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© 2001 American Society for Clinical Oncology Fluorouracil Plus Leucovorin as Effective Adjuvant Chemotherapy in Curatively Resected Stage III Colon Cancer: Results of the Trial adjCCA-01From the Department of Gastroenterology, University of Tübingen, Tübingen; Medical Department, Municipal Hospital Dortmund, Dortmund; Institute of Medical Statistics G.E.M., Meerbusch; and Department of Gastroenterology, University of Düsseldorf, Düsseldorf, Germany. Address reprint requests to Prof. R. Porschen, MD, Clinic of Internal Medicine, Central Hospital Bremen Ost, Züricher Str. 40, D-28325 Bremen, Germany; email: porsch{at}zkhost.bremen.de
PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body-surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days; 12 cycles, plus leucovorin 100 mg/m2 (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P = .037) and significantly decreased overall mortality (P = .0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P = .0059) and disease-free survival (P = .03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.
COLORECTAL CANCER represents a significant health problem in Germany. It is estimated that there will be approximately 52,000 new cases of colorectal cancer per year. Although the advances in surgery, intensive care, screening, and diagnosis have reduced perioperative mortality and have increased the proportion of cancers detected in early stages, overall survival has improved only slightly during the last decades.1 The prognosis of patients after the complete surgical removal of a clinically localized colon cancer is related to the pathologic staging of the resected primary tumor. According to the Munich tumor registry2 and a German multicentric observation study,3 5-year survival decreases to 34% to 77% after tumor invasion into regional lymph nodes depending on the number and location of involved lymph nodes as well as on T category. The substantial rate of postoperative recurrence and death in this subset of colon cancer patients provides the rationale for combining adjuvant chemotherapy with surgery in an attempt to attain an improved disease control. In the adjuvant setting, fluorouracil (5-FU)-containing regimens seem to result in a small benefit of therapy in terms of overall survival.4 Based on reports suggesting a possible benefit from the combination of 5-FU and levamisole,5 a large confirmatory Intergroup trial was launched.6 In patients with a curatively resected stage III colon cancer, the combination of 5-FU plus levamisole reduced the risk of cancer recurrence by 41% and the overall death rate by 33%. Various attempts at modulating the activity of 5-FU with other compounds have been tried. Remission rates induced by 5-FU chemotherapy in patients with advanced colorectal cancer can be enhanced by the addition of leucovorin (LV).7 A randomized trial of the Arbeitsgemeinschaft Gastrointestinale Onkologie (AGO) comparing 5-FU alone and the combination of 5-FU plus leucovorin also demonstrated increased remission rates and improved survival with the combined treatment.8 A combination of 5-FU and leucovorin might therefore prove to be a more effective adjuvant treatment regimen than 5-FU and levamisole. The promising observations in metastatic colorectal cancer formed the basis of a comparative randomized multicentric trial of the Arbeitsgemeinschaft Gastrointestinale Onkologie in North Rhine-Westphalia (AGO). The aim of this prospective adjuvant study was to evaluate the effectiveness and toxicity of 5-FU plus leucovorin in comparison with 5-FU plus levamisole in patients with a curatively resected stage III colon cancer.
This trial, called adjCCA-01, was initiated by the Arbeitsgemeinschaft Gastrointestinale Onkologie in North Rhine-Westphalia and approved by the Ethical Committee of the Faculty of Medicine of the Heinrich-Heine-University of Düsseldorf.
Patients and Eligibility Criteria To be eligible, patients had to fulfill the following inclusion criteria: potentially curative en bloc resection of an adenocarcinoma of the colon without gross or microscopic evidence of residual disease, presence of lymph node metastasis (International Union Against Cancer stage III tumor), a leukocyte count of at least 4,000/µL, a platelet count of at least 130,000/µL, Eastern Cooperative Oncology Group performance status of 0 or 1, and written informed consent. Pathohistologic tumor staging was based on the fourth edition of the tumor-node-metastasis classification.9 A colon cancer was defined as a malignant lesion that did not require opening of the pelvic peritoneum to define the distal extent of the tumor. Patients were ineligible if they had been treated because of any other cancer within 5 years (except for superficial squamous or basal cell skin cancer or in situ carcinoma of the cervix) or if they had any other severe concomitant disease that would limit life expectancy. Eligibility was determined by careful review of the operative reports, pathohistologic reports, and study forms. Study forms were screened for consistency. Site visits were performed in the case of inconsistency of the data to check the original data concerning eligibility and to review the follow-up and chemotherapy data.
Randomization and Stratification Procedures
Chemotherapy Administration Schedules Dosages for 5-FU and levamisole (LEV) in arm B were the same as those used in the Intergroup trial.6 Levamisole 50 mg was given orally three times a day for a period of 3 days; this was repeated every 2 weeks. Patients received 5-FU 450 mg/m2 by a short infusion daily for 5 consecutive days. Twenty-eight days after the start of this induction course, IV treatment with 5-FU was given once per week and continued for 44 weeks. After the induction course, four weekly infusions were regarded as one chemotherapy course. In both study arms, chemotherapy should start within 42 days after tumor resection. Toxicity was evaluated according to World Health Organization standard criteria. A complete blood cell count was performed before each chemotherapy infusion. Depending on the World Health Organization grade of toxicity—especially hematologic or gastrointestinal toxicity—5-FU dosage was reduced by 25% to 50% in the following cycle.
Follow-Up Procedures
Statistical Analysis
Survival time and disease-free survival time were defined as the interval between the date of surgery and the date of death or the date of diagnosis of the first recurrence, respectively. The cutoff date for analysis was August 31, 1998. Survival curves were generated by the Kaplan-Meier method11 and compared by means of the one-sided log-rank test.12 The multivariate Cox proportional hazards model13 was applied to identify factors significantly related to recurrence and survival using the backward regression procedure and progressively eliminating parameters whose maximum partial likelihood estimate statistic satisfied the criterion of a P value
Patient and Tumor Characteristics Seven hundred two patients entered this prospective randomized multicentric trial. Twenty-two patients (3.1%) were erroneously randomized but not included into the study (five assigned to 5-FU/leucovorin and 17 to 5-FU/levamisole) because of the following reasons: distant metastasis at the time of randomization (12 patients), concomitant second cancer (one patient), N0 category (one patient), rectal primary carcinoma (four patients), and missing informed consent (four patients). Characteristics of the remaining 680 patients and of the tumors are reported in Table 1. Partly as a consequence of stratification, patient and tumor characteristics were well balanced between the two treatment groups. Slightly more male patients received levamisole plus 5-FU. Bowel obstruction and tumor perforation were seen more often in the 5-FU/leucovorin group. Multiple primaries were found in 11 and five cases, respectively. The mean number of lymph nodes amounted to 14.3 (± 10.5) and to 13.7 (± 9.7) in the 5-FU/leucovorin and the 5-FU/levamisole arm, respectively (P = not significant [NS]). A total of 3.7 ± 4.2 (arm A) and 3.7 ± 3.7 lymph nodes (arm B) were invaded by cancer. Mean tumor diameter did not differ significantly between the two treatment groups (4.6 ± 2.1 cm and 4.5 ± 1.9 cm). The length of resected colonic segments was comparable (arm A, 27.7 ± 13.1 cm; arm B, 28.5 ± 15.3 cm).
Treatment and Protocol Compliance Sixteen patients did not receive adjuvant treatment at all (eight patients in each treatment group). Postoperative chemotherapy was planned to be started within 42 days after tumor resection. Although randomization was performed in time, adjuvant treatment had to be postponed in 25 patients (5-FU plus leucovorin, 13 patients; 5-FU plus levamisole, 12 patients) because of various reasons, most of them postoperative complications not present at the time of randomization. The mean interval between surgery and start of treatment was 27.0 in arm A (median, 26 days; range, 10 to 59 days) and 27.8 days in arm B (median, 27 days; range, 11 to 82 days) (P = NS). Adjuvant chemotherapy was prematurely discontinued in 84 patients (24.1%) in the 5-FU plus leucovorin group and in 75 patients (22.7%) in the 5-FU plus levamisole group after a median of six and four cycles, respectively. In the majority of cases, the reasons for discontinuation of treatment were toxicity (26 and 18 patients, respectively) and lack of compliance (33 and 26 patients, respectively). In the leucovorin group, the mean relative 5-FU dose-intensity (dose-intensity received/dose-intensity planned) decreased from 100.6% ± 8.1% in the first course to 93.4% ± 16.4% in the 12th course; a smaller decrease was observed in the levamisole group (from 98.5% ± 8.1% to 97.4% ± 12.3%). Obviously, this decrease of chemotherapy dose was related to the occurrence of adverse events. At this writing, the median follow-up time of the living patients is 46.5 months. In 17 patients no follow-up data are available (seven in the 5-FU/leucovorin group; 10 in the 5-FU/levamisole group). The data of all 680 patients were included according to the intention-to-treat principle.
Tumor Relapse The univariate analysis of disease-free survival ( Fig 1) showed that therapy with 5-FU/leucovorin was significantly superior to treatment with 5-FU/levamisole (P = .037); mean survival time 58 months (95% confidence interval, 54 to 61 months) versus 49 months (95% confidence interval, 46 to 53 months). Cox regression analysis with T category, N category, tumor differentiation, age, sex, interval between surgery and start of chemotherapy, tumor obstruction, tumor location, and adjuvant treatment as predictors revealed that nodal status (P < .0001) and tumor invasion (P = .0002) were the most significant contributors to tumor relapse. However, besides tumor differentiation, preoperative tumor obstruction and interval between surgery and start of chemotherapy (interval < 27.5 days associated with a lower recurrence rate) adjuvant treatment (P = .03) emerged as another independent determinant of recurrence. In univariate analysis however, the impact of the interval between surgery and initiation of chemotherapy on disease-free survival was only significant in the levamisole/5-FU group.
During this study, 20 second primary cancers were documented: nine (2.6%) of 349 in the 5-FU plus leucovorin arm versus 11 (3.3%) of 331 in the 5-FU plus levamisole arm (P = NS). No case of leukemia was observed. Two patients in the levamisole group developed a non-Hodgkin’s lymphoma. The large bowel was the site of a second primary cancer in four cases.
Survival
A multivariate Cox analysis demonstrated that age, tumor grading, tumor obstruction, T category, and N category were independent prognostic factors for overall survival. The Cox proportional hazards model also confirmed a significant survival advantage for the 5-FU/leucovorin arm (P = .0059).
Toxicity
After several randomized controlled trials of adjuvant chemotherapy did not show a clinically convincing survival benefit, the North Central Cancer Treatment Group (NCCTG) study5 was the first study to demonstrate promising results of adjuvant treatment with 5-FU/levamisole. These results were confirmed by a large Intergroup trial.6 Despite the debated immunomodulatory effects, the contribution of levamisole remains obscure.14 In metastatic colorectal cancer, the cytotoxic activity of 5-FU can be potentiated by biochemical modulation with leucovorin. In several randomized studies, tumor remission rates were significantly increased after therapy with 5-FU/leucovorin in comparison with 5-FU monotherapy (23% v 11%).7 In a preceding multicentric German trial of the AGO,8 treatment with 5-FU/leucovorin (400 to 450 and 100 mg/m2 as an IV short infusion) prolonged survival and improved tumor remission rates in patients with metastatic colorectal cancer in comparison with 5-FU treatment alone. These data formed the basis for the design of the prospective adjuvant chemotherapy trial adjCCA-01 of the AGO comparing the effectiveness of 5-FU/leucovorin versus 5-FU/levamisole. When the present study was designed, optimal treatment duration was still thought to be 1 year, as indicated by the Intergroup trial.6 Several studies have analyzed the effects of a leucovorin-modulated 5-FU combination in a direct comparison with surgery alone. In an Italian study,15 adjuvant treatment consisted of leucovorin 200 mg/m2 plus 5-FU 400 mg/m2 on days 1 through 5 every 4 weeks for 12 cycles. In Dukes’ C cancer, the postoperative treatment produced a significant prolongation of disease-free survival and of overall survival, whereas there was no survival benefit in patients with a Dukes’ B cancer. The surgical resection of colon tumors was performed in a single center by only three surgical teams thus reducing the impact of the prognostic factor "surgeon" in this study. Three studies (Gruppo Italiano di Valutazione Interventi in Oncologia, National Cancer Institute of Canada Clinical Trials Group, and Fondation Française de Cancerologie Digestive) have been performed to find determine the efficacy of six cycles of 5-FU (370 to 400 mg/m2) and leucovorin (200 mg/m2) after surgery for Dukes’ B and C colon cancer. The pooled analysis demonstrated a significant survival benefit after adjuvant chemotherapy.16 An Intergroup study in patients with high-risk stage II or stage III colon cancer proved that six cycles of 5-FU plus leucovorin (425 mg/m2 and 20 mg/m2, days 1 through 5, every 4 to 5 weeks) led to a significant improvement in time to relapse and survival compared with control patients treated with surgery alone.17 In conclusion, the trials using surgery-only controls demonstrated that the leucovorin modulated 5-FU schemes are active compared with surgery alone. For the first time, our data provide evidence that a significant disease-free survival and survival benefit resulted from adjuvant treatment with 5-FU/leucovorin in comparison with 5-FU/levamisole. The study of O’Connell et al18 assessed the effectiveness of a double modulation of the 5-FU activity (370 mg/m2, days 1 through 5, every 4 to 5 weeks) by leucovorin and levamisole and evaluated the necessary duration of the postoperative adjuvant therapy (6 v 12 months). The data suggested that 6 months of treatment with the three-drug combination was effective and superior to treatment with 5-FU plus levamisole over 6 months in patients with poor-prognosis stage II or stage III colon cancer. A significant survival benefit for the double modulation of 5-FU compared with the standard 5-FU plus levamisole regimen given for 12 months could not be demonstrated. The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-04 study compared 48 weeks of adjuvant treatment with weekly injections of 5-FU and leucovorin with the Moertel scheme and the modulation of 5-FU with leucovorin and levamisole in Dukes’ B and C patients.19 There was no significant difference in disease-free survival or overall survival. Pair-wise statistical comparisons indicated a survival advantage for 5-FU plus leucovorin versus 5-FU plus levamisole (P < .05) similar to our results. However, a recent statistical analysis of the C-04 trial20 did not yield a survival difference after adjuvant treatment with either 5-FU plus levamisole or 5-FU plus leucovorin in Dukes’ C patients. In patients who underwent surgery for high-risk stage II and III colon cancer, the INT-0089 study21 proved that levamisole is not a mandatory component of 5-FU–based adjuvant treatment. Whereas there was no survival difference between 1 year of treatment with 5-FU/levamisole and adjuvant therapy with 5-FU plus low-dose (six cycles every 4 to 5 weeks) or high-dose leucovorin (four 8-week cycles), our study demonstrated a significant survival benefit in favor of the adjuvant 5-FU/leucovorin treatment given for 1 year. Considering the studies using a 5-FU/leucovorin–based therapy versus the Moertel scheme, the highest total planned dose of 5-FU (assuming a body-surface area of 1.7 m2) during the first 3 months was given in the adjCCA-01 study (11.05 g). This dose was 8.5 g in the NSABP C-04 study19 and 9.4 g in the NCCTG/National Cancer Institute of Canada Clinical Trials Group study.18 An analysis of published adjuvant chemotherapy trials22 demonstrated a significant reduction in the odds of death for those receiving 5-FU regimens compared with untreated controls. This effect was dose-dependent; for a total 5-FU dose in the first 3 months of greater than 10 g, 8 to 10 g, or less than 8 g, estimates were 0.71, 0.79, and 0.93, respectively. It remains speculative whether the significant difference seen in the adjCCA-01 study can be explained by this difference in 5-FU dose, because the study populations differed also (eg, inclusion of stage II tumors). After a median follow-up of nearly 4 years, our total rate of recurrence was 33.5% in arm A and 39.3% in arm B, with the majority of relapses being distant metastases. In initially curative resected colonic carcinomas with lymph node metastasis and without adjuvant treatment, relapse rates of 49%6 and up to 60%15,23 have been reported. Locoregional recurrence after curative resection is significantly influenced by tumor stage, tumor grading, obstruction, and tumor perforation.24 In contrast to other adjuvant chemotherapy studies, the number of involved and analyzed lymph nodes was documented in our study. The mean number of analyzed and involved lymph nodes compares very well with a pathohistologic study from a population-based register in which these numbers amounted to 11 ± 6.8 and 3.3 ± 4.7.25 Sole locoregional recurrence plus a combination of locoregional recurrence and distant metastasis was observed in 28.5% of the patients in arm A and in 33.1% of the patients in arm B. The Munich tumor registry reports on locoregional recurrence in 46% of the patients.2 The total percentage of local failure in the study of Willett et al26 and in the study of Russell23 was 33% to 34% after resection of a colon tumor with lymph node metastasis. In the studies comparing surgery with surgery plus postoperative chemotherapy, relapses could be diminished significantly in node-positive colon cancers.6,15 The observed rate of second cancers (2.9%) is comparable to that of other reports either with or without adjuvant treatment.6,16,27 Toxicity of adjuvant chemotherapy regimens needs to be considered in defining optimal therapy. In the Intergroup study, the predominant reactions to levamisole plus 5-FU were those that might have been anticipated with 5-FU alone.6 One to seven percent of the side effects were judged to be severe in that study. The single drug-related death observed in the Intergroup study was caused by profound leucopenia and sepsis. The toxicity profile tended to be lower in our 5-FU plus levamisole treatment arm. Fortunately, severe neurotoxic effects or a multifocal leukoencephalopathy28 were not observed in this AGO study. Although the same treatment regimen as in the Intergroup study6 was given, grade 3 and 4 toxicities increased to 7% to 12% for diarrhea, 14% to 18% for leukopenia, and 3% to 6% for stomatitis in the two levamisole plus 5-FU treatment arms in the NCCTG 894651 trial.18 In the levamisole groups, there were two treatment-related fatalities. Grade 3 or 4 toxic reactions were observed in 28% of the patients of the 5-FU/levamisole group of the NSABP C-04 study.19 The toxic effects in the 5-FU plus leucovorin arm were acceptable. With the same chemotherapy regimen, Löffler et al8 reported on a good tolerance in patients with metastatic colorectal cancer. The Italian study15 documented low percentages of diarrhea, stomatitis, and leukopenia. Only approximately 3% of the patients had grade 4 stomatitis or diarrhea. Using a weekly chemotherapy scheme with leucovorin and bolus injection of 5-FU, the NSABP study C-04 reported on grade 3 or 4 toxicity in 36% of their patients, with 11 fatalities in the 5-FU/leucovorin/levamisole arm, four in the 5-FU/leucovorin arm, and three in the 5-FU/levamisole arm.19 Compared with the weekly chemotherapy application, a higher incidence of stomatitis, leukopenia, and neutropenia was observed in the daily-times-five low-dose leucovorin schedule.21,29 It could be argued that the good tolerance of the two chemotherapy regimens in our study could be due to the fact that 5-FU was given by short infusion. However, variable percentages of toxic reactions are reported in studies using the same chemotherapy regimen, eg, in the three substudies of the Impact trial.16 Another German adjuvant trial30 observed a similar good tolerance after chemotherapy with 5-FU/levamisole and an identical 5-FU/leucovorin schedule, despite the fact that 5-FU was given as an IV bolus injection. Four-year survival estimates range from 46% to 57% after a curative resection of a stage III colon cancer.6,15,16 Adjuvant therapy with 5-FU/levamisole has been shown to increase postoperative survival to 65% (our own study) and to 69%.6 However, after adjuvant treatment with 5-FU modulated by leucovorin, 4-year survival estimates even further increase to 71%,15 66%,16 and 72% (our own study) after the resection of a node-positive colon cancer. Combining the results of the aforementioned trials with our own significant data, a 5-FU–based therapy modulated by leucovorin should represent standard chemotherapy for patients with curatively resected colon cancers with lymph node metastasis. Prolongation of disease-free survival and overall survival will remain the aim of future efforts in colon cancer. This aim might be reached by new drugs being active in metastatic colon cancer such as irinotecan and oxaliplatin or by changing the 5-FU application mode. The observation that dose-intensity might play a critical role in the adjuvant treatment of colon cancer22 constitutes the basis for the new adjuvant trial adjCCA-02 evaluating the benefit of weekly high-dose 5-FU/leucovorin and of weekly high-dose 5-FU monotherapy versus the daily-times-five 5-FU/leucovorin schedule.
APPENDIX Participating Hospitals
Supported by the Arbeitsgemeinschaft für Krebsbekämpfung, Bochum the Ernst and Berta Grimmke Foundation, and the Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität, Düsseldorf, Germany. We thank all of the colleagues taking part in this study. Without their support this trial could not have been performed.
1. Sant M, Capocaccia R, Verdecchia A, et al: Comparisons of colon-cancer survival among European countries: The EUROCARE study. Int J Cancer 63: 43-48, 1995[Medline] 2. Munich tumor registry: Epidemiologische Daten des Tumorregisters München: Http://www.krebsinfo.de. Tumor Zentrum München, April 2, 1998 3. Hermanek P, Wiebelt H, Riedl St, et al: Long-time results of surgical therapy for colorectal cancer: Results of the German Study Group for Colorectal Cancer (SGCRC). Chirurg 65: 287-297, 1994[Medline]
4.
Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer: Why we still don’t know. JAMA 259: 3571-3578, 1988 5. Laurie JA, Moertel CG, Fleming TR, et al: Surgical adjuvant therapy of large bowel-carcinoma: An evaluation of levamisole and fluorouracil. J Clin Oncol 7: 1447-1456, 1989[Abstract] 6. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322: 352-358, 1990[Abstract] 7. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rates. J Clin Oncol 10: 896-903, 1992[Abstract] 8. Löffler TM, Korsten FW, Reis HE, et al: Fluorouracil als Monotherapie oder in Kombination mit Folinsäure in der Behandlung des metastasierten kolorektalen Karzinoms. Dtsch med Wschr 117: 1007-1013, 1992[Medline] 9. Hermanek P, Sobin LH (eds): TNM Classification of Malignant Tumours (ed 4). Berlin, Germany, Springer Verlag, 1987 10. Freedman LS: Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1: 121-129, 1982[Medline] 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 12. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719-748, 1959 13. Cox DR: Regression models and life tables. J R Stat Soc [B] 34: 187-220, 1972 14. Mayer RJ: Does adjuvant therapy work in colon cancer? N Engl J Cancer 322: 399-401, 1990 15. Francini G, Petriolo R, Lorenzini L, et al: Folonic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology 106: 899-906, 1994[Medline] 16. IMPACT Investigators: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345: 939-944, 1995[Medline]
17.
O’Connell MJ, Mailliard JA, Kahn MJ, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15: 246-250, 1997
18.
O’Connell MJ, Laurie JA, Kahn MJ, et al: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16: 295-300, 1998 19. Wolmark N, Rockette H, Mamounas EP, et al: The relative efficacy of 5-FU + leucovorin (FU-LV), 5-FU + levamisole (FU-LEV), and 5-FU + leucovorin + levamisole (FU-LV-LEV) in patients with Dukes’ B and C carcinoma of the colon. Proc Am Soc Clin Oncol 15: 205, 1996 (abstr 460)
20.
Mamounas E, Wieand S, Wolmark N, et al: Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17: 1349-1355, 1999 21. Haller DG, Catalano PJ, Macdonald JS, et al: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV): Adjuvant therapy for colon cancer: five year final report of INT-0089. Proc Am Soc Clin Oncol 17: 256a, 1998 (abstr 982)
22.
Zalcberg JR, Siderov J, Simes J: The role of 5-fluorouracil dose in the adjuvant therapy of colorectal cancer: The Australasian Gastrointestinal Trials Group. Ann Oncol 7: 41-46, 1996 23. Russell AH, Tong D, Dawson LE, et al: Adenocarcinoma of the proximal colon: Sites of initial dissemination and patterns of recurrence following surgery alone. Cancer 53: 360-367, 1984[Medline] 24. Phillips RKS, Hittinger R, Blesovsky L, et al: Local recurrence following [lsquo]curative[rsquo] surgery for large bowel cancer: I. The overall picture. Br J Surg 71: 12-16, 1984[Medline] 25. Hernanz F, Revuelta S, Redondo C, et al: Colorectal adenocarcinoma: Quality of the assessment of lymph node metastases. Dis Colon Rectum 37: 373-377, 1994[Medline] 26. Willett CG, Tepper JE, Cohen AM, et al: Failure patterns following curative resection of colonic carcinoma. Ann Surg 200: 685-690, 1984[Medline] 27. Safi F, Link KH, Beger HG: Is follow-up of colorectal cancer patients worthwhile? Dis Colon Rectum 36: 636-644, 1993[Medline] 28. Savarese DM, Gordon J, Smith TW, et al: Cerebral demyelination syndrome in a patient treated with 5-fluorouracil and levamisole. Cancer 77: 387-394, 1996[Medline]
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Zaniboni A: Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: Impact on disease-free survival and overall survival. J Clin Oncol 15: 2432-2441, 1997 30. Hartung G, Queißer W, Diezler P, et al: Adjuvant chemotherapy with 5-fluorouracil and folinic acid in colorectal cancer: Evaluation of toxicity. Onkologie 19: 62-67, 1996 Submitted May 22, 2000; accepted November 21, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.1, allowing reinclusion of parameters with a P value less than .05. The 
2 or the Mann-Whitney U test was used to detect between-group differences with regard to categorical or ordinal parameters, respectively. All analyses were performed on an intention-to-treat basis. 
