Vol. 4, 935-939, April 1998 Clinical Cancer Research 935 3 The abbreviations used are: 5-FU, 5-fluorouracil; NCCTG, North Central Cancer Treatment Group: KPS. Karnofsky performance status. Prospective Randomized Trial of 5-Fluorouracil versus 5-Fluorouracil plus Levamisole in the Treatment of Metastatic Colorectal Cancer: A Hoosier Oncology Group Trial’ Malik T. Bandealy, Ren#{233}Gonin, Patrick J. Loehrer, Frank Monaco, and Lawrence H. Einhorn2 Divisions of Hematology/Oncology [M. T. B., P. J. L., L. H. E.] and Biostatistics [R. G.], Indiana University, and Hoosier Oncology Group [F. M.], Indianapolis, Indiana 46208-4646 ABSTRACT The purpose of this study was to compare the objective response rate, duration of remission, and survival of 5-flu- orouracil (5-FU) versus those of 5-FU plus levamisole in metastatic colorectal cancer using the same dose and sched- ule of these agents as in the North Central Cancer Treat- ment Group and intergroup studies of adjuvant therapy. Patients with no prior history of chemotherapy for meta- static disease were entered on this Hoosier Oncology Group randomized Phase III trial. Patients were stratified by Karnofsky performance status and presence or absence of liver metastases. They were randomized to receive 450 mg/rn2 5-FU i.v. for 5 days followed by 15 mg/kg i.v. weekly (arm 1) or the same dose of 5-FU plus levamisole 50 mg p.o. every 8 h for 3 days every 2 weeks (arm 2). The duration of treatment for both arms was 26 weeks. From April 1990 to March 1995, 199 patients were entered. One hundred eighty-two patients, 91 in each arm, were fully evaluable. The response rates were 12% on arm 1 and 13% on arm 2. The median duration of response was 18 weeks on both arms. The median survival was 48 weeks on arm 1 and 41 weeks on arm 2 (P = 0.20). This study failed to show any improvement in survival, response, or duration of remission with the addition of levamisole to 5-FU in the treatment of metastatic colorectal cancer. Received 10/2/97; revised 1/22/98; accepted 1/26/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This work was supported in part by National Cancer Institute Grant 2R35CA 39844- 1 1 and the Walther Cancer Institute and was presented in part at the Annual Meeting of the American Society of Clinical Oncology, held May 1 8-21 , 1996 in Philadelphia, PA. 2 To whom requests for reprints should be addressed, at Hoosier On- cobogy Group, 3202 North Meridian Street, Indianapolis, IN 46208- 4646. INTRODUCTION Colorectal carcinoma is the second leading cause of cancer death in the United States. In 1996, it was estimated that 1 3 1 ,200 new cases of colorectal cancer would be diagnosed and that 54,900 men and women would die from this disease ( 1). Heidelberger and colleagues (2) at the University of Wis- consin first reported clinical trials with 5-FU3 in 1957. Since then, 5-FU has been the mainstay of therapy for metastatic coborectal cancer. However, the results with single agent 5-FU reveal only a 10-20% objective response rate, with no impact on survival. Attempts to improve upon this have lead to devel- opment of various regimens using biochemical modulation of 5-FU, based upon laboratory and preclinical data. The most popular of these has been the combination of 5-FU and leucov- orin, based upon a sound preclinical pharmacological rationale. There have been various schedules of 5-FU in combination with leucovorin that have demonstrated encouraging results in Phase II trials (3). Subsequently, these have led to Phase III studies in metastatic coborectal cancer evaluating 5-FU (as the control arm) compared to 5-FU plus leucovorin. There has been a lack of congruence in the results from these disparate Phase III studies (4). Review of the 12 published randomized studies comparing 5-FU with 5-FU plus leucovorin reveals that the consistently higher response rate of the combination regimen has failed to translate into significant survival advantage (5-16). These studies all used 5-FU given by iv. push. Only three studies have shown marginal survival advantage for the combi- nation over 5-FU alone ( 1 1 , 1 3, 15). In fact, in one study, the benefit was significant only for patients with nonmeasurable and, hence, probably low volume disease ( 1 1 ). Even a meta- analysis failed to show any significant improvement in survival with 5-FU plus leucovorin (17). Furthermore, combining 5-FU with other agents, such as cisplatin, methotrexate, PALA, and thymidine, has not improved the survival statistics in metastatic coborectal cancer ( 1 8 -20). Levamisole is a pure chemical that was first used as an antihelminthic drug and has documented immunomodulatory effects. Verhacgen et a!. (2 1 ) initially evaluated levamisole versus placebo in a very small patient population in surgically resected colon cancer and demonstrated a statistically signifi- cant survival advantage. The Western Cancer Study Group and the European Organization for Research and Treatment of Can- cer compared levamisole to placebo in the adjuvant setting and found no significant survival benefit (22, 23). on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/ 936 5-FU +/- Levamisole in Metastatic Colorectal Cancer The major interest in levamisole as adjuvant therapy of Duke’s B and C colon cancer is because of a positive NCCTG study (24) and a larger confirmatory intergroup study (25), both demonstrating a significant advantage for 5-FU plus levamisole over levamisole alone. However, this dose and schedule of 5-FU plus levamisole has never been adequately tested in metastatic disease. Surprisingly, there have been only three published Phase III studies of 5-FU plus levamisole in metastatic coborec- tal cancer. Borden et al. (26) at the University of Wisconsin published a positive study demonstrating a survival advantage for 5-FU plus levamisole, whereas the NCCTG study was neg- ative (20). However, neither of these studies these used the same dosage and schedule as in the successful adjuvant trials. The study by the Eastern Cooperative Oncology Group, published only in abstract form thus far, was also negative (27). The dose and schedule of 5-FU and levamisole in this trial were also different from those used in the adjuvant studies. There are few, if any, examples in oncology in which a regimen that provides a significant survival advantage in the adjuvant setting is not also effective in metastatic disease. Therefore, the Hoosier Oncology Group embarked upon this study evaluating 5-FU plus levamisole in previously untreated patients with metastatic colorectal cancer, using dosage and schedule of these agents that were identical to those in the adjuvant trials. PATIENTS AND METHODS All patients had histologically proven adenocarcinoma of the colon or rectum and had not received prior chemotherapy for metastatic disease. Patients may have had adjuvant therapy but not within the 6 months prior to registration. Patients with measurable as well as nonmeasurable disease were included. Measurable disease was defined as being bidimensionally meas- urable on physical or roentgenographic examination. Malignant hepatomegaly could be used as measurable disease if the liver edge was palpable at beast 5 cm below the costal margin at the right midclavicubar line or xiphoid on quiet respiration. The liver span should have been greater than 12 cm. All patients had a KPS of at least 50%, as well as adequate bone marrow reserve (absolute granubocyte count of 2,500 cells/mm3 and platelet count of 125,0004i.l). Patients were excluded if they had a history of prior malignancy, except squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix, unless they had been disease-free for at least 5 years. Pretreatment studies included complete history and physi- cal examination, complete blood count including WBC differ- ential and platelet counts, 1 2-channel sequential multiple anal- ysis, carcinoembryonic antigen measurement, chest X-ray, and abdominal computerized tomographic scan. During treatment, patients were evaluated by history and physical examination every 4 weeks, and radiographs were repeated every 8 weeks for tumor measurement. In addition, a complete blood count includ- ing WBC differential and platelet count was obtained every week. All patients provided written informed consent. Eligible patients were stratified by KPS (80-100 versus 50-70) and presence or absence of liver metastases. Patients were then randomized by telephone through the Hoosier Oncology Group office to receive 5-FU alone or 5-FU plus levamisole. 5-FU was administered at a dose of 450 mg/m2 by iv. push on days 1-5; thereafter, beginning on day 29, it was given weekly at 15 mg/kg by iv. push. This was identical for both arms. Patients randomized to the combination arm received 50 mg of levamisole p.o., every 8 h for 3 days, every 2 weeks. The total duration of therapy was 26 weeks. There was no dose escalation of 5-FU, and cross-over to 5-FU plus levamisole was not allowed. All patients with prior pelvic irradiation received a 25% reduction in the 5-FU dose initially. 5-FU was given as sched- uled if the WBC count was greater than 3000 cells/mm3, and platelet count was greater than 90,000/gil. If counts were below these levels, treatment was held until these levels were reached, and then it was initiated with 25% reduction in the 5-FU dose. If 5-FU was delayed, levamisole was concomitantly delayed, but its dose was not reduced. In cases of severe diarrhea or stomatitis lasting more than 3 days, granubocytopenic fever, or thrombocytopenia requiring platelet transfusion, the dose of 5-FU was reduced by 25% with no change in the bevamisole dose. A complete response was defined as complete disappear- ance of all objective evidence of disease. A partial response was defined as a decrease of 50% or more in the sum of products of diameters of measurable disease. When malignant hepatomeg- aly was used for tumor measurement, at least a 30% decrease in the sum of the measurements of the liver edge below the costal margin at the right midclavicular line and the xiphoid process was required for a PR. A decrease of less than 50% in the sum of product of diameters of measurable disease was considered stable disease provided no new lesions had appeared, and an increase of 25% or more or appearance of new lesions defined progression. Survival was measured from the date entered on study until death. Remission duration was measured from the date of doe- umented response until relapse. Patients who relapsed were treated at the investigator’s discretion. Statistical Considerations. Descriptive statistics are re- ported as frequencies, medians, and ranges. Grade 3/4 toxicities were compared between the two arms (5-Hi versus 5-FU + levamisole) using Fisher’s exact test (28). Survival was defined from date on study until date of death or date last known alive. Follow-up was the survival of all patients alive. The survival curve for each treatment arm was constructed using the Kaplan- Meier product limit method (29). Survival curves between the two treatment arms were compared with the log-rank test of survival (30). The association of treatment arm and survival, adjusting for the stratification factors, liver metastases and KPS, was assessed by the Wald x2 of Cox’s proportional hazards regression (31). All tests were two-sided. The intention-to-treat principle was used throughout. RESULTS From April 1990 through March 1995, 199 patients with metastatic adenocarcinoma of the colon or rectum were entered on this trial. Of the 99 patients randomized to 5-FU, 4 patients never received treatment, 1 was lost to follow-up, and 3 had on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/ Table 1 Patient characteristics ap 0.067. bp 0.0146. C p treatment-related only. a PD, progressive disease; PSR, poor subjective response (�20% fall in KPS, 10% weight loss, and increased pain without radiographic documentation of progression). b Not rebated to disease or therapy. Clinical Cancer Research 937 5-Hi 5-Hi + levamisole No. of patients registered 99 100 Sex (male/female) 62/37 53/47 Median age (yr) 66 65 Range (yr) 20-86 27-87 KPS 50-70 24 25 80-100 75 75 Prior pelvic Ri”' 10 11 Metastatic sites Liver 79 80 Lung 28 22 Other 22 25 a RT, radiotherapy. Table 2 Treatment compliance 5-FU 5-nj + levamisole (n94) (n�96) Completed treatment 32 27 Reasons for discontinuation PD” 45 48 PSR 4 1 Toxicity 7 12 Noncompliance 4 5 Death” 2 4 inadequate response data. One hundred patients were random- ized to 5-Hi plus levamisole, of whom 4 never received treat- ment and S had inadequate response data. In all, 182 patients were fully evaluable for survival and response, and another 8 patients were evaluable for survival only. Patient characteristics are shown in Table 1. Patients on the two arms were well matched for age, KPS, presence or absence of liver metastases, and prior pelvic radiotherapy. Thirty-two patients on the 5-FU arm and 27 on the 5-FU plus levamisole arm completed 26 weeks of treatment. Reasons for discontinuation of therapy are listed in Table 2. The most frequent reason for early termination of chemotherapy was secondary to tumor progression during therapy. Toxicity. The toxicity data are shown in Table 3. This table reflects the worst grade of toxicity experienced by each patient at any time while in the study. The higher incidence of grade 3/4 diarrhea in the 5-FU plus levamisole arm was statis- tically significant (P = 0.0146), whereas the difference in the incidence of grade 3/4 granulocytopenia between the two arms did not reach statistical significance (P = 0.067). There were no treatment-related deaths on the 5-FU arm, whereas there were four on the combination arm. Response and Survival. There were 23 objective re- sponses in 1 82 fully evaluable patients. There was one complete response on each arm. Overall, the response rate was 12% (95% CI = 6-21%) on the 5-FU arm and 13% (95% CI = 7-22%) on the 5-Ri plus levamisole arm. The median duration of response Table 3 Toxicity (grade 3/4) Percentage of patients 5-FU 5-Hi + levamisole Anemia 4 1 Granulocytopenia” 13 24 Thrombocytopenia 0 2 Nausea S S Vomiting 6 3 Diarrhea” 8 21 Stomatitis 5 7 Infection 2 5 Fever 2 1 Neurological 1 6 Death’ 0 4 on both arms was 18 weeks. Thirty-eight patients on the 5-Hi arm and 25 patients on the combination arm had stable disease. The median time to progression was 1 8 weeks on the 5-Hi arm and 13 weeks on the 5-Hi plus levamisole arm (P - 0.06). Median survival was 48 weeks on the 5-Hi arm and 41 weeks on the 5-Hi plus levamisole arm (Fig. 1). Survival times on the two arms were not significantly different by the log-rank test (P = 0.20). In the Cox proportional hazards regression, the Wald x2 was 1.968 (P = 0.16; 1 degree of freedom) for treatment arm, adjusting for the stratification factors, liver me- tastases and KPS. At the time of analysis of this data, 1 1 patients on the 5-Hi arm and 3 on the combination arm were alive. DISCUSSION One of the basic principles of medical oncology is that the use of a regimen to improve the surgical cure rate in a malig- nancy is preceded by documented efficacy in advanced disease. However, the choice of 5-Hi plus levamisole in the adjuvant NCCTG trial was quite empirical (24). This dose and schedule of these agents had never been adequately tested in metastatic coborectal cancer. The University of Wisconsin randomized study of 5-Hi versus 5-Hi plus levamisole showed a statistically significant advantage for the combination (26). However, the dosage and schedule of these agents was different from that used in the successful adjuvant trials. Furthermore, only 19 of 72 patients on this study had measurable disease. Adjustment by a Cox regression model for the influence of measurable disease re- duced the significance of treatment difference. The NCCTG study in metastatic coborectal cancer was a 5-arm trial testing 5-Hi against various combinations with 5-FU and included a 5-Hi plus levamisole arm (20). Again, the dosage and schedule were different from those used in their subsequent adjuvant study. This study failed to demonstrate superiority of any of the combination arms over 5-Hi alone. Remarkably, 5-Hi in this study had a response rate of 30%, which is unusually high for 5-Hi as a single agent in metastatic coborectal cancer. The Eastern Cooperative Oncology Group has reported a trial of 5-Hi versus 5-Hi plus levamisole in meta- static colorectal cancer in patients with nonmeasurabbe disease on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/ Log Rank Test: p = 0.20 median 48 41 938 5-FU +/- Levamisole in Metastatic Colorectal Cancer a 0 I.0 0.8 0.6 0.4 0.2 0.0 Survival in Weeks arm cnsr death tot -5-FU 11 83 94 5-FU+Levamisole 3 93 96 Fig. I Survival. and found no benefit for the combination (27). However, this study has been reported in abstract form only, and the doses are different from those used in the NCCTG (24) and intergroup (25) studies. Therefore, in the adjuvant setting, the success of the 5-Hi plus levamisole regimen in the NCCTG trial (24) was quite surprising and bed to some skepticism. However, the results of the larger intergroup study (25) established 5-Hi plus levamisole as standard adjuvant therapy in completely resected stage III colorectal cancer. It is unusual for a regimen to prolong survival in the adjuvant setting and have no substantive activity in metastatic disease. This trial included patients with metastatic colorectal cancer, most of whom had good performance status. Both of the patient groups were well matched. The combination of 5-FU and levamisole failed to demonstrate any superiority over 5-FU alone in terms of response rate, duration of remission, or sur- vival. Another interesting aspect of this trial is the toxicity of 5-Hi plus levamisole. In prior studies in coborectal cancer, levamisole has not been shown to have significant hematolog- ical toxicity, and only minor nonhematological toxicities such as mild nausea, stomatitis, and diarrhea have been reported. Treat- ment-related deaths were rare in these studies. Even trials that have tested the 5-Hi plus levamisole combination have not reported any increase in the usual 5-Hi toxicity with the com- bination. Longr#{233}eet al. (32), in their studies of adjuvant therapy in Duke’s B and C coborectal cancer, found a higher incidence of grade III and iv. granulocytopenia when levamisole was added to 5-Hi. In our study, the incidence of grade 3/4 diarrhea was significantly higher in the 5-FU plus levamisole arm, and there was a trend toward higher incidence of grade 3/4 granu- locytopenia as well. Treatment compliance was, however, the same as for the 5-Hi arm. This study indirectly raises questions about the role of levamisole in adjuvant therapy of colon cancer. There have been speculations that levamisole has no role at all and that the successful adjuvant studies demonstrate the effectiveness of more intense administration of 5-FU in properly selected pa- tients (33). The NCCTG and intergroup studies of adjuvant therapy compared 5-Hi plus levamisole to levamisole alone and did not include a 5-Hi alone arm (24, 25). More recently, the National Surgical Adjuvant Breast and Bowel Project reported the results of their adjuvant trial comparing 5-Hi plus leucov- orin versus 5-Hi plus levamisole versus 5-Hi plus leucovorin plus levamisole (34). The 5-Hi plus leucovorin arm was ad- ministered in 42-day cycles for six courses, whereas the levami- sole containing arms were administered for a period of 1 year. There was a statistically significant advantage for 5-FU plus leucovorin over 5-Hi plus levamisole in terms of disease-free (P < 0.05) and overall (P < 0.05) survival. The addition of levamisole did not improve the results of 5-Hi plus leucovorin. 300 Two other trials evaluated 5-Hi plus levamisole. The NCCTG evaluated 5-FU/levamisole (6 months versus 12 months) versus 5-FU/leucovorin/levamisole (6 months versus 12 months) and demonstrated that 6 months of 5-Hi/levamisole was inferior to 6 months of 5-Hilleucovorinllevamisole (35). The Eastern Cooperative Oncology Group evaluated several different regimens, including high versus low dose leucovorin plus 5-Hi and 5-FU/levamisole and 5-Hillevamisolelleucovo- rim. Six months of 5-Hi + leucovorin was equivalent, if not superior to, 12 months of 5-Hi + levamisole, and the addition of levamisole to 5-Hi + leucovorin did not provide any addi- tional benefit (36). In conclusion, this cooperative group failed to demonstrate any advantage to the addition of levamisole to 5-Hi in the treatment of metastatic colorectal cancer. The role, if any, of levamisole in Duke’s C colorectal cancer is further questioned by this negative study in metastatic disease. APPENDIX Study Participants: Arnett Clinic, Lafayette, IN; Ball Memorial Hospital, Muncie, IN; Community Hospitals, Indianapolis, IN; Consultants in Blood Disorders and Cancer, Louisville, KY; Lewis Domke, M.D., Merrillville, IN; Juan Correa, M.D., Terre Haute, IN; Ray Drasga, M.D., Merrillville, IN; Elkhart Clinic, Elkhart, IN; Edward Fox, M.D., Evansville, IN; Fort Wayne Hematology/Oncology, Fort Wayne, IN; Galesburg Clinic, Galesburg, IL; Georgia Hematology/Oncology, Atlanta, GA; Alan Grosbach, M.D., Shreveport, LA; Indiana University, Indianapolis, IN; Johnson Memorial Hospital, Franklin, IN; Thomas Lutz, M.D., Evansville, IN; Memorial Hospital, South Bend, IN; Methodist Hospital, Indianapolis, IN; St. Vincent’s hospital, Indianapolis, IN; and Washington University, St. Louis, MO. REFERENCES 1. Parker, S. L., Tong, T., Bolden, S., and Wingo, P. A. Cancer statistics, 1996. CA Cancer J. Clin., 46: 5-27, 1996. on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/ Clinical Cancer Research 939 2. Heidelberger, C., Chaudhari, N. K., Danneberg, P., et al. Fluorinated pyrimidine. A new class of tumor-inhibitory compounds. Nature (Lond.), 179: 663-666, 1957. 3. Grem, J. L., Hoth, D. F., Hamilton, J. M., et al. Overview of current status and future direction of clinical trials with 5-fluorouracil in com- bination with folinic acid. Cancer Treat. Rep., 71: 1249-1264, 1987. 4. Einhorn, L. H. Improvements in 5-Hi chemotherapy? J. Clin. Oncol., 7: 1377-1379, 1989. 5. Nobile, M. T., Rosso, R., Sertoli, M. R., et al. Randomized compar- ison of weekly bolus 5-fluorouracil with or without leucovorin in metastatic coborectal carcinoma. Eur. J. Cancer, 28A: 1823-1827, 1992. 6. Petrelli, N., Douglass, H. 0., Herrera, L., et a!. The modulation of fluorouracil with leucovorin in metastatic coborectal carcinoma: a pro- spective randomized phase III trial. J. Clin. Oncol., 7: 1419-1426, 1989. 7. Petrelli, N., Herrera, L., Rustum, Y., Burke, P., Creaven, P., Stulc, J., Emrich, L. J., and Mittelman, A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracib and methotrexate in previously untreated patients with advanced colorectal carcinoma. J. Clin. Oncol., 5: 1559-1565, 1987. 8. Valone, F. H., Friedman, M. A., Wittlinger, P. S., Drakes, T., Eisenberg, P. D., Malec, M., Hannigan, J. F., and Brown, B. W., Jr. Treatment of patients with advanced colorectal carcinomas with flu- orouracil alone, high dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group. J. Clin. Oncol., 7: 1427-1436, 1989. 9. Di Costanzo, F., Bartolucci, R., Calabresi, F., Sofra, M., Marzola, M., Belsanti, V., Boni, C., and Bacchi, M., Fluorouracil-alone versus high-dose folinic acid and fluorouracil in advanced coborectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann. Oncol., 3: 371-376, 1992. 10. Labianca, R., Pancera. G., Aitini, E., et al. Folinic acid + 5- fluorouracil versus equidose 5-Hi in advanced colorectal cancer. Phase Ill study of “GISCAD” (Italian Group for the Study of Digestive Tract Cancer). Ann. Oncol., 2: 673-679, 1991. 11. Poon, M. A., O’Connell, M. J., Moertel, C. G., et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced coborectal carci- noma. J. Clin. Oncol., 7: 1407-1418, 1989. 12. Doroshow, J. H., Multhauf, P., Leong, L., et al. Prospective ran- domized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable coborectal cancer in patients previously unexposed to chem- otherapy. J. Clin. Oncol., 8: 491-501, 1990. 13. Erlichman, C., Fine, S., Wong, A., and Elhakim, T. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J. Clin. Oncol., 6: 469-475, 1988. 14. Martoni, A., Cricca, A., Guaraldi, M., Covizzi, M., Farris, A., and Pannuti, F. Weekly regimen of 5-Hi versus 5-Hi + intermediate dose folimc acid in the treatment of advanced coborectal cancer. Anticancer Res., 12: 607-612, 1992. 15. Petrioli, R., Lorenzi, M., Aquino, A., et al. Treatment of advanced colorectal cancer with high-dose intensity folinic acid and 5-fluorouracil plus supportive care. Eur. J. Cancer, 31A: 2105-2108, 1995. 16. Steinke, B., Gunther, E., Hirschmann, W. D., Sondern, W., Konic- zek, K. H., Wander, H. E., Natt, F., Wagner, T., Hinrichs, H. F., and Werdier, D. Fluorouracil versus folinic acid/fluorouracil in advanced colorectal cancer: preliminary results of a randomized trial. Semin. Oncol., 19: 141-147, 1992. 17. The Advanced Coborectal Cancer Meta-Analysis Project. Modula- tion of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J. Clin. Oncol., 10: 896-903, 1992. 18. Loehrer, P. J., Turner, S., Kubilis, P., Hui, S., Correa, J., Ansari, R., Stephens, D., Woodbum, R., and Meyers, S. A prospective randomized trial of fluorouracil versus fluorouracil plus cisplatin in the treatment of metastatic coborectal cancer: a Hoosier Oncology Group Trial. J. Clin. Oncob., 6: 642-648, 1988. 19. Labianca, R., Pancera, G., Cesana, B., et al. Cisplatin + 5-fluorou- racil versus 5-fluorouracil alone in advanced colorectal cancer: a ran- domized study. Eur. J. Cancer Clin. Oncol., 24: 1579-1581, 1988. 20. Buroker, 1. R., Moertel, C. G., Fleming, T. R., et al. A controlled evaluation of recent approaches to biochemical modulation or enhance- ment of 5-fluorouracil therapy in colorectal carcinoma. J. Clin. Oncob., 3: 1624-1631, 1985. 21. Verhaegen, H., DeCree, J., DeCook, W., et al. Levamisole therapy in patients with coborectal cancer. In: W. D. Terry and S. A. Rosenberg (eds.), Immunotherapy of Human Cancer, pp. 225-229. New York: Elsevier North Holland, 1982. 22. Chlebowski, R. T., Nystrom, S., Reynolds, R., et al. Long-term survival following levamisole or placebo adjuvant treatment of coborec- tab cancer: a Western Cancer Study group trial. Oncology, 45: 14 1-143, 1988. 23. Arnaud, J. P., Buyse, M., Nordlinger, B., Martin, F., Pector, J. C., Zeitoun, P., Adboff, A., and Duez, N. Adjuvant therapy of poor prog- nosis colon cancer with levamisole: results of an EORTC double-blind randomized clinical trial. Br. J. Surg., 76: 284-289, 1989. 24. Laurie, J. H., Moertel, C. G., Fleming, T. R., et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J. Clin. Oncol., 7: 1447- 1456, 1989. 25. Moertel, C. G., Fleming, T. R., Macdonald, J. S., et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann. Intern. Med., 122: 321-326, 1995. 26. Borden, E. C., Davis, T. E., Crowley, J. J., et al. Interim analysis of a trial of levamisole and 5-fluorouracil in metastatic colorectal carci- noma. In: W. D. Terry and S. A. Rosenberg (eds.), Immunotherapy of Human Cancer, pp. 231-235. New York: Elsevier North Holland, 1982. 27. Mansour, E. G., Cnaan, A., Davis, T., et al. Combined modality therapy following resection of coborectal carcinoma in patients with non-measurable intra-abdominal metastases. An ECOG study 3282. Proc. Am. Soc. Clin. Oncol. Annu. Meet., 9: 107, 1990. 28. Zar, J. H. Biostatistical Analysis (2nd ed), pp. 138-146, 290-395. Englewood Cliffs, NJ: Prentice-Hall, 1984. 29. Kaplan, E. L., and Meier, P. Nonparametric estimation from incom- plete observations. J. Am. Stat. Assoc., 53: 457-481, 1958. 30. Armitage, P., and Berry, G. Statistical Methods in Medical Re- search (2nd ed), pp. 427-433. Oxford: Blackwell Scientific Publica- tions, 1987. 31. Cox, D. R. Regression models and life-tables. J. R. Stat. Soc. B, 34: 187-220, 1972. 32. Longr#{233}e, L., Focan, C., Bury, J., Beauduin, M., Brohee, D., Du- vivier, A., Lecomte, M., Markiewicz, S., Vindevoghel, A., and Weerts, J. Levamisole adds granulocyte toxicity to 5-Hi based chemotherapies in adjuvant treatment of Dukes B-C coborectal cancer. A preliminary report. Anticancer Res., 15: 1561-1564, 1995. 33. Mayer, R. J. Does adjuvant therapy work in colon cancer? N. Engl. J. Med., 322: 399-401, 1990. 34. Wolmark, N., Rockett, H., Mamounas, E. P., et al. The relative efficacy of s-as + leucovorin, 5-Hi + levamisole, and 5-Hi + leucovorin + levamisole in patients with Duke’s B and C carcinoma of the colon: first report of NSABP C-04. Proc. Am. Soc. Clin. Oncol. Annu. Meet., 15: 205, 1996. 35. O’Connell, M. J., Laurie, J. A., Shepherd, L., et al. A prospective evaluation of chemotherapy duration and regimen as surgical adjuvant treatment for high risk colon cancer: a collaborative trial of the North Central Cancer Treatment Group and the National Cancer Institute of Canada Clinical Trials Group. Proc. Am. Soc. Clin. Oncol. Annu. Meet., 15: 209, 1996. 36. Haller, D. G., Catalona, P. J., MacDonald, J. S., and Mayer, R. J. Fluorouracil, leucovorin, and levamisole adjuvant therapy for colon cancer: four year results of INT-0089. Proc. Am. Soc. Clin. Oncol. Annu. Meet., 16: 265, 1997. on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/ 1998;4:935-939. Clin Cancer Res M T Bandealy, R Gonin, P J Loehrer, et al. colorectal cancer: a Hoosier Oncology Group trial. 5-fluorouracil plus levamisole in the treatment of metastatic Prospective randomized trial of 5-fluorouracil versus Updated version http://clincancerres.aacrjournals.org/content/4/4/935 Access the most recent version of this article at: E-mail alerts related to this article or journal.Sign up to receive free email-alerts Subscriptions Reprints and .pubs@aacr.orgDepartment at To order reprints of this article or to subscribe to the journal, contact the AACR Publications Permissions Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) .http://clincancerres.aacrjournals.org/content/4/4/935 To request permission to re-use all or part of this article, use this link on April 5, 2021. © 1998 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from http://clincancerres.aacrjournals.org/content/4/4/935 http://clincancerres.aacrjournals.org/cgi/alerts mailto:pubs@aacr.org http://clincancerres.aacrjournals.org/content/4/4/935 http://clincancerres.aacrjournals.org/