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Originally published as JCO Early Release 10.1200/JCO.2004.01.029 on July 12 2004 © 2004 American Society of Clinical Oncology. Phase III Study of Adjuvant Chemotherapy and Radiation Therapy Compared With Chemotherapy Alone in the Surgical Adjuvant Treatment of Colon Cancer: Results of Intergroup Protocol 0130From the North Central Cancer Treatment Group; Mayo Clinic, Rochester, MN; Radiation Therapy Oncology Group, Philadelphia, PA; Missouri Valley Cancer Consortium, Omaha, NE; Southwest Oncology Group, San Antonio, TX; National Cancer Institute of Canada—Clinical Trials Group, Kingston, Ontario, Canada; Eastern Cooperative Oncology Group, Boston, MA; Cancer and Leukemia Group B, Chicago, IL Address reprint requests to James A. Martenson, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: jmartenson{at}mayo.edu
PURPOSE: Some patients with colon cancer have a high risk of local recurrence postoperatively. This trial was undertaken to determine whether radiation therapy added to an adjuvant chemotherapy regimen improves outcome in high-risk patients. PATIENTS AND METHODS: Patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or with T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive fluorouracil and levamisole therapy with or without radiation therapy. Patients who received chemotherapy and radiation therapy (chemoRT) received 45 to 50.4 Gy in 25 to 28 fractions beginning 28 days after starting chemotherapy. Patient enrollment was terminated because of slow accrual after 222 patients enrolled (original goal was 700 patients); 187 patients were assessable.
RESULTS: Overall 5-year survival was 62% for chemotherapy patients and 58% for chemoRT patients (P > .50); 5-year disease-free survival was 51% for both groups (P > .50). Toxicity ( CONCLUSION: Patients who received chemotherapy or chemoRT had similar overall survival and disease-free survival. Toxicity was higher among chemoRT patients. These results must be interpreted with caution because of the high number of ineligible patients and the limited power of the study to detect potentially meaningful differences.
Studies of patients who have had a second operation1 and autopsy findings2-4 after a potentially curative operation for colon cancer suggest that the risk of local-regional recurrence is substantial for patients with tumor adherence to surrounding structures or with involvement of regional lymph nodes. The Minnesota reoperation series, for example, documented a 37% incidence of local-regional recurrence among 41 patients with tumor penetration through the wall of the colon, and involvement of lymph nodes. Among 24 patients with tumor adherence to, or invasion of, surrounding structures, the incidence of local-regional recurrence was 67%. In an analysis of autopsy findings from the University of Washington, local recurrence was documented among 69% of patients who had tumor adherence to, or invasion of, surrounding structures at the time of their initial operation, and among 30% of patients with involvement of regional lymph nodes and penetration of tumor through the bowel wall.2 Analyses of patterns of recurrence in clinical series support the hypothesis that the risk of local-regional recurrence is potentially clinically significant in specific subgroups of patients after curative resection for colon cancer.5-9 At University Hospital in Boston, for example, in 33% of the patients with cecal cancer and tumor adherence or invasion of surrounding structures, local-regional recurrence developed after a potentially curative operation. Similarly, local-regional recurrence developed in 33% of the patients with regional lymph node involvement and tumor penetration through the large bowel.7 At Massachusetts General Hospital, local-regional recurrence was observed after a potentially curative operation in at least 30% of the patients with tumor adherence to surrounding structures or with tumor penetration through the bowel wall and involvement of regional lymph nodes.5 Prospective and retrospective studies of patients with large bowel cancer have suggested a possible role for radiation therapy in selected patients with colon cancer. Several randomized clinical trials with rectal cancer patients who have tumor penetration through the bowel (T3 or T4) or positive nodes have shown that, when compared with no adjuvant treatment or radiation therapy alone, postoperative pelvic radiation therapy in combination with fluorouracil-based chemotherapy improved freedom from local recurrence, disease-free survival, and overall survival.10-13 More recently, results from a phase III clinical trial have suggested that the major contribution of radiation therapy to the postoperative adjuvant treatment of rectal cancer may be improved local control rather than improved survival.14 Retrospective studies of patients with colon cancer have suggested that the potential role of adjuvant radiation therapy should be evaluated in a prospective randomized clinical trial.15-22 A nonrandomized study from Massachusetts General Hospital, for example, suggested that postoperative adjuvant radiation therapy might result in decreased local recurrence for patients with resected colon cancer who had tumor adherence to surrounding structures or tumor penetration through the bowel wall and involvement of regional lymph nodes. In the subgroup of patients with tumor adherence to surrounding structures and positive nodes, for example, the local control rate was 47% with surgery alone and 69% with surgery and postoperative radiation therapy.19 A landmark phase III study provided the first unequivocal evidence that systemic therapy using fluorouracil and levamisole improved survival among patients with completely resected lymph node–positive colon cancer.23,24 After publication of this study, the use of adjuvant fluorouracil and levamisole became the standard of care for this group of patients. Many oncologists also began to give adjuvant chemotherapy to patients with node-negative colon cancer who had unfavorable prognoses, such as patients with nondiploid tumors, high proliferative indexes,25 or unfavorable clinical features such as obstruction.26 The availability of effective adjuvant systemic therapy created an opportunity to design a study of selected patients with colon cancer that had a high risk of local recurrence, comparing postoperative fluorouracil and levamisole therapy with fluorouracil, levamisole, and radiation therapy (chemoRT). Before initiation of this study, it was determined that chemoRT could be safely administered.27
The primary goal of this study was to determine whether the addition of radiation therapy to an adjuvant chemotherapy regimen would improve survival among patients considered at high risk of local-regional recurrence after complete resection of colon cancer. Secondary objectives included evaluation of disease-free survival, patterns of recurrence, and toxicity.
To be eligible for this study, patients had to have a history of completely resected colon cancer that was at high risk of local-regional recurrence. Specifically, patients were eligible if they met the following criteria: (1) The tumor was at any site in the colon with adherence to, or invasion of, surrounding structures, as determined by either the surgeon or the pathologist (tumors designated as T4 only on the basis of peritoneal invasion were not included), or the tumor involved the ascending or descending colon with penetration through the wall of the colon (T3) and involvement of metastatic regional lymph nodes. For T3 node-positive patients with ascending or descending colon cancer, the protocol initially required evidence of gross tumor penetration through the entire bowel wall, or invasion more than 2 mm beyond the bowel wall. In December 1994, the protocol was modified to allow all T3 node-positive ascending or descending colon cancer patients to participate without regard to the degree of tumor penetration beyond the bowel wall. (2) Their surgical procedure occurred within the previous 21 to 36 days, there were no active complications, and the patient was receiving adequate oral nutrition without significant nausea or vomiting. (3) Laboratory test results were as follows: WBC count Ineligible patients included those with incompletely resected tumor, those with coexistent medical conditions that would preclude protocol therapy, those with a history of prior radiation therapy to the abdomen or pelvis, or those who had previous chemotherapy or levamisole therapy. Additional contraindications included age younger than 18 years, an Eastern Cooperative Oncology Group performance status of 2 to 4, current pregnancy or lactation, a history of invasive cancer in the preceding 5 years, or distant metastases or metastatically involved lymph nodes along a named vascular trunk (N3 nodes). Patients were stratified by tumor extent (T3 or T4) and number of lymph nodes involved (0, 1-3, or > 3) and were then randomly assigned to receive either fluorouracil and levamisole23,24 or chemoRT. Protocol therapy for all patients included administration of levamisole at a dosage of 50 mg orally three times daily for 3 days, to be repeated every 14 days for 1 year. Therapy with fluorouracil 450 mg/m2 administered as an intravenous bolus on 5 consecutive days was initiated concurrently with the first day of levamisole therapy. Patients who were assigned to receive chemotherapy without radiation therapy received weekly doses of fluorouracil 450 mg/m2 intravenously, beginning 28 days after the first dose of chemotherapy, until therapy had been given for a total of 1 year. Patients assigned to receive chemoRT began radiation therapy 28 days after the first fluorouracil dose. A total dose of 45 Gy in 25 fractions was given to fields designed to encompass the preoperative tumor volume and regional lymph nodes, including the adjacent para-aortic or pelvic lymph nodes. An additional three fractions of 1.8 Gy each were given to the preoperative tumor volume if all small bowel could be excluded from this boost field. The protocol required that two-thirds of the liver receive less than 30 Gy, that at least two-thirds of one kidney receive less than 20 Gy (as assessed by excretory urography done at simulation or CT scan), and that the maximal dose to the spinal cord be less than 50 Gy. Systemic treatment during radiation therapy consisted of fluorouracil 450 mg/m2 given intravenously on the days of the first, second, and third radiation fractions, and again on the days of the 23rd, 24th, and 25th radiation fractions. During radiation therapy, levamisole 50 mg by mouth was given three times daily for 3 days approximately every 2 weeks, beginning with the day of the first, 11th, and 23rd radiation fractions. Weekly treatment with fluorouracil was initiated 28 days after completion of radiation therapy according to the same schedule and dose as the weekly treatment administered to the patients assigned to receive chemotherapy alone. As with those patients, treatment continued until therapy had been given for a total of 1 year. According to the protocol, patients were evaluated at 12, 15, 18, and 21 months after initiation of treatment. Subsequent to this, patients were followed up every 6 months, until the patient had been followed up for 5 years, and then annually until the patient had been followed up for 8 years. Routine evaluations at each follow-up visit included history, physical examination, complete blood count, liver function tests, and chest radiography. A barium enema or colonoscopy was required at 18, 38, and 60 months after study entry. CT scans of the abdomen and pelvis at 12 months after study entry and at the time of tumor recurrence were considered optional, to be done at the discretion of the patient's physician. Enrollment began in October 1992 with an accrual goal of 700 patients, which was estimated to provide 82% power for detecting a 33% decrease in the death rate. Accrual was lower than expected, and in March 1996, the goal was decreased to 400 patients, which, by extending the duration of follow-up, would have provided 81% power to detect a 33% decrease in the death rate. Enrollment ended in December 1996 because of slow accrual. Of the 222 accrued patients, 187 were eligible and assessable. The resulting study had 80% power to detect a 75% decrease in the death rate for patients assigned to the chemoRT group, using a one-sided log-rank test with a significance level of .05. Survival was defined as the time from random assignment to death or last contact. The disease-free interval was defined as the time from random assignment to the date of the earliest of the following: last evaluation for disease status if no recurrence was evident, recurrence, or death. Patients who withdrew before the study treatment or who were declared ineligible (n = 35) were excluded from the primary analyses of study end points, including disease-free survival, overall survival, and toxicity.
Frequency tables and summary statistics (eg, mean and median) were used to describe the distributions of patient characteristics and toxicity. Parametric and
Between October 16, 1992, and December 17, 1996, a total of 222 patients were enrolled onto this study. Subsequent review determined that 34 patients were ineligible (Table 1), and one patient withdrew before receiving any protocol treatment. The remaining 187 patients were the subject of the primary analyses of study end points. Information about pathologic radial margin status was requested but was not reliably provided and was not used in the determination of protocol eligibility. Six of the 94 eligible patients assigned to receive chemoRT refused radiation therapy, but all 94 patients were included in the primary analysis of the chemoRT arm results. No significant differences in baseline characteristics were observed between the treatment arms (Table 2).
The median duration of follow-up of living patients was 6.6 years. Overall survival (Fig 1) and disease-free survival (Fig 2) were similar for the two treatment arms (P > .50 for both analyses). The 5-year disease-free survival was 52% for the chemotherapy-only arm and 51% for the chemoRT arm. Overall survival at 5 years was 58% for the chemoRT patients and 62% for patients assigned to receive only chemotherapy. Table 3 presents the estimated 5-year rates and hazard ratios for overall and disease-free survival by treatment arm. In a secondary analysis of all 222 patients entered in the study, results were substantially similar (data not shown). Of the 187 eligible patients, 18 in each study arm experienced local recurrence (defined as recurrence at the initial site of disease progression).
Results of an analysis of prognostic factors are summarized in Table 4. In univariate analyses, an increased number of positive lymph nodes was the only factor significantly associated with reduced survival, with hazard ratios for overall survival of 1.7 (95% CI, 1.0 to 2.8) for patients with one to three positive nodes and 2.7 (95% CI, 1.5 to 4.7) for patients with more than three positive nodes, as compared with patients with 0 positive nodes (P = .003; Table 4). A test for interaction between the assigned treatment and each of the protocol-specified stratification factors did not show a differential treatment effect between patient subsets and survival, disease-free survival, or local control (data not shown).
There were two treatment-related deaths, one in each arm of the study. A patient assigned to the chemotherapy group died of sepsis after experiencing severe leukopenia. A patient assigned to the chemoRT group died of liver failure, which was believed to be caused by fluourouracil and levamisole. A summary of toxicity that was grade 3 or worse is provided in Table 5. A significantly higher rate of toxicity (  grade 3) was observed in patients assigned to receive chemoRT than in those assigned to receive chemotherapy (54% v 42%; P = .04). Most of this difference was attributable to a significantly higher rate of hematologic toxicity in the patients assigned to the chemoRT group (23% v 11%; P = .01). No significant difference was observed in symptomatic, nonhematologic toxicity between the two groups (44% for chemoRT v 35% for chemotherapy; P = .26). The most common nonhematologic toxicity was diarrhea, which occurred in 20% of patients assigned to receive chemoRT and 13% of those assigned to receive chemotherapy (P = .17).
Because of the large number of ineligible patients, a secondary analysis of toxicity ( grade 3) was performed for all 222 patients in this study. In this analysis, there was no significant difference in overall toxicity between the two arms (57% for chemoRT v 42% for chemotherapy; P = .09). Symptomatic nonhematologic toxicity was observed in 37% of the patients assigned to receive chemoRT and in 32% of the patients assigned to receive chemotherapy (P = .48). A significantly higher rate of hematologic toxicity ( grade 3) was observed in the patients assigned to receive chemoRT than in the patients assigned to receive chemotherapy (23% v 12%; P = .04). Review of the radiation therapy quality assurance for this study showed that the dosimetry and radiation fields, as defined by the marked tumor volume on the simulation film and protocol guidelines, were satisfactory. One critical caveat is related to the method of determining the tumor volume to guide radiation therapy planning. Ideally, radiopaque clips would be positioned around the surgical bed and preoperative radiologic imaging (ie, barium enema or abdominal pelvic CT scan) would be used to accurately define the tumor volume, thus aiding in the design of the radiation fields. Although use of clips was encouraged in the protocol, clip placement was performed in only 18 (19%) of 94 patients. Preoperative radiologic imaging (ie, barium enema or abdominal and pelvic CT scan) was used to facilitate treatment planning for 45 patients (48%). For 17 patients (18%), the tumor volume was defined by clinical means (by review with the surgeon or by review of operative reports without clips or imaging). It was unclear whether preoperative radiologic imaging was obtained for 14 of the patients.
Survival, disease-free survival, and local control were similar in this study for patients assigned to receive chemoRT as compared with those assigned to receive chemotherapy alone. Although this clinical trial did not meet its accrual objective, it is one of the largest studies of adjuvant radiation therapy in colon cancer. The number of patients in most previous studies has been 40 to 150.15-19,21,22,30 Only the retrospective study from Massachusetts General Hospital, which described results in 203 patients, was larger.20 Our study is also the only published randomized clinical trial that addresses the role of adjuvant radiation therapy for colon cancer. The results of this study must be interpreted with caution because of several limitations. The study fell dramatically short of its accrual objective and therefore lacked the power to detect potentially clinically significant differences in outcome. With 187 eligible patients, the study had 80% power to detect a 75% decrease in the death rate for patients treated with chemoRT. This degree of improvement in the death rate is more than has been demonstrated in any positive surgical adjuvant trial of chemotherapy for colon cancer.23,24,31-35 The 95% CI for the hazard ratio for overall survival, comparing chemotherapy with chemoRT, is large (0.7 to 1.7). Because of this, a possible meaningful advantage for chemoRT cannot be excluded. Radiopaque surgical clips to guide the design of radiation therapy fields were used in a minority of patients, and preoperative imaging was not available for most patients. Because of the lack of reliable information about radial surgical margins, it is virtually certain that some patients with microscopic residual disease were included in this study. The local control data must be interpreted with caution because CT scans were not required for patient follow-up. The large number of ineligible patients indicates that physicians often had difficulty selecting appropriate patients for this trial. For these reasons, the results of this study cannot be considered definitive.
Our study did demonstrate significant differences in toxicity between patients treated with chemoRT and those treated with chemotherapy alone (Table 5). Overall, significantly more chemoRT patients than chemotherapy patients experienced toxicity of grade 3 or worse (54% v 42%; P = .04). Most of the overall differences in toxicity between the two treatment arms can be accounted for by the higher rate of leukopenia observed among patients treated with chemoRT than among those treated with chemotherapy alone (21% v 10%; P = .02). There was no significant difference in overall symptomatic nonhematologic toxicity ( In conclusion, similar outcomes were observed between patients treated with chemoRT and patients treated with chemotherapy alone. Our study demonstrated potential issues that may be encountered in clinical trials of adjuvant therapy, which require close cooperation among surgeons, pathologists, medical oncologists, and radiation oncologists. It is possible that a different result might have been observed with a larger number of patients if preoperative imaging had been consistently available; if radiopaque clips had been consistently placed at the time of surgery to guide design of radiation therapy fields; and if more reliable pathologic details had been available to better identify appropriate patients for consideration of adjuvant radiation therapy. Our experience suggests that any future investigation of adjuvant radiation therapy for patients with colon cancer should be considered only at institutions with a high degree of commitment and expertise in multiple specialties, so that patient selection criteria and treatment parameters can be optimized. One possible area for future investigation would be the role of preoperative chemotherapy and radiation therapy in patients found to have unresectable disease at the time of initial diagnosis.
Additional participating institutions include Iowa Oncology Research Association Community Clinical Oncology Program, Des Moines, IA (Roscoe F. Morton, MD); Rapid City Regional Oncology Group, Rapid City, SD (Larry P. Ebbert, MD); Medcenter One Health Systems, Mid Dakota Clinic, Bismarck, ND (Ferdinand Addo, MD); Geisinger Clinical Oncology Program, Danville, PA (Suresh Nair, MD); CentreCare Clinic, St Cloud, MN (Harold E. Windschitl, MD); and Wichita Community Clinical Oncology Program, Wichita, KS (Shaker R. Dakhil, MD).
The authors indicated no potential conflicts of interest.
Supported in part by Public Health Service grants CA 25224, CA 37404, CA 15083, and CA 63849; CA 21661, CA 37422, and CA 32115 (Radiation Therapy Oncology Group); CA 32102 and CA 22433 (Southwest Oncology Group); CA 21115 (Eastern Cooperative Oncology Group); CA 31946 and CA 774400 (Cancer and Leukemia Group B); and a grant from the National Cancer Institute of Canada (NCIC 4448). Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15, 1999. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests were used to test for significant differences in patient characteristics and toxicity by treatment arm. The Kaplan-Meier method
