards model.21 Variables for inclusion in the model were assigned treatment, sex, age, performance status, primary site of disease, synchronous/metachronous metastases, number of metastatic sites, liver metastases, adjuvant chemotherapy, prior radiotherapy, baseline alkaline phosphatase, CEA, lactate dehydrogenase (LDH), serum creatinine, serum ALT, serum AST, institution, and poststudy chemotherapy.
Patient Characteristics From August 1995 to July 1997, 420 patients were randomized at 35 institutions and nine countries, 210 in each arm (Table 1). No significant imbalances in major prognostic variables occurred in the randomization; minor differences in performance status, CEA, and alkaline phosphatases would, if anything, favor the control arm. Seven patients were unassessable for treatment efficacy, four on arm A (one patient was ineligible, two were not treated, and one withdrew early) and three on arm B (one patient was not treated and two experienced early disease-related death). These patients were retained for the intent-to-treat analysis. At the cutoff date (December 1, 1998), the median potential follow-up time for the entire cohort was 27.7 months.
Objective Tumor Responses The investigators’ assessments of objective response were recorded as follows: the RRs for arms A and B were 28.6% (60 of 210 patients) and 49.5% (104 of 210 patients), respectively. The external panel of radiologists was able to review CT scans of 380 patients (90.5%), confirming 46 and 105 responses on arms A and B, respectively. The RRs obtained in the population of assessable patients are, therefore, 22.3% and 50.7%, respectively. The intent-to-treat RRs are 21.9% (95% confidence interval, 17.9% to 25.9%) and 50.0% (95% confidence interval, 46.1% to 54.9%; P = .0001), respectively. The RRs are reported as a function of various patient characteristics in Table 2.
For arm A and arm B, the median times to response were 12 weeks and 9 weeks, respectively, and the median durations of the responses were 46.1 and 45.1 weeks. Secondary surgery to remove metastases could be performed in seven patients (3.3%) on arm A and 14 (6.7%) on arm B. Only two independent prognostic factors were found to be significant for response in the multivariate analysis: treatment allocation to oxaliplatin and synchronous metastases (Tables 3 and 4). CEA levels normalized or decreased more than 50% in 57 (34.5%) of 165 patients with elevated CEA level at baseline on arm A versus 107 (62.6%) of 171 patients on arm B (P = .0001).
PFS According to the investigators’ assessments, median PFS was significantly shorter for arm A than for arm B (with oxaliplatin): 6.2 months (26.9 weeks) versus 9.0 months (39.0 weeks), respectively (P = .0001). According to the external review, these values were 6.0 months (26.1 weeks) and 8.2 months (35.6 weeks), respectively (P = .0003; Fig 2). In the multivariate analysis, there were three independent prognostic factors for improved PFS: treatment allocation to oxaliplatin, low LDH level, and good performance status (Tables 3 and 4).
Survival Although median OS was shorter for arm A than arm B (14.7 months [63.9 weeks] v 16.2 months [70.6 weeks], respectively), this difference was not statistically significant (log-rank test P = .12; Wilcoxon P = .05; Fig 3). Sixty-nine percent of the patients receiving the LV5FU2-oxaliplatin combination (arm B; FOLFOX4) were alive at 1 year compared with 61% of the patients in the control arm. Poststudy chemotherapy was administered to 127 patients on arm A (60.5%) and 122 patients on arm B (58.1%). Among those, 78 patients on arm A and 62 patients on arm B received poststudy chemotherapy with oxaliplatin (arm A, 58 patients, 27.6%) and/or irinotecan (arm A, 42 patients, 20%; arm B, 62 patients, 29.5%). For the patients in this study who did not receive second-line poststudy oxaliplatin or irinotecan, the median OS was 12.2 months (52.9 weeks) for arm A (132 patients) and 14.8 months (64.1 weeks) for arm B (148 patients) (P = .04). The median time from progression to death was 8.2 months (35.7 weeks) for arm A and 7.2 months (31.1 weeks) for arm B.
In the multivariate analysis, independent prognostic factors for improved OS were treatment allocation to oxaliplatin, low LDH level, good performance status, low alkaline phosphatase level, and a limited number of involved sites (Tables 3 and 4).
Toxicity
Although grade 3/4 neutropenia was common on arm B, patients responded well to dose modification and few complications were seen. Only 22 patients (10.5%) had more than one episode, and only two patients (1%) experienced febrile neutropenia. Neurosensory toxicity was observed in 68% of the arm B patients and reached grade 3 in 18%. Cold-related dysesthesia was reported in 141 patients (67.5%). Paresthesia without pain was observed in 136 patients (65.1%). Paresthesia with pain occurred in 22 patients (10.5%). Cumulative paresthesia interfering with function occurred in 34 patients (16.3%). Investigators also reported pharyngolaryngeal dysesthesia in 47 patients (22.5%), but only two patients (1%) had a laryngospasm-like syndrome. Cramps were experienced in 12 patients (5.7%), loss of deep tendon reflexes in 24 patients (11.5%), and a Lhermitte’s sign in seven patients (3.3%). The estimated incidences of grade 2 and 3 neuropathies, respectively, calculated for patients exposed to oxaliplatin, reached 10% after three and nine cycles, 25% after eight and 12 cycles, and 50% after 10 and 14 cycles. Reversibility of grade 3 sensory neurotoxicity was observed in 25 (74%) of 34 patients. The median time to recovery from grade 3 neurotoxicity was 13 weeks (Fig 4).
Seven patients (3.4%) were withdrawn from the study because of toxicity on arm A and 22 (10.6%) were withdrawn because of toxicity on arm B, including eight patients with sensory neuropathy (3.8%). The elderly patients (> 65 years; n = 160) did not experience increased toxicity as compared with the younger patients, except for grade 3/4 diarrhea (18% v 8%; P = .034).
Dose-Intensity
QoL
Weight increase of at least 5% was recorded for 83 patients (39.5%) on arm A and in 90 (42.9%) on arm B. Performance status improved in 59 (54.6%) of 108 patients on arm A and in 71 (59.7%) of 119 patients on arm B.
The results of this study demonstrate that the addition of oxaliplatin to the LV5FU2 bimonthly regimen significantly extends the PFS of patients with metastatic colorectal cancer. The results we obtained with the control arm, ie, the LV5FU2 bimonthly regimen alone, were consistent with those observed in prior phase III studies: the median PFS of 6.2 months and RR of 29% in the present study (as assessed by the investigators) are comparable to the median PFS of 6.4 months and RR of 32.6% in the previous French Intergroup study and the RR of 27% in the study conducted by the Medical Research Council.5,22 The present study also confirmed the good tolerability of this regimen, which makes it a reasonable option for combination with other drugs. The median PFS as assessed by investigators was improved by 45% or 12.1 weeks (2.8 months). Multivariate analyses identified only three factors that contributed to prolonged PFS: assignment to oxaliplatin, baseline LDH level, and performance status. The median OS in both arms was well in excess of 1 year, in contrast to most of the studies performed before the era of second-line therapies.22-26 The prolonged survival cannot be attributed to a selected patient population with a good prognosis; 58% of the patients in the study had more than one metastatic site. Among nine other randomized studies5,13,23-30 that specified the number of metastatic sites, only two had enrolled more than 50% of the patients with more than one metastatic site.29,30 There was a nonsignificant survival advantage on arm B, with 10.4% or 6.7 weeks median survival improvement (1.5 month). This raises the question of why a higher RR and an extended PFS were not translated into extended OS. In the meta-analysis of 5FU plus LV in advanced colorectal cancer, where no difference in survival was observed between 5FU and 5FU plus LV, the authors proposed four hypotheses to answer this question: first, duration of tumor responses may have been too short; second, the RR could be too small; third, the complete RR may be too low; fourth, cross-over may have obscured a small impact on survival.3 In our study, we can retain only the two latter hypotheses. As of today, no study, including ours, has ever reported a high complete RR. Therefore, only cross-over or active poststudy chemotherapy are relevant in our purpose. As a matter of fact, we observed an unusually good survival among patients on the control arm in which 37% (78 patients) received poststudy chemotherapy with oxaliplatin and/or irinotecan. The efficacy of these two new agents as second-line therapies has already been demonstrated.7,8,11,31,32 The impact on survival of the second-line therapies suggests that PFS rather than OS should be the end point of first-line studies in metastatic colorectal cancer or that therapeutic strategy studies that include two lines of therapy in the study design should be initiated. The RR was more than two times higher in the LV5FU2 plus oxaliplatin arm (FOLFOX4) compared with LV5FU2 alone. This high RR in patients with oxaliplatin may have contributed to the early divergence in the survival curves observed in this study. This suggests that patients with bulky or rapidly progressive disease might particularly benefit from the early use of oxaliplatin, as these patients might not otherwise survive to receive subsequent therapy. Furthermore, the high RR (54%) obtained in patients with isolated liver metastases, which might improve the possibility of curative liver resection, supports the use of oxaliplatin as first-line therapy in this population. Another phase III trial evaluating the contribution of oxaliplatin to a chronomodulated LV5FU regimen also found a significantly higher RR with the addition of oxaliplatin.33 Median QoL scores were similar for the two arms in the study, despite the increased incidence of 5FU-related side effects and the specific peripheral neurotoxicity recorded for patients who received the oxaliplatin-containing regimen. Furthermore, the time to deterioration in global health status was prolonged in the oxaliplatin-containing arm. Among patients who were assigned to receive oxaliplatin, neutropenia grade 3/4 occurred in 41.7% of patients but was febrile in only 1.0%, whereas grade 3/4 vomiting and mucositis affected only 5.8% of patients and diarrhea affected 11.9%. On the other hand, the incidences and severities of 5FU skin toxicity and alopecia remained particularly low. The cumulative dose-limiting toxicity of the oxaliplatin arm was sensory neuropathy. Reversible paresthesia interfering with function was observed in 16.3% of the patients and led to oxaliplatin withdrawal for 3.8% after they had received a minimum of nine cycles (or at least 4 months) of chemotherapy. This time to onset should be put into perspective with the median time to response of 2.1 months, allowing the maximum effect of the treatment to be obtained before cumulative toxicity appeared and thus not negatively affecting patients who did not benefit from treatment in terms of an objective response. The reversibility of the significant sensory neuropathy is important for future adjuvant studies. Because the elderly group performed quite similarly to the other patients, we concluded that the oxaliplatin-LV5FU2 combination may be safely administered to patients older than 65 years. This study also demonstrates that oxaliplatin-5FU/LV combination provides a significant improvement of disease control versus 5FU/LV alone. In this setting, raltitrexed, a pure thymidylate synthase inhibitor, and antimetabolites such as capecitabine, uracil and tegafur, and trimetrexate, given alone, did not generate superior results over the monthly 5-day LV5FU bolus regimen.34-39 However, irinotecan in combination with 5FU/LV was associated with an improved PFS and a prolonged survival.40,41 These results and those achieved in phase III studies using oxaliplatin provide clear evidence that the addition of an active anticancer drug to 5FU/LV improves the disease outcome as compared with 5FU/LV alone. The LV5FU2 plus oxaliplatin combination, which seems beneficial as first-line therapy of metastatic colorectal cancer, will be further examined as adjuvant therapy for colon cancer (Multicenter International Study of Oxaliplatin 5FU-LV in the Adjuvant Treatment of Colon Cancer) to verify whether it can improve survival in this setting. A higher oxaliplatin dose, which induced a high RR in second-line therapy in combination with a simplified bimonthly regimen,42,43 is also to be studied as first-line therapy.
Supported by Debiopharm SA, Lausanne, Switzerland. We thank the physicians who contributed to this study: from France, T. André, J.P. Lotz, K. Beerblock, J.F. Bosset, J.M. Ciribilli, P.L. Etienne, R. Favre, and H. Naman; from Austria, W. Scheithauer; from Belgium, H. Bleiberg; from Spain, M. Benavides and A. Abad; from Italy, R. Labianca and A. Zaniboni; from Israel, P. Rath, T. Peretz, N. Haim, and A. Shani; from Portugal, J. Oliveira and T. Fiuza; from the United Kingdom, M. Slevin; and from Germany, H.J. König and K. Höffken. We also thank J. Vignoud (study initiation), I. Tabah-Fisch (QoL study), and J. Jacobson (editorial assistance).
1. American Cancer SocietyCancer facts and figures: 1995. Atlanta, GA,American Cancer Society, 1995 2. Glimelius B, Hoffman K, Graf W, et al: Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer: The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 73:556–562, 1994[Medline] 3. 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] 4. 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]
5.
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 6. Raymond E, Buquet-Fagot C, Djelloul S, et al: Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast, and ovarian cancers. Anticancer Drugs 8:876–885, 1997[Medline]
7.
Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95–98, 1996 8. Levi F, Perpoint B, Garufi C, et al: Oxaliplatin activity against metastatic colorectal cancer: A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate. Eur J Cancer 29A:1280–1284, 1993
9.
Diaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9:105–108, 1998 10. Becouarn Y, Ychou M, Ducreux M, et al: A phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. J Clin Oncol 8:2739–2744, 1998 11. 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
12.
André T, Louvet C, Raymond E, et al: Bimonthly high-dose leucovorin, 5-fluorouracil 48-hour infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same LV-5FU regimen. Ann Oncol 9:1251–1253, 1998
13.
Levi F, Zidani R, Vannetzel JM, et al: Chronomodulated versus fixed infusion rate delivery of ambulatory chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid in patients with colorectal cancer metastases: A randomized multiinstitutional trial. J Natl Cancer Inst 86:1608–1617, 1994
14.
Aaranson NK, Ahmedsai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376, 1993 15. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trials. Biometrics 31:103–115, 1975[Medline] 16. Machin D, Campbell MJ: Statistical tables for the design of clinical trials. Oxford, United Kingdom,Blackwell Scientific Publications, 1987 17. Fleming TR: One sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151, 1982[Medline] 18. Geller NL, Pocock SJ: Interim analysis in randomized clinical trials: Ramifications and guidelines for practitioners. Biometrics 43:213–223, 1987[Medline] 19. Mantel N, Haenzel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748, 1959 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958 21. Cox DR: Regression models and life-tables. J R Stat Soc 34B:187–220, 1972 22. Seymour MT, Slevin M, Kerr DJ, et al: Randomized trial assessing the addition of interferon-2-alpha to fluorouracil and leucovorin in advanced colorectal cancer. J Clin Oncol 14:2280–2288, 1996[Abstract]
23.
Laufman LR, Bukowski RM, Collier MA, et al: A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 11:1888–1893, 1993 24. Blijham GH, 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]
25.
Labianca R, Pancera G, Aitini E, et al: Folinic acid + 5-fluorouracil (5-FU) versus equidose of 5-FU in advanced colorectal cancer: Phase III study of GISCAD (Italian group for the study of digestive tract cancer). Ann Oncol 2:673–679, 1991 26. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Superiority of sequential methotrexate, fluorouracil and leucovorin to fluorouracil alone in advanced symptomatic colorectal cancer. J Clin Oncol 7:1437–1446, 1989[Abstract]
27.
Scheithauer W, Kornek G, Marczell A, et al: Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: A randomized phase III study. J Clin Oncol 15:908–914, 1997 28. Labianca R, Pancera G, Cesana B, et al: Cisplatin + 5-fluorouracil versus 5-fluorouracil alone in advanced colorectal cancer: A randomized study. Eur J Cancer Clin Oncol 24:1579–1581, 1988[Medline] 29. Köhne CH, Schöffski 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] 30. Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 350:681–686, 1997[Medline] 31. Cunningham D, Pyrhönen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418, 1998[Medline] 32. Rougier P, Van Custem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407–1412, 1998[Medline]
33.
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
34.
Cunningham D, Zalcberg JR, Rath U, et al: Final results of a randomised trial comparing Tomudex (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol 7:961–965, 1996 35. Cox J, Pazdur R, Thibault A, et al: A phase III trial of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:265a, 1999 (abstr 1016) 36. Twelves C, Harper P, Van Custem E, et al: A phase III trial of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999 (abstr 1010) 37. Pazdur R, Douillard JY, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999 (abstr 1009) 38. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of Orzel (oral uracil/tegafur (UFT) plus leucovorin (LV)) versus parenteral 5-fluorouracil (5-FY) plus LV in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:264a, 1999 (abstr 1015) 39. Punt CJA, Keizer HJ, Douma J, et al: Multicenter randomized trial of 5-fluorouracil (5FU) and leucovorin (LV) with or without trimetrexate (TMTX) as first line treatment in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 18:262a, 1999 (abstr 1006) 40. 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] 41. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan, leucovorin and fluorouracil is superior to dailyx5 LV/FU in patients with prviously untreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:233a, 1999 (abstr 898) 42. Tournigand C, de Gramont A, Louvet C, et al: A simplified bimonthly regimen with leucovorin and 5-fluorouracil for metastatic colorectal cancer. Proc Am Soc Clin Oncol 17:274, 1998 (abstr 1052) 43. Maindrault-Goebel F, Louvet C, André T, et al: Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). Eur J Cancer 35:1338–1342, 1999 Submitted June 30, 1999; accepted April 20, 2000. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
