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Controlled Trial of Fluorouracil and Low-Dose Leucovorin Given for 6 Months as Postoperative Adjuvant Therapy for Colon Cancer By Michael J. O'Connell, James A. Mailliard, Michael J. Kahn, John S. Macdonald, Daniel G. Hailler, Robert J. Mayer, and Harry S. Wieand Purpose: The goal of this study was to determine the efficacy-of intensive-course fluorouracil (5FU) plus lowdose leucovorin given for 6 months following potentially curative resection of colon cancer. Patients and Methods: Three hundred seventeen patients with high-risk stage IIor stage IIIcolon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m 2) plus leucovorin (20 mg/m 2 ) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation. Results: The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant im- E XPERIMENTAL STUDIES from a variety of preclinical model tumor systems have established the ability of leucovorin to enhance the cytotoxicity of fluorouracil (5FU).' -3 Early controlled clinical trials demonstrated improved tumor response rates when the combination of 5FU and leucovorin, given in various dosage administration schedules, was compared with singleagent 5FU in patients with metastatic colorectal cancer. 4 5 Some of these studies also demonstrated short-term survival improvement with SFU/leucovorin4 '5 in the palliative treatment of metastatic colorectal cancer. With this background, a prospectively randomized clinical trial was initiated in 1988 to test the value of intensive-course 5FU combined with low-dose leucovorin as postoperative adjuvant therapy in patients with high-risk primary colon cancer. We desired to determine whether the use of this chemotherapy regimen, which had been shown to be more active than 5FU alone in patients with advanced disease, could improve long-term survival when provement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths. Conclusion: These results indicate that intensivecourse 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration. 1997 by American SoJ Clin Oncol 15:246-250. ciety of Clinical Oncology. given as adjuvant therapy in the minimal residual disease setting following surgical removal of the primary tumor. We elected to give chemotherapy for 6 months. As originally conceived, this study had an untreated control arm, since it had not been established that adjuvant chemotherapy was effective in patients with colon cancer when the trial was started. We believed that it was no longer appropriate to randomize high-risk colon cancer patients to observation without adjuvant chemotherapy when the emerging results of a national intergroup trial clearly demonstrated that relapse-free and overall survival were significantly improved with the use of 5FU plus levamisole given for 1 year following surgery. 9 Our trial was thus prematurely discontinued after the entry of 317 patients. The preliminary results of this study were reported at the American Society of Clinical Oncology Meeting in 1993.' ° This report presents the mature results of our clinical trial. PATIENTS AND METHODS Eligibility Criteria From the North Central Cancer Treatment Group, Rochester, MN. Submitted February 20. 1996; accepted June 25, 1996. Supported by thefollowing grantsfrom the National Cancer Institute, Bethesda, MD: U10 CA 25224 (North Central Cancer Treatment Group), U10 CA 32102 (Southwest Oncology Group), U10 CA 21115 (Eastern Cooperative Oncology Group), and U1O CA 31946 (Cancer and Leukemia Group B). Address reprint requests to Michael J. O'Connell, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; Email [email protected]. © 1997 by American Society of Clinical Oncology. 0732-183X/97/1501-0015$3.00/0 246 Patients must have had histologic proof of adenocarcinoma of the colon and have undergone complete resection of the primary tumor without gross or microscopic evidence of residual disease. All known tumor had to be resected en bloc. Only patients at high risk for tumor relapse following surgery were eligible, as indicated by one or more of the following features of the primary colon cancer: (1) regional lymph node metastases; (2) transmural penetration of the muscular wall of the bowel with evidence of bowel obstruction, perforation, adherence, or invasion of adjacent organ(s); and (3) regional peritoneal or mesenteric implants resected en bloc. The inferior margin of the tumor had to be above the peritoneal reflection. Patients had to be ambulatory and maintaining adequate oral nutri- Journal of Clinical Oncology, Vol 15, No 1 (January), 1997: pp 246-250 Downloaded from www.jco.org on July 24, 2005 . For personal use only. No other uses without permission. Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved. COLON CANCER SURGICAL ADJUVANT THERAPY tion; patients were randomized into the study between 21 and 30 days postoperatively. Informed consent was required. The following factors were contraindications to participating in this trial: WBC count less than 3,500/L, platelet count less than 100,000/giL, prior or concurrent radiation or chemotherapy for colon cancer, concurrent or previous second malignant disease within the preceding 3 years (except superficial squamous or basal cell skin cancer, or in situ carcinoma of the uterine cervix), pregnancy, or lactation. Patient Eligibility and Follow-Up Patients underwent a history and physical examination, complete blood cell count, and liver function tests at weeks 4. 8, 13, 18, and 23 during chemotherapy, or at weeks 13 and 23 if randomized to observation. Chest x-ray was performed at week 13, and proctoscopic examination and colon x-ray (or colonoscopy) were performed within the first 6 months for all patients. All patients were subsequently evaluated at 9 months, 12 months, and every 6 months to 5 years with a history and physical examination, complete blood cell count, liver function tests, and chest x-ray. Proctoscopic examination and colon x-ray (or colonoscopy) were performed annually. Testing for serum carcinoembryonic antigen (CEA) was optional. Chemotherapy Dosage Administration Schedule 5FU was given by rapid intravenous infusion (push) at a dose of 425 mg/m 2 /d for 5 consecutive days. Leucovorin was also given by rapid intravenous infusion at dose of 20 mg/m immediately preceding each dose of 5FU. Courses were repeated at 4 weeks, 8 weeks, and then every 5 weeks for a total of six cycles. Randomization Procedures Before randomization, patients were stratified according to the following criteria: extent of invasion by the primary tumor, presence or absence of intestinal obstruction, presence or absence of regional peritoneal metastases resected en bloc, and extent of regional lymph node metastases. Patients were then randomized to receive six courses of 5FU/ leucovorin chemotherapy, or to be monitored without the use of adjuvant chemotherapy. StatisticalMethods Statistical analyses were performed using the statistical language S-plus1 and SAS.' 2 Relapse-free and survival curves were calculated using standard Kaplan-Meier methodology." The log-rank statistic was used to compare survival distributions. 4 Proportional hazards models were used for all multivariate analyses 5 to identify factors significantly related to relapse and survival times. Factors were retained in the models if the corresponding estimates had a two-sided P value less than .05. To adjust for covariates when evaluating treatments, we forced the variable that indicated the patients' treatment regimens into the model and used a backward-selection regression method to identify which of the remaining covanates were significantly associated with the end point. RESULTS Administrative Data Three hundred seventeen patients entered the study between February 1988 and August 1989. Patients were 247 Table 1. Patient Characteristics Vaorable No. of patients Age, years Median Range %of patients Sex (male/female) Regional implants (yes/no) Obstruction* (yes/no) Extent of invasion Bowel wall Into or through serosa Perforation Adjacent organs-adhesion Adjacent organs-invasion Nodal involvement 0 1-4 >4 Surgery Alone Surgery + Chemotherapy 151 158 64.1 29.1-81.7 62.7 22 4-79.4 62/38 13/87 35/65 52/48 13/87 37/63 15 67 3 12 3 13 70 4 9 4 18 58 24 19 56 25 *Bowel obstruction determined by preoperative symptoms; or endoscopic, surgical, or pathologic findings indicating definite narrowing of bowel lumen and producing at least partial obstruction. entered from 17 individual institutions, including 106 from the North Central Cancer Treatment Group, 86 from the Southwest Oncology Group (SWOG), 70 from the Eastern Cooperative Oncology Group (ECOG), and 55 from Cancer and Leukemia Group B (CALGB). Eight patients (2.5%) were ineligible: five from the chemotherapy arm and three from the observation arm. Statistical analyses have used data from the 309 eligible patients. The median patient follow-up duration is 72 months, while 195 of 205 patients who are still alive have at least 4 years of follow-up evaluation. Baseline patient characteristics are listed in Table 1. There were no significant differences between the two groups. Tumor Relapse Among 309 eligible patients, 105 have relapsed: 62 of 151 (41%) in the control group and 43 of 158 (27%) in the chemotherapy group. The proportion of patients relapse-free at 5 years was 0.74 for those who received chemotherapy and 0.58 for those treated with surgery alone. These data provide strong evidence that chemotherapy patients had a significantly better time to relapse than control patients (Fig 1) as seen by the two-sided P values (.004 before adjusting for other covariates and .001 after adjusting for covariates). When the stratification factors plus sex and age were combined with treatment in a multivariate proportional hazards model, only age, extent of nodal involvement (zero, one to four, or > four), and whether the patient had regional implants (yes/no) re- Downloaded from www.jco.org on July 24, 2005 . For personal use only. No other uses without permission. Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved. O'CONNELL ET AL 248 100 - 80 a> a) C: It n=158 __ 60 - 40 - for other covariates and .01 after adjusting for covariates). When the stratification factors plus sex and age were combined with treatment in a multivariate proportional hazards model, only extent of nodal involvement and -- _ _, cc presence of regional implants were significantly associated with an increased risk of death. There were no significant interactions between treatment and any of the prognostic variables. The 95% confidence interval for the relative risk of death for control patients versus chemotherapy patients was 1.06 to 2.31 with no covariate adjustment and 1.12 to 2.45 after covariate adjustment. n=151 Surgery plus chemotherapy - - Surgery alone P values. Log-rank 0.004 Covanate mod el0001 20 - 1 2 3 4 6 5 Years since randomization Fig 1. Toxicity Time-to-relapse. sected en bloc were significantly associated with an increased risk of tumor relapse. Increased nodal involvement, the presence of regional implants, and older ages were significantly associated with an increased risk of relapse. There were no significant interactions between treatment and any of the prognostic variables. The 95% confidence interval for the relative risk of relapse for control patients versus chemotherapy patients was 1.19 to 2.60 with no covariate adjustment and 1.29 to 2.82 after covariate adjustment. Survival One hundred of 309 eligible patients have died: 60 of 151 (40%) in the control group and 44 of 158 (28%) in the chemotherapy group. The proportion of patients alive at 5 years was 0.74 for patients who received chemotherapy and 0.63 for patients treated with surgery alone. These data also provide strong evidence that chemotherapy patients had longer survival times than control patients (Fig 2) as seen by the two-sided P values (.02 before adjusting 100 80- ., 60_> 40- t--_ Surgery plus chemotherapy - - Surgery alone n=158 . -n= 151 There were no deaths associated with chemotherapy. Toxicities were generally tolerable and were manageable with reduction of 5FU dose on subsequent cycles. Table 2 lists the percentages of chemotherapy patients who experienced grade 3 or 4 toxicities. Table 3 lists the amount of 5FU chemotherapy actually administered, relative to the targeted dose, according to treatment cycle. DISCUSSION This study provides strong evidence that 6 months of postoperative adjuvant chemotherapy with intensivecourse 5FU combined with low-dose leucovorin can substantially reduce rates of tumor relapse and death in patients with high-risk colon cancer. This favorable outcome was observed with a regimen that had only a modest effect on short-term survival, and no impact whatsoever on long-term survival, in patients with metastatic colorectal cancer. 5 '16 A recent meta-analysis of clinical trials that used other dosage schedules of 5FU and leucovorin in combination for advanced colorectal cancer confirmed a significant improvement in tumor response rates, but no improvement in survival.'7 The 5FU/low-dose leucovorin regimen used in this study has been directly compared with two other schedules of 5FU/leucovorin in metastatic colorectal cancer, 6 ' 8 with no significant differences in treatment efficacy observed. Taken together, these data demonstrate that chemotherapy with definite but modest cytoreductive capability in colorectal cancer patients with a large tumor burden may be curative when applied in a minimal residual disease setting. P values: Log-rank 0 02 Covariate model 0.01 20- 0 Years randomizaton6 since Years since randomization Fig 2. Survival. 7 Table 2. Severe Chemotherapy Toxicities 8 Toxicity Grade 3 %} Stomatitis Diarrhea Leukopenia Nausea 33 20 14 7 Grade 4 (%1 Downloaded from www.jco.org on July 24, 2005 . For personal use only. No other uses without permission. Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved. 3 4 0 0 COLON CANCER SURGICAL ADJUVANT THERAPY 249 Table 3. 5FU Dose Administration as a Function of Ideal Full Dose Cycle No 1 2 3 4 5 6 No of Patients 157 146 142 141 138 134 5FU Dose Administered/ Target Median, %) 99 80 78 77 76 76 * PatientsReceiving 2 80% of Target 5FU Dose (%)' 95 51 44 36 31 35 *Numbers in these columns indicate the median percent of 5FU actually administered as a function of targeted dose for all patients beginning a given cycle of treatment, and the percent of patients receiving at least 80% of the targeted dose for that cycle, respectively. For example, 50% of 142 patients who received cycle 3 were given at least 78% of the target dose on that cycle, and 44% of these patients received at least 80% of the targeted 5FU dose. It is important to observe from this study that a significant improvement in outcome resulted from just six cycles of postoperative adjuvant chemotherapy in patients with colon cancer. Previous clinical trials have documented the effectiveness of 5FU plus levamisole given for 1 year,9 and weekly 5FU plus high-dose leucovorin (500 mg/m 2) given for I year."9 More recently, a pooled analysis of 1,526 patients from three separate randomized clinical trials of intensive-course 5FU (370 to 400 mg/m 2) plus leucovorin (200 mg/m 2) demonstrated significant improvement in event-free and overall survival with 6 months of adjuvant therapy.2 0 These data provide complementary evidence that administration of adjuvant chemotherapy with intensive-course 5FU/leucovorin regimens for only 6 months is sufficient to have a favorable impact on patient survival when used as postoperative adjuvant treatment for colon cancer. There were too few patients entered onto this study to allow definitive analyses of treatment effect according to stage. However, exploratory analyses of survival within node-positive and node-negative patients were undertaken. The majority of patients in our trial had evidence of regional lymph node metastases at the time of surgery (82%), and it was within this subgroup that the survival benefit of treatment with chemotherapy was most clearly seen (P = .06 unadjusted; .03 with covariate adjustment). There was a trend toward fewer deaths in the node-negative patients who received chemotherapy (three deaths among 30 patients) compared with those treated with surgery alone (seven deaths among 27 patients), although the difference in survival distributions was not statistically significant (P = .15 unadjusted; covariate modeling could not be appropriately performed in this small subset). The side effects associated with the intensive-course 5FU/low-dose leucovorin regimen were clinically tolerable and consisted primarily of stomatitis and diarrhea. The incidence and severity of stomatitis associated with 5FU-based chemotherapy has been demonstrated to be reduced through the use of oral ice chips given for 30 minutes at the time of 5FU administered by bolus injection.2 The routine application of this ancillary technique may help to reduce the dose-limiting side effect of this chemotherapy regimen. Intensive-course 5FU combined with low-dose leucovorin significantly improves relapse-free and overall survival in patients with high-risk colon cancer. It can be conveniently administered in the outpatient setting and is safe and clinically tolerable. It is also relatively inexpensive. The current cost for a 5-day course of treatment with this regimen, including chemotherapy drug charges and nursing administration fees, is $696 at the Mayo Clinic in Rochester, MN. An intergroup colon cancer surgical adjuvant study (INT-0089) conducted by ECOG, SWOG, and CALGB directly comparing the chemotherapy regimen used in this study with the same regimen plus levamisole, a weekly 5FU/high-dose leucovorin regimen, and a standard 5FU/ levamisole regimen is currently in the follow-up phase. This large multicenter trial will help to place the intensive-course 5FU/low-dose leucovorin regimen into further clinical perspective. REFERENCES 1. Keyomarsi K, Moran RG: Folinic acid augmentation of the effects of fluoropyrimidines on munne and human leukemic cells. Cancer Res 46:5229-5235, 1986 2. Rustum YM, Trave F, Zakrzewski SF, et al: Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin. NCI Monogr 5:165-170, 1987 3. Park J, Collins JM, Gazdar AF, et al: Enhancement of fluorinated pyrimidine-smduced cytotoxicity by leucovorin m human colorectal carcinoma cell lines. J Natl Cancer Inst 80:1560-1564, 1988 4. 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No other uses without permission. Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved. 250 O'CONNELL ET AL 8. Gastrointestinal Tumor Study Group: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III. J Clin Oncol 7:1419-1426. 1989 9. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352, 1990 10. O'Connell MJ, Mailliard J. Macdonald JS, et al: An intergroup trial of intensive course 5FU and low-dose leucovorin as surgical adjuvant therapy for high-risk colon cancer. Proc Am Soc Clin Oncol 12:190, 1993 (abstr) 11. Becker R, Chambers J, Wilks A: The New S Language. Wadsworth & Brooks/Cole, Pacific Grove, CA, 1988 12. SAS/STAT User's Guide. Version 6 ed, vol 2. Cary, NC, SAS Institute, 1990 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 14. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719748. 1959 15. Cox DR: Regression models and life-tables. J R Stat Soc B 34 187-220, 1972 16. Poon MA, O'Connell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967-1972, 1991 17. 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 18. Buroker TR, O'Connell MJ, Wieand, et al: Randomized comparison of two schedules of fluorouracil and leucovcrin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994 19. Wolmark N, Rockette H. Fisher B, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:18791887. 1993 20. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators: Efficacy of adjuvant fluorouracil and fohnic acid in colon cancer. Lancet 345:939-944, 1995 21. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of 5fluorouracil-lnduced mucositis by oral cryotherapy. J Clin Oncol 9:449-452, 1991 Downloaded from www.jco.org on July 24, 2005 . For personal use only. No other uses without permission. Copyright © 1997 by the American Society of Clinical Oncology. All rights reserved.