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© 2002 American Society for Clinical Oncology Adjuvant Therapy in Rectal Cancer: Analysis of Stage, Sex, and Local Control—Final Report of Intergroup 0114ByFrom the Department of Radiation Oncology, University of North Carolina, Chapel Hill, and Cancer and Leukemia Group B Statistical Office, Duke University Medical Center, Durham, NC; Mayo Clinic Cancer Center, Rochester, MN; Division of Hematology Oncology, Northwestern University, Chicago, IL; Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada; Radiation Oncology, Mayo Clinic, Scottsdale, AZ; Gastrointestinal Oncology Service, St Vincent’s CCC, New York, NY; and Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA. Address reprint requests to Joel E. Tepper, MD, Department of Radiation Oncology, Campus Box #7512, University of North Carolina, Chapel Hill, NC 27599-7512; email: tepper{at}radonc.unc.edu
PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.
ADJUVANT CHEMOTHERAPY and radiation therapy have been generally accepted in the United States and Canada as standard therapy for patients who have had surgical resection for an adenocarcinoma of the rectum with tumor extending through the muscularis propria (T3 or T4) or with nodal metastases.1 This adjuvant therapy has generally been given as initial fluorouracil (5-FU)-based chemotherapy followed by concurrent chemoradiation therapy and additional chemotherapy. There have been substantial changes in the surgery of rectal cancer in many centers. The blunt dissection often used in the past is now thought to be inadequate because it may not fully excise disease, both nodal and soft tissue, located in the mesorectum. Data from Enker et al,2 Heald et al,3 and others4-7 have suggested that the local failure rate is low in patients who have a formal total mesorectal excision (TME). This has made some investigators question the need for routine radiation therapy. Many chemotherapy regimens have been examined in the adjuvant therapy of rectal cancer, although virtually all have been based on 5-FU. Bolus 5-FU alone is now rarely used because the data in metastatic disease patients have suggested that other regimens are more effective.8-11 A previously reported gastrointestinal (GI) Intergroup trial of continuous-infusion 5-FU during radiation therapy in an attempt to maximize local control demonstrated a nonsignificant improvement in local tumor control but a statistically significant improvement in disease-free survival (DFS) and overall survival (OS) compared with bolus 5-FU.12 In 1990, the GI Intergroup initiated a trial of adjuvant chemoradiation therapy to examine the relative merits of several 5-FU based regimens. This study was designed before the results of the previously discussed continuous-infusion trial were available. Because there was much interest at the time in the combinations of 5-FU and leucovorin and 5-FU and levamisole, these combinations as well as the use of all three drugs were tested against bolus 5-FU alone, which was standard at that time. Initial results have been reported,13 and this study represents the final planned analysis, with an emphasis on long-term outcomes, impact of sex, and local control.
Eligibility Patients were eligible if they had adenocarcinoma of the rectum after a potentially curative resection of the primary tumor and regional lymph nodes with neither gross nor microscopic residual disease. The tumor had to have either extension of the primary tumor through the bowel wall or positive lymph nodes without evidence of distant metastatic disease (T3, T4, or N1 to N3, and M0). A tumor was considered to be a rectal cancer if a portion of the tumor was located below the peritoneal reflection or if the lower margin of the tumor was within 12 cm of the anal verge on endoscopy. All patients had to be older than 18 years of age, have a performance status (Zubrod) of 0 to 2, not pregnant or lactating, and have normal hematopoietic function. Exclusion criteria included previous radiation therapy to the pelvis, previous chemotherapy or immunotherapy, malignancy within 5 years, or other serious medical illnesses that would limit the ability of the patient to receive protocol therapy. Patients began therapy between 3 and 10 weeks after surgery. All institutions had appropriate institutional review board approval, and informed consent was obtained. All patients were to receive an initial two cycles of intravenous bolus 5-FU–based chemotherapy, followed by pelvic radiation therapy plus chemotherapy, then two more cycles of chemotherapy. The treatment schema has been fully described in an earlier report.
Chemotherapy Arm 2 The drug regimen for arm 2 was 5-FU 425 mg/m2/d and leucovorin 20 mg/m2/d, days 1 to 5 and 29 to 33. During radiation therapy, it was 5-FU 400 mg/m2/d and leucovorin 20 mg/m2/d for 4 days during weeks 1 and 5. After radiation therapy, the regimen was 5-FU 380 mg/m2/d and leucovorin 20 mg/m2/d for 5 consecutive days for two cycles. Arm 3 The drug regimen for arm 3 was 5-FU 450 mg/m2/d, days 1 to 5 and 29 to 33, and levamisole 50 mg tid for 3 days every 14 days for four cycles. During radiation therapy, it was 5-FU 500 mg/m2/d for 3 days during weeks 1 and 5. After radiation therapy, the regimen was 5-FU 400 mg/m2/d for 5 consecutive days for two cycles and levamisole 50 mg tid for 3 days every 14 days for four cycles. Arm 4 The drug regimen for arm 4 was 5-FU 425 mg/m2/d and leucovorin 20 mg/m2/d, days 1 to 5 and 29 to 33, plus levamisole 50 mg tid for 3 days every 14 days for four cycles. During radiation therapy, it was 5-FU 400 mg/m2/d with leucovorin 20 mg/m2/d for 4 days during weeks 1 and 5. After radiation therapy, the regimen was 5-FU 380 mg/m2/d and leucovorin 20 mg/m2/d for 5 consecutive days for two cycles plus levamisole 50 mg tid for 3 days every 14 days for four cycles. Doses of 5-FU were modified for all arms depending on the severity, type, and timing of the toxicity.
Radiation Therapy
A boost dose of 5.4 Gy in three fractions was given to a reduced field that encompassed, as a minimum, the tumor bed and adjacent lymph nodes with a margin of 2 cm. A second boost field of 3.6 Gy was given in two fractions to the tumor bed plus a margin of 2 cm if all small bowel could be excluded from the field. Radiation treatments were interrupted for GI or hematologic toxicity of
Follow-Up
Statistical Analysis Initially, a minimum accrual of 1,268 eligible patients was planned over a 4-year period. Subsequently, the protocol was amended to increase the sample size to a minimum of 1,668 eligible patients. For the outcomes of interest, the amended sample size yielded power in the range of 74% to 92% for a control group to treatment group proportional hazards ratio of 1.3:1 using a two-sided 0.06 level log-rank test. Interim analyses of the data were performed after approximately 25%, 50%, and 75% of the expected number of failures in the 5-FU–alone arm were observed. The study was activated August 10, 1990, and the last patient was registered on November 20, 1992. A dynamic balanced randomization scheme at the central data management center of the North Central Cancer Treatment Group was used to randomly assign patients to a treatment group. Patients were stratified according to type of operation (abdominal perineal resection v low anterior resection), extent of nodal involvement (none, one to three, or > three involved regional nodes), and extent of invasion of perirectal fat or adjacent structures (none, extension into perirectal fat, and adherence to or invasion of adjacent organs or structures). They were not specifically stratified into the high-risk and low-risk categories as defined in this article, although they were stratified by the T- and N-stage components of the risk categories.
Patient eligibility was reviewed by the study chair(s) for all patients. Study end points, including site of relapse, cause of death, and toxicity
A total of 1,792 patients were entered onto the study, and 1,695 were fully assessable. At the time of this analysis, the median follow-up of the survivors was 7.4 years. The OS and DFS were not statistically different among treatment groups, as shown in Figs 1 and 2. As expected, there was a significant difference in outcome by tumor stage. We were able to define a low-risk and high-risk patient group. The low-risk patients were those with T1-2N+ or T3N0 tumors, whereas the high-risk group had T3N+ and T4 tumors. The 5- and 7-year survival by grouping is illustrated in Table 1 (OS, relative risk [RR] = 2.1, P < .0001; DFS, RR = 2.0, P < .0001) and Figs 3 and 4. There was a continued decrease in both OS and DFS between 5 and 7 years. The OS decreased from 76% to 70% for the low-risk group between 5 and 7 years and from 55% to 45% in the high-risk group. Recurrence-free rates decreased to a lesser extent, which suggests that many of the deaths after 5 years are because of intercurrent disease.
Local recurrence did not vary by treatment type but did vary by disease stage. Patients in the low-risk group had a local failure rate of 9% at 5 years compared with 18% for patients in the high-risk group (RR = 2.2, P < .0001). Patients with T4 disease had the highest rate of local failure of 24% at 5 years. Overall, the local failure rate was 14% at 5 years and 17% at 7 years. These are larger figures than have been reported in recent studies after adjuvant chemoradiation therapy of rectal cancer. We also evaluated the impact of sex on outcome. DFS and local recurrence did not differ significantly by sex. However, sex was significant for OS with a RR of 1.2 (P = .03), with males having a worse outcome. There was no interaction between sex and stage. As previously reported, toxicity was more severe in females, with 81% of females who experienced a grade 3 to 5 toxicity compared with 69% of males (P < .001). This suggests that females received a biologically greater treatment intensity of chemotherapy or radiation therapy as measured by the end point of toxicity. There was an interaction between sex and treatment modality. Females who received the most aggressive regimen with 5-FU, leucovorin, levamisole, and radiation therapy experienced a significantly worse outcome compared with the control arm of 5-FU alone (Fig 5). There was a nonstatistically significant trend for improved survival in males receiving the 5-FU leucovorin regimens compared with 5-FU alone (Fig 6), but this trend did not exist for females.
Combined-modality therapy is routinely used in the United States and Canada for adjuvant therapy of rectal cancer patients who have T3/4 or N+ disease. Chemotherapy is used because of the proven ability to decrease distant metastases. Radiation therapy is used because of multiple reports of high local failure rates after surgery alone and a decrease in these local failure rates with the use of concurrent chemoradiation therapy.20-24 Previous studies by the GI Intergroup have shown a DFS and OS advantage to the use of continuous-infusion 5-FU chemotherapy given concurrently with radiation therapy compared with a bolus regimen of 5-FU alone,12 although the results of that study were not available at the time the present study was designed. We had hoped that a more aggressive chemotherapy regimen would further increase cure rates. This was based on data in patients with metastatic disease where 5-FU and leucovorin improved response rates compared with bolus 5-FU alone.9-11,25 Levamisole was of interest because of adjuvant data from colon cancer patients in the early 1990s that seemed to show improved survival when given alone26 or in combination with 5-FU.27,28 The results of this study were somewhat surprising because many people expected that the more aggressive drug regimens would improve DFS and OS rates. Thus, it is not possible to recommend regimens other than 5-FU alone as standard therapy, especially because there are data demonstrating a survival advantage to continuous-infusion 5-FU given concurrently with radiation therapy compared with bolus 5-FU alone. There is clearly no advantage to the use of levamisole in this study or colon adjuvant studies.29-31 An Intergroup study evaluating the use of 5-FU and leucovorin compared with continuous-infusion 5-FU regimens has not yet reported results. Additional assessment of the risk-benefit of leucovorin-based regimens would be required to fully assess whether there is any value to the use of leucovorin in this setting. We demonstrated a continued decrease in OS rates and a small decrease in DFS rates between 5 and 7 years. Although not frequent, patients still recurred after 5 years, and a number of late deaths occurred in patients who already had disease recurrence. The sex differences noted may be of importance. The increased grade 3 to 5 toxicity in females shows that, defined by the morbidity produced, females are receiving biologically greater treatment intensity. This could reflect increased sensitivity to treatment, altered drug metabolism, or an inaccurate dosing scheme. This should be considered in future study designs. One would prefer to have equitoxic doses of therapy in all patient subsets because our dosing schemes are geared to a maximum-tolerated dose. There was a nonstatistically significant trend to improved outcome in males with the more aggressive drug regimens but not in females. We could not demonstrate that these trends were correlated with toxicity by sex. There have been many changes in the surgical management of rectal cancer over the past two decades. The blunt pelvic dissection often used in the past is now considered inappropriate. A TME, as popularized by Enker et al,2 Heald et al,3 and others,4-7,32 is generally accepted to produce improved local control and OS. Local failure rates have been low enough in selected series to suggest that radiation therapy may not be necessary as a standard component of treatment. There is also an increasing body of literature to suggest that the experience of the surgeon is important in decreasing local failure rates,33 and teaching proper techniques to surgeons may decrease local failures.34 Pelvic radiation therapy has known morbidity. Earlier studies have shown substantial rates of acute and long-term toxicity from pelvic radiation therapy.35-37 Some of the earliest of these studies used large anterior to posterior and posterior to anterior fields and/or high doses per fraction, which increase the risk of toxicity. Careful treatment planning can lessen, although not eliminate, the complication rate.38-41 Preoperative radiation therapy may produce a lower complication rate because much of the irradiated rectum will be removed in the surgical specimen, and there is less likely to be small bowel fixed in the pelvis. There is substantial interest in the use of preoperative radiation therapy. A meta-analysis by Camma et al42 demonstrated an advantage in survival and local control with preoperative radiation therapy compared with surgery alone. Preoperative radiation therapy may also increase the sphincter preservation rate. Although two trials in North America were developed to determine the relative value of preoperative versus postoperative radiation therapy, both studies were closed because of poor patient accrual. A German study testing the same question has completed accrual, although outcome data are not available.43 The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-02 trial demonstrated improved local control with postoperative radiation therapy, but there was no survival advantage.24 The local failure rate in the irradiated patients was 8% compared with 14% in nonirradiated patients. These rates are substantially lower than in the present study. The reasons for the difference are not clear, but there are a few possibilities. First, there may be a bias in patient entry. In some institutions, the NSABP and the Intergroup studies were open concurrently. Because patients entered onto the NSABP trial might not receive radiation therapy, higher-risk patients could have been selectively entered onto the Intergroup study or not been entered onto the study at all. Second, the NSABP scored the first site of local failure only, whereas we attempted to score all local failures. Third, after extensive central review, we found a large error rate in the reported site of failure from the reporting institution. Fourth, the NSABP, being a surgically oriented group, may have had better surgical quality control. Kapiteijn et al44 have reported preliminary results of a randomized study of a confirmed TME with or without a short course of preoperative irradiation of 5 Gy x 5; the same regimen was used in a Swedish study45 that showed a survival advantage to preoperative radiation therapy compared with surgery alone. Approximately a third of the patients had stage I disease. There was no survival difference at 2 years. Preoperative radiation therapy decreased local failure from 8.2% to 2.4% (actuarial at 4 years of 10% v 3%). Local failure was less for tumors high in the rectum and with lower stage disease. Patients with node-positive disease treated with TME alone had a local failure rate at 4 years of 20%. Thus, radiation therapy was required to optimize local control. To make treatment management decisions, pathologic assessment of the tumors is critical. Quirke et al46 have demonstrated that a careful evaluation of the circumferential tumor margins can define patients at high risk for local failure. A circumferential margin of at least 2 to 5 mm results in a much lower rate of local failures than with lesser margins. In the United States and Canada, this type of assessment is not routinely performed.47 A thorough pathologic assessment of the lymph nodes is also of importance. Tepper et al48 have previously reported on the importance of the number of nodes found in the specimen as a predictor of outcome. For patients classified as N0, outcome was far worse for patients who had less than 14 nodes identified in the specimen by the pathologist. This may be a function of the thoroughness of the surgeon who removed the nodes or of the pathologist that identified the nodes. There have been other reports that confirm the importance of adequate assessment of the lymph nodes in colon and rectal cancer.49-52 The data from the present trial support the need for trimodality therapy for many patients with rectal cancer. Even with the use of all three treatment modalities, the local and distant relapse rates for T4 or T3N+ tumors are disappointingly high. Multiple factors influence whether patients receive postoperative radiation therapy. Schrag et al53 have shown that older patients are less likely to receive adjuvant therapy. However, there are subsets of patients in this study where the outcomes were favorable and where the risk of local recurrence was low (albeit with the use of trimodality therapy). Based on our data as well as that of others, these favorable factors include tumors located high in the rectum, patients with T1-2N+ or T3N0 disease, tumors where the surgeon has been formally trained to perform a TME and there is confirmation that this has been performed, tumors where the pathologist has analyzed the surgical margins by the method of Quirke et al,46 and where at least 12 to 14 nodes have been identified in the pathology specimen to confirm N0 status. In patients who meet most of these criteria, routine adjuvant radiation therapy may not be required. The state of care of patients in North America is such that at present these criteria are rarely met. We need to try to improve the quality of care so patients with relatively early tumors can be safely treated with more conservative management.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 3 and were resumed when the toxicity decreased to 
grade 2. 
2 and logistic regression models were used to test for differences in toxicity and rates of relapse.
