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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 1819-1825 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.169 Phase III Southwest Oncology Group 9415/Intergroup 0153 Randomized Trial of Fluorouracil, Leucovorin, and Levamisole Versus Fluorouracil Continuous Infusion and Levamisole for Adjuvant Treatment of Stage III and High-Risk Stage II Colon CancerFrom the Cancer Institute of New Jersey, New Brunswick, NJ; Southwest Oncology Group Statistical Center; Puget Sound Oncology Consortium, Seattle, WA; University of Illinois College of Medicine at Peoria, Peoria, IL; University of Pennsylvania Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; University of North Carolina at Chapel Hill, Chapel Hill, NC; The University of Texas Health Science Center, San Antonio, TX; and St Vincent's Comprehensive Cancer Center, New York, NY Address reprint requests to Southwest Oncology Group (SWOG-9415), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org
PURPOSE: Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer. PATIENTS AND METHODS: After surgery, patients were randomly assigned to CIFU 250 mg/m2/d for 56 days every 9 weeks for three cycles or FU 425 mg/m2 and LV 20 mg/m2 daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS). RESULTS: The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively. CONCLUSION: CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.
Colorectal cancer is the second leading cause of cancer mortality in the United States. In 2004, it was estimated that there were approximately 146,900 new cases and 56,700 deaths from colorectal cancer.1 Approximately 80% of patients present with cancer that is deemed resectable.1 The 5-year survival rate after surgery alone for stage II disease is approximately 72% to 90%; for stage III disease, the 5-year survival rate disease is approximately 50% to 60%.2-7 Multiple cooperative group trials of adjuvant therapy, in the 10 years preceding initiation of this study, had shown consistent benefit for fluorouracil (FU) -based treatment.8-10 In Intergroup (INT) study 0035, the study most recently published before this trial's initiation, both disease-free and overall survival benefit were shown for FU plus levamisole compared with surgery alone for stage III disease. For patients with node-positive cancers, the progression-free survival was 44% in patients with no additional therapy, 45% for levamisole alone, and 61% in those receiving FU plus levamisole.11 In the follow-up study, INT-0089, this FU plus levamisole regimen was compared with two different regimens of bolus FU plus leucovorin (FU/LV) and bolus FU/LV plus levamisole. While awaiting the mature results of the latter study, we chose to ask whether FU, administered by an infusion rather than bolus injection, would be superior in the adjuvant treatment of high-risk colon cancer. FU delivered by continuous infusion has long been considered a less toxic and effective alternative to bolus FU or FU/LV for the treatment of colorectal cancer.12-15 Continuous infusion FU, though uniquely associated with hand-foot syndrome, is less myelosuppressive than bolus therapy.16 A meta-analysis comparing infusional and bolus therapy in the treatment of metastatic colorectal cancer determined that the response frequency for infusional therapy was higher, and that the duration of response and survival was slightly longer with infusional compared with bolus FU.15 In addition, a prior adjuvant study had assessed the utility of continuous-infusion FU in patients with resected rectal cancer. Patients received either bolus or continuous-infusion FU concurrent with radiotherapy and were also randomly assigned to FU alone or FU with semustine before and after radiotherapy. Patients treated with continuous-infusion FU had a lower relapse rate (37% v 47%) and higher survival (70% v 60%) compared with patients treated with bolus FU. Local control was not different between the two FU regimens.17 The results of this last study suggested that continuous-infusion FU might have increased benefit compared with bolus therapy in the eradication of micrometastases. Because of this potential for better outcome in the setting of micrometastatic disease, the Southwest Oncology Group coordinated study INT-0153, which was developed to determine if continuous-infusion FU plus levamisole would decrease recurrence and improve overall survival compared with FU/LV plus levamisole in high-risk colon cancer. Levamisole was included in both arms because in the mid-1990s, this drug was still deemed to be a component of standard therapy.5 The original dosing of continuous-infusion FU had been well studied in metastatic disease at 300 mg/m2/d.12 Because hand-foot syndrome and stomatitis were common adverse effects with such protracted treatment and because the treatment goal of this trial was to deliver 24 weeks of therapy with only two mandated breaks of 1 week each, a slightly lower dose (250 mg/m2/d) was chosen, combined with levamisole. A pilot study of this combination was completed at the University of Southern California (Los Angeles, CA) and at Wayne State University (Detroit, MI), and acceptable tolerance was demonstrated.18 FU/LV plus levamisole, one arm of INT-0089, was chosen as the control arm of this trial because it was expected to be at least equivalent in activity to the original FU plus levamisole schedule.
Eligibility Criteria Patients must have had histologic proof of adenocarcinoma of the colon and undergone complete resection of the primary tumor without gross or microscopic evidence of residual disease. All known tumor had to be resected en bloc. The entire tumor had to be above the peritoneal reflection. Surgical margins had to be more than 5 cm, although this requirement was subsequently revised to 5 cm as documented by the surgeon and/or 2.5 cm as documented by pathologic examination. Patients were eligible if they had stage II disease (TNM T3-4a, N0, M0) with total or near-total bowel obstruction or perforation, or stage III disease (TNM T1-4a, N1-3, M0). N3 defined lymph nodes along a named vascular trunk or metastasis to apical nodes as defined by the surgeon. There could be no evidence of distant metastasis as determined by the surgeon at operation and by chest radiographs. Computed tomography scan or ultrasound of the liver was encouraged but not required. Full evaluation of the colon and rectum by colonoscopy or by sigmoidoscopy with barium enema was required to exclude other synchronous, unresected primary cancers. These requirements were subsequently amended to permit intraoperative assessment of the remaining colon by the surgeon. Patients had to have evidence of adequate organ function as measured by Southwest Oncology Group performance status 0 to 2, bilirubin  2x institutional upper limits of normal (IULN), AST 2x IULN, alkaline phosphatase 2x IULN, and serum creatinine 2x IULN; white blood count more than 3,500/µL; and platelets  institutional lower limit of normal. Patients may not have had a prior malignancy within the preceding 5 years, except for resected basal cell or squamous cell skin cancer, in situ cervical cancer, or stage I colon cancer. Patient registration had to have occurred between days 21 to 35 after definitive surgery. All patients signed informed consent forms. Institutional review board approval was required.
Treatment Venous access was established using a venous access device selected by the investigator. Because of the increased risk of thrombosis, anticoagulation was recommended. Either unfractionated heparin 10,000 U was coadministered, mixed with each week's total FU dose, or warfarin 1 to 2 mg/d orally was prescribed. Platelets and coagulation parameters were monitored weekly for 4 weeks and then monthly. A warfarin dose was chosen to be small enough not to alter PT. Heparin was to be halted if there was evidence of heparin-induced thrombocytopenia. Dose reductions were mandated for myelosuppression, diarrhea, stomatitis, and hand-foot syndrome caused by FU. Granulocyte colony-stimulating factor could be used for persistent grade 3 to 4 neutropenia. Patients also could have dose reduction or cessation for levamisole toxicities, including fever, rash, nausea, or encephalopathy. Treatment in both arms of the study was to be given for 6 months, with early discontinuation for unfavorable toxicity or early disease progression. After completion of chemotherapy, patients were re-evaluated by history and physical examination, hematology and chemistry panel, and chest x-ray at 9 and 12 months, and then every 6 months up to 5 years after treatment initiation. There were no mandated post-treatment carcinoembryonic antigen assessments or computed tomography scans; these were done at the discretion of the treating physician. Colonoscopy was recommended at intervals of 6 and 12 months, and then yearly or less frequently at the discretion of the investigator. Patients were observed for disease recurrence, disease-free survival, and survival.
Statistical Considerations The study was monitored by the Southwest Oncology Group Data and Safety Monitoring Committee (DSMC). The protocol specified two formal interim analyses, timed to occur when approximately one third of the expected deaths would have occurred (expected when two thirds of the patients had been accrued), and approximately 1.5 years after the end of accrual when two thirds of the expected deaths had occurred. In 1998, the DSMC approved a modification of the accrual goal to 1,500 patients, based on slower than expected accrual and because the necessary number of events could be attained with fewer patients. This decision was based solely on accrual patterns and not on interim study results. The three stratification factors, T stage (three levels), N stage (three levels), and time from surgery (two levels), were included as covariates in the Cox regression analysis. This model allowed for assessment of other covariates, such as race or ethnicity, sex, and age. All eligible patients were included in the analysis of survival and disease-free survival by their assigned treatment according to the intent-to-treat principle. Patients who refused treatment were not included in toxicity analyses.
Between December 1994 and December 1999, 1,135 patients were registered. In addition to the Southwest Oncology Group, patients were accrued from the Eastern Cooperative Oncology Group, the Cancer and Leukemia Group B, and the North Central Cancer Treatment Group. In October 1999, the first formal interim analysis of this study was reviewed by the DSMC, which recommended early termination. This decision was based on the finding that the alternative hypothesis of a 35% improvement in survival could be rejected based on protocol-specified stopping rules. Of the 1,135 patients, 195 were ineligible; 64 were ineligible because of insufficient prestudy documentation. The majority of the remaining ineligible patients did not have the correct disease stage, had disease below the peritoneal reflection, received inadequate prestudy surgery, or lacked pretreatment bowel assessment by sigmoidoscopy and barium enema or colonoscopy. Twenty eligible patients had major protocol violations. Fifteen patients never started protocol treatment, and one patient who was randomly assigned to the bolus FU arm received 2 days on the continuous-infusion arm instead. These patients are not included in the toxicity analysis. Of the other four major deviations, three were for patients who had incorrect doses of FU, and one patient received levamisole every other day. Patient characteristics are listed in Table 1. There is a slightly higher percentage of males in the continuous-infusion arm than the bolus arm, although this difference is not statistically significant. The majority of patients were non-Hispanic whites. Most patients had T3 disease, and 15% were node negative. The majority of patients were registered between 29 and 35 days after surgery.
Nine hundred nineteen patients were assessable for toxicity assessment (Table 2). There were four treatment-related deaths among the eligible patients. In the bolus arm, one patient died as a result of a bowel infection, and one died as a result of sepsis. On the continuous-infusion arm, one patient developed leukemia, and one patient had a deep vein thrombosis.
Overall, at least one grade 4 toxicity occurred in 22% of the patients, with 39% in the bolus arm, and 5% in the continuous-infusion arm. The majority of the grade 4 toxicity in the bolus arm was hematologic. Febrile grade 3 to 4 neutropenia occurred in 14 patients with bolus FU/LV and was associated with two deaths. There was no grade 3 to 4 neutropenia with infusional FU. Grade 4 gastrointestinal toxicity was three-fold more common in the FU/LV arm than in the continuous-infusion arm and consisted of stomatitis and pharyngitis or diarrhea. Grade 3 to 4 thrombosis occurred in 10 patients receiving FU/LV and in 16 patients receiving continuous-infusion FU, with one additional patient dying as a result of complications of a clot. Thrombosis was usually related to the catheter for patients receiving continuous-infusion FU. Grade 2 hand-foot syndrome occurred in 35% and grade 3 hand-foot syndrome occurred in 7% of patients receiving continuous-infusion FU compared with 3% and less than 1% with bolus FU/LV. Seventy-one percent of patients completed protocol treatment as planned. Fifteen patients refused any protocol treatment after random assignment, and an additional 15 patients refused to continue after beginning treatment. Despite the greater number of grade 4 toxicities experienced on the bolus arm, twice as many patients (106 v 64) discontinued treatment early because of adverse effects in the continuous-infusion arm compared with the bolus arm. On the basis of comments noted on the data flow sheets, many patients receiving continuous-infusion FU complained, not necessarily about high-grade toxicities, but about the logistics of pump therapy, pump malfunctions, clotting episodes, neck pain that seemed to be related to the catheter, and chronic hand-foot syndrome. Median follow-up time was 6.52 years. The overall 5-year survival was 70% (95% CI, 66% to 74%) for the FU/LV plus levamisole arm, and 69% (95% CI, 64% to 73%) for the continuous-infusion FU plus levamisole arm (Fig 1). The corresponding 5-year disease-free survival was 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively (Fig 2). The estimated hazard ratio for survival based on the Cox model was 1.16 (95% CI, 0.93 to 1.44; P = .18) for continuous-infusion FU plus levamisole compared with FU/LV plus levamisole. The estimated hazard ratio for disease-free survival was 1.05 (95% CI, 0.86 to 1.3; P = .65).
We also assessed potential treatment interactions by race and sex. We were unable to detect any differences in survival between males and females, nor between races or ethnicities, nor any treatment interactions with these variables. Given the lack of differences between the treatment arms, we explored the impact of nodal involvement and of time to treatment initiation on the outcome of patients enrolled onto this trial. The estimate of 5-year disease-free survival was 78%, 67%, and 47% for N0, N1, and N2-3 patients, respectively. Five-year overall survival was 83%, 74%, and 55%, respectively (Fig 3). There were no differences in disease-free survival and overall survival based on time of treatment registration between those who registered at days 21 to 28 versus days 29 to 35.
This adjuvant study was based on the observation that continuous-infusion FU by was less toxic and had a somewhat higher level of activity than FU/LV in patients with metastatic disease. It was hypothesized that this higher level of response in metastatic disease might be amplified in the adjuvant setting. The study suffered from a high ineligibility rate (17.2%). Patients were excluded for a number of reasons. Colonoscopy or sigmoidoscopy with barium enema was mandated to exclude synchronous colon or rectal primary tumors. Adequate surgical margins were similarly mandated. No part of the tumor could be below the peritoneal reflection. When these criteria were not fulfilled or could not be documented, registered patients were deemed ineligible. There were no differences in the results of this study in an analysis that included all patients, regardless of eligibility. However, this high ineligibility rate should prompt greater awareness of the surgical guidelines for the management of colorectal cancer patients and the need for documentation in clinical trials.19 No overall benefit was demonstrated for continuous infusion in this adjuvant treatment. The dose chosen for the continuous infusion was 250 mg/m2/d rather than the standard 300 mg/m2/d to avoid toxicity-related interruption of therapy. This lower dose may have compromised maximum benefit. However, compliance was difficult, even at this dose, because hand-foot syndrome occurred frequently, as did thrombotic episodes related to catheters. Ultimately, twice as many patients withdrew from the continuous-infusion arm as from the FU/LV plus levamisole arm. Saini et al20 compared short-course continuous-infusion FU to 6 months of bolus therapy, with a somewhat different outcome. Patients with stages II and III colon or rectal cancer were randomly assigned to either six cycles of FU 425 mg/m2 and LV 20 mg/m2 days 1 through 5 every 4 weeks for 6 months, or to continuous-infusion FU 300 mg/m2/d for 12 weeks. Patients with rectal cancer could also receive radiation therapy, given concurrently with bolus therapy or sequentially, after the 12-week infusional regimen was completed. Patients in the infusion arm received an additional 5 weeks of FU 200 mg/m2/d concurrent with the radiotherapy. Among the 692 eligible patients, 68% had colon cancer and 31% had rectal cancer; 42% had stage II and 57% had stage III cancers. With a median follow-up of 19.8 months, the overall survival was not statistically different. The projected 3-year relapse-free survival favored continuous-infusion FU (80% v 69%, respectively; log-rank P = .023). The subsets of stage II patients and those with rectal cancer had lower relapse rates after treatment with infusional FU compared with bolus-treated patients, although this difference was only statistically significant for patients with rectal cancer. The study by Saini et al20 included a wider variety of patients than in our study and demonstrated benefit in patient subtypes specifically excluded from our study. However, it is noteworthy that benefit from FU infusion was achieved with only 12 weeks of therapy. We chose to include levamisole in both arms of our study because at the time of this study's initiation, levamisole in combination with FU was a standard of care.11 Ultimately, INT-0089 demonstrated that FU/LV plus levamisole was not superior to FU/LV alone.21 The QUASAR trial in the United Kingdom also compared the treatments of FU with either low- or high-dose LV and with or without levamisole in the adjuvant treatment of colorectal cancer. Again, no benefit was seen for the addition of levamisole. We can now conclude that levamisole does not add benefit to FU/LV regimens.22 The results of our study also emphasize the poor survival of patients with four or more positive nodes. These poor results are consistent with the extensive review by Greene et al23 of 50,000 patients. Among patients treated from 1987 through 1993, the 5-year survival for patients with four or more positive nodes with surgery alone was approximately 22% and improved to only 33% with adjuvant therapy. Similarly, data from Gill et al7 demonstrate 5-year disease-free survivals of 9% to 28% for patients with five or more positive nodes without additional treatment and only 5-year disease-free survivals of 21% to 44% with adjuvant therapy. This clearly is a population requiring special attention. Trials of more intensive chemotherapy or chemoradiotherapy might be considered.24 Perhaps more rigorous staging, for example with positron emission tomography scanning, should be used in this high-risk group in which, if macrometastases were demonstrated, stage and treatment would be affected.25 Data based on the control arms of previous adjuvant studies would suggest that approximately 75% to 90% of stage II and approximately 50% of stage III patients will not experience disease recurrence after appropriate surgical resection and therefore do not require adjuvant therapy. Conversely, 15% to 20% of stage II and 30% of stage III patients develop progressive disease despite having received currently available adjuvant therapy.2-5 Thus, only an estimated one third or fewer of patients treated postoperatively benefit from adjuvant FU or FU/LV treatments.3,7,26 Intensive effort has been directed toward identified subsets with higher and lower risks, beyond TNM status. We await testing and confirmation of newer methodology with genetic profiling to help identify those at risk and those likely to benefit from adjuvant therapy.27,28 FU/LV has been used for adjuvant therapy for at least a decade, but it still is effective only for a portion of the currently defined at-risk population. Where are the next improvements in drug treatment? Andre et al29 have demonstrated in a study of 905 patients with stage II and III colon cancer that LV as a 2-hour infusion plus FU 400 mg/m2 bolus and 600 mg/m2 22-hour continuous infusion on days 1 and 2 every 2 weeks (LVFU2) was less toxic than bolus FU/LV given daily for 5 days each month, with similar disease-free and overall survival. However, the small size of the study precludes any definitive conclusion about the relative survival benefit. The oral thymidylate synthase inhibitors are additional alternatives. Capecitabine is already approved for use in colorectal metastatic disease when fluoropyrimidine single-agent therapy is chosen.30,31 The X-ACT adjuvant study randomly assigned 1,987 resected stage III patients to 24 weeks of FU/LV daily for 5 days each month or to capecitabine 1,250 mg/m2 bid days 1 through 14 every 21 days. Preliminary data suggest that capecitabine appears to be equivalent with regard to disease-free survival, with a median follow-up of 3.8 years.32 In National Surgical Adjuvant Breast and Bowel Project C-06, oral uracil plus tegafur UFT and LV taken daily for 28 of every 35 days for five cycles was compared with three cycles of FU/LV weekly for 6 of 8 weeks as the treatment of stages II and III carcinoma of the colon. Oral uracil plus tegafur and LV achieved equivalent disease-free and overall survival compared with FU/LV.33 The two newer chemotherapy drugs, oxaliplatin and irinotecan, have undergone their initial assessments. Irinotecan in combination with bolus FU/LV did not increase the duration of failure-free survival or overall survival compared with FU/LV alone in stage III colon cancer, and was more toxic.34 In contrast, the MOSAIC trial, comparing 12 cycles of LVFU2 to LVFU2 with the addition of oxaliplatin 85 mg/m2 (FOLFOX) accrued 2,248 stage II and III patients between October 1998 and January 2001. With short follow-up, the 3-year disease-free survival for stage II patients was 84% for LVFU2 and 87% for FOLFOX, whereas for stage III patients, the 3-year disease-free survival was 65% and 72%, respectively.35 Thus, the preliminary results of the MOSAIC trial suggest an incremental benefit in disease-free survival with the addition of oxaliplatin. We look forward to the assessment in the adjuvant setting of the newly available monoclonal antibodies, cetuximab and bevacizumab; both have demonstrated activity in the treatment of metastatic colorectal cancer.36-38 The North Central Cancer Treatment Group is now comparing an adjuvant trial of irinotecan plus FU infusion and LV to FOLFOX to sequential FOLFOX followed by irinotecan plus FU infusion and LV. All patients are also randomly assigned to no biologic treatment or cetuximab. The National Surgical Adjuvant Breast and Bowel Project is studying FOLFOX, with and without bevacizumab, for the adjuvant treatment of stages II and III colon cancer.
The authors indicated no potential conflicts of interest.
Supported in part by the following public health service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA15488, CA21115, CA32291, CA25224, CA22433, CA35090, CA20319, CA58416, CA45807, CA45450, CA12644, CA35119, CA58861, CA04919, CA63845, CA45377, CA46282, CA76429, CA35192, CA63844, CA58348, CA58882, CA76447, CA67575, CA04920, CA37981, CA27057, CA14028, CA58686, CA63850, CA46441, CA12213, CA58723, CA35281, CA46368, CA35262, CA58658, CA45560, CA42777, CA35261, CA67663, CA46113, CA28862, CA35178, CA13612, CA35996, CA76462, CA58415, CA35176, CA45461, 35128, CA52654, CA35431, CA16385, CA46136, CA68183, and CA74647. Presented in part at the 36th Annual Meeting of the American Cancer Society, New Orleans, LA, May 20-23, 2000. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
