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© 2002 American Society for Clinical Oncology Randomized Trial of Postoperative Adjuvant Therapy in Stage II and III Rectal Cancer to Define the Optimal Sequence of Chemotherapy and Radiotherapy: A Preliminary ReportByFrom the Departments of Medicine, Surgery, and Radiation Oncology, Asan Medical Center, University of Ulsan, Seoul, Korea. Address reprint requests to Je-Hwan Lee, MD, Department of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-040, Korea; email: jhlee3{at}www.amc.seoul.kr
PURPOSE: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m2/d and leucovorin 20 mg/m2/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v 70% at 4 years; P = .043). Twenty-three recurrences occurred in arm I and 38 in arm II (P = .047). Overall survival was not significantly different between arms I and II (84% v 82% at 4 years; P = .387). CONCLUSION: Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.
APPROXIMATELY 75% of rectal cancer patients will have a primary surgical resection with the hope of complete tumor eradication.1 Despite this high resectability rate, nearly 50% of patients die of recurrent tumors.1 Effective postoperative adjuvant treatment is needed to reduce the recurrence and mortality rate of rectal cancer. Recent clinical trials have demonstrated that adjuvant therapy benefits stage II and III rectal cancers.2-5 A 1990 National Institutes of Health (NIH) consensus conference on the adjuvant treatment of colorectal cancer identified three independent primary scientific end points by which the efficacy of the adjuvant treatment of rectal cancer should be evaluated: the incidence of pelvic recurrence, disease-free survival, and overall survival.6 Because of anatomic characteristics, almost half of the recurrences of rectal cancer are located in the pelvis after conventional surgery without adjuvant radiotherapy.3 Adjuvant radiotherapy alone decreases local recurrences but without survival benefit.7-11 A recent meta-analysis showed that preoperative radiotherapy improved survival in patients with resectable rectal cancer, but the magnitude of the benefit was small.12 Only combined chemotherapy plus radiotherapy has consistently demonstrated efficacy in all three parameters. It is still necessary to define optimal combinations of chemotherapy and radiotherapy, such as drug regimen, route of delivery, and sequencing of chemotherapy and radiotherapy. Regarding the sequencing of postoperative combined therapy, there has been no randomized clinical trial. In an effort to investigate the optimal sequence of chemotherapy and radiotherapy in the setting of postoperative adjuvant treatment for rectal cancer, we conducted a random-allocation design clinical trial in patients with resected stage II and III rectal cancer. We compared two different sequences of chemotherapy and radiotherapy (early radiotherapy v late radiotherapy). We chose a combination of low-dose leucovorin plus fluorouracil as the chemotherapeutic regimen because of its demonstrated activity in the adjuvant therapy of colon cancer.13 We present the preliminary results of our study.
Patient Population All the patients in our study had histologically confirmed adenocarcinoma of the rectum. They had undergone a potentially curative resection, with neither gross nor microscopical evidence of residual disease. Total mesorectal excision was performed in all patients. Patients were eligible for the study if a pathologic examination demonstrated that the tumor had penetrated the rectal wall and involved perirectal fat or adjacent organs by direct extension (stage II), or had metastasized to regional lymph nodes (stage III). Patients were excluded if they had a history of malignancy within the previous 5 years (except curatively treated cervix carcinoma-in-situ or basal cell carcinoma of the skin), if they had previously received chemotherapy or radiotherapy of the pelvis, or if they had severe coexistent disease. Pregnant or lactating women were also excluded. Patients had to have adequate performance status (Karnofsky score of 80 or higher). Normal hepatic, renal, and bone marrow function (ie, bilirubin level < 2.0 mg/dL, creatinine level < 1.5 mg/dL, leukocyte count > 4,000/µL, and platelet count > 130,000/µL) had to have been documented before study entry. This study was approved by the institutional review board of the Asan Medical Center. Patients provided informed consent before randomization. We randomly assigned patients to the early radiotherapy group (arm I) or the late radiotherapy group (arm II). Randomization was performed within 3 weeks after surgery by means of the block randomization method using random number tables and included stratification according to the nodal stage (N0 v N1 v N2).
Treatment
Radiotherapy was given with a linear accelerator. Patients were simulated to a three-field (one posteroanterior and two lateral) approach. The borders of the posteroanterior radiation fields had to be 1.5 cm lateral to the widest bony margin of the true pelvis. In patients with abdominal perineal resections, the lower-field border included the perineum. In patients with anterior resections, the field was at the inferior aspect of the obturator foramina. The superior border was at the lumbosacral junction. The lateral fields had the same superior and inferior extent as the posteroanterior fields. The posterior margin of lateral portals was located 1 cm posterior to the anterior border of the sacrum. The anterior margin was 4 cm anterior to the sacral promontory. A dose of 1.8 Gy a day was delivered 5 days a week over 5 weeks for a total dose of 45 Gy.
Patient Follow-Up For 5 years, we regularly evaluated patients for disease recurrence. History taking and physical examination, complete blood counts, blood chemistry studies, carcinoembryonic antigen (CEA), and chest radiography were repeated every 3 months for the first 24 months after surgery and then every 6 months, for a total of 5 years. Computed tomography of the abdomen and pelvis was performed every 6 months for the first 2 years after surgery and then every 12 months. Colonofiberscopy or radiography of the colon was performed every 12 months. Whenever reasonably possible, we biopsied suspect lesions to confirm metastatic or recurrent disease. If histologic or cytologic evidence was not available, a clear demonstration of the presence of metastases to the lung, liver, lymph node, or brain or the demonstration of an enlarging pelvic mass by computed tomography was accepted as evidence of disease recurrence. Positive radiography or a bone scan provided evidence of bone metastasis. An elevated CEA alone was not considered as evidence of recurrence. We recorded information on the site of the first recurrence only, and these sites were categorized as locoregional or distant.
Statistical Design and Analysis
Patient Characteristics Between February 1996 and March 1999, a total of 308 patients were enrolled onto the study. We randomly assigned 155 to the early radiotherapy group (arm I) and 153 to the late radiotherapy group (arm II). Thirty-four (11.0%) of those randomly assigned patients were subsequently determined to be ineligible for the following reasons: 31 refused their assigned treatment, two patients had distant metastasis at the time of registration, and one died of postoperative complications after randomization. Thus, 274 patients were eligible with follow-up and were included in the statistical analyses. As of November 30, 2000, the median follow-up duration for surviving eligible patients was 37.3 months (range, 20.1 to 57.9 months). Table 1 shows the distribution of eligible patients according to treatment group. The distribution of patients according to sex, age, type of surgical resection, tumor-node-metastasis (TNM) stage, and preoperative CEA level was well balanced between the treatment groups. The median age of the 274 patients analyzed was 55 years (range, 22 to 78 years). Fifty-eight percent of the patients were men. Abdominal perineal resections were performed in 33% of the patients. Classification according to the TNM staging system revealed that 65% of the patients had stage III lesions and 35% had stage II lesions.
Treatment Compliance The median time from surgical resection to the initiation of adjuvant treatment was 27 days (range, 16 to 89 days) in arm I and 26 days (range, 12 to 90 days) in arm II. Adjuvant treatment was begun in 59% of the patients within 4 weeks of surgery and in 95% within 6 weeks. The treatment of four patients (three in arm I and one in arm II) was delayed beyond 60 days after surgery. The median time to the initiation of radiotherapy was 27 days (range, 16 to 103 days) after surgery in arm I and 84 days (range, 31 to 199 days) in arm II. One patient, who was assigned to arm I, received the arm II treatment, and radiotherapy began at 103 days after surgery in this patient. Another patient, who was assigned to arm II, was treated with the schedule for arm I and started to receive radiotherapy 31 days after surgery. These two patients were analyzed by the intention-to-treat analysis. Table 2 shows the treatment compliance of the patients. Fourteen patients (one in arm I and 13 in arm II) did not receive radiotherapy because they refused the treatment. Two patients in arm I received only radiotherapy without chemotherapy. Radiotherapy of 40 Gy or more was given to 96% of the patients in arm I and 90% of those in arm II. Of 274 eligible patients, 193 (70.4%) completed eight cycles of chemotherapy. The reasons for discontinuation of chemotherapy were patients’ refusal (41 in arm I and 29 in arm II), disease recurrence during treatment (three in arm I and seven in arm II), and the occurrence of second malignancy (one in arm I).
Toxicity Gastrointestinal and mucocutaneous toxicities were generally mild (Table 3). We observed no grade 4 nonhematologic toxicity. Among grade 3 toxicities, stomatitis and diarrhea occurred most frequently. The nonhematologic toxicities experienced by patients in the two treatment groups were comparable. The major hematologic side effect was leukopenia (Table 3). Grade 4 hematologic toxicities occurred in less than 1% of the patients. Leukopenia was more prominent in arm I than in arm II. There was no treatment-related death.
Disease Recurrence At the time of analysis (November 2000), 61 (22%) of 274 patients had a recurrence of rectal carcinoma. This group included 23 (17%) of the patients in arm I and 38 (27%) of those in arm II (P = .047). The 4-year rate of disease-free survival was 81% in arm I and 70% in arm II (P = .043; Fig 2). The prognostic value of several variables other than the treatment group was assessed. The type of surgery (anterior v abdominal perineal resection), the TNM stage (stage II v III), and perioperative transfusion (no v yes) were found to be significantly associated with disease-free survival (Table 4). The preoperative CEA level (  6 v > 6 ng/mL) was marginal. When these factors and the treatment group were included in the Cox proportional hazards model, the treatment group remained statistically significant (Table 5) along with TNM stage (P < .001) and type of surgery (P = .003). The hazard ratio for relapse in arm I, as compared with arm II, was 0.59 (95% confidence interval, 0.35 to 0.99; P = .049).
Of the 61 patients in whom recurrent disease developed, 50 (18%) had distant metastases only as the first sign of recurrence, 10 (4%) had locoregional recurrences only, and one (< 1%) had both locoregional and distant recurrence (Table 6). The liver and lung were the most common sites of initial recurrences. Both distant metastases (15% v 22%; P = .111) and locoregional recurrences (2% v 6%; P = .136) showed a tendency to be less frequent in arm I compared with arm II without statistical significance.
Survival Of the 274 patients included in the analysis, 35 (13%) died. Thirty-two deaths were due to rectal carcinoma, and three patients died without evidence of disease recurrence. The causes of death in these three patients were bladder cancer, hepatic failure due to hepatitis B virus, and unknown. Fifteen (11%) of the patients in arm I and 20 (14%) of those in arm II died. The 4-year overall survival rate was 84% in arm I and 82% in arm II (P = .387; Fig 3). When we analyzed prognostic factors for overall survival, the type of surgery, the TNM stage, and perioperative transfusion significantly affected the survival times (Table 4). The preoperative CEA level was marginal. These factors and the treatment group were included in the Cox proportional hazards model. The TNM stage (P = .005), the type of surgery (P = .007), and perioperative transfusion (P = .020) were independent prognostic factors for overall survival (Table 5).
The results of our study suggest that the timing of postoperative radiotherapy is important in rectal cancer. Early administration of postoperative pelvic irradiation had a significant advantage for disease-free survival compared with late radiotherapy. In 1990, the NIH consensus conference determined that patients with the adverse prognostic factors of regional nodal metastases and invasion of perirectal fat or adjacent organs should receive postoperatively 6 months of fluorouracil-based chemotherapy plus concurrent pelvic radiotherapy.2 This recommendation was based on the benefits observed in randomized trials from the Gastrointestinal Study Group (GITSG) and the North Central Cancer Treatment Group (NCCTG).3-5 There were several important differences between the GITSG study and that of the NCCTG. One difference was the sequence of chemotherapy and radiotherapy in a combined-therapy group. In the GITSG study, the patients in a combined-therapy group received postoperative pelvic radiotherapy plus fluorouracil, then 18 months of chemotherapy with fluorouracil plus semustine.3,4 In the NCCTG study, first two cycles of fluorouracil plus semustine were administered, then pelvic radiotherapy plus fluorouracil was given to the patients.5 In both studies, survival was significantly improved by the combined therapy. Reduction of the rate of distant metastasis as the initial recurrence was significant in the NCCTG study, but it was marginal and not significant in the GITSG study. The authors of the NCCTG study suggested that administration of full doses of chemotherapy might be important during the early postoperative period.5 Thereafter, most clinical trials of postoperative treatment for rectal cancer have administered postoperative radiotherapy after two cycles of full-dose chemotherapy.14-16 The 1996 Patterns of Care Rectal Cancer Committee also recommended six cycles of fluorouracil-based chemotherapy plus concurrent pelvic radiotherapy during the third and fourth cycles of chemotherapy in the setting of postoperative adjuvant treatment for stage II and III rectal cancer.17 However, this recommendation was not based on the results of randomized trials about the sequence of combined therapy. The optimal sequence of chemotherapy and radiotherapy has yet to be defined. Our study is the first randomized clinical trial about the timing of radiotherapy during postoperative treatment for rectal cancer. Recurrences were less frequent in the early radiotherapy group (arm I) compared with the late radiotherapy group (arm II), which followed the usual postoperative combined-therapy scheme for rectal cancer. Despite radical surgery, locoregional failure occurs frequently in patients with transmural or node-positive rectal cancers. The incidence of locoregional failure is less than 10% in stage I rectal cancer, but this rate increases to 15% to 35% in stage II and is as high as 45% to 65% in stage III.18-21 It is a well-documented phenomenon that surgical technique significantly affects the outcome in rectal cancer, particularly rates of local recurrence. The introduction of a specialized technique, total mesorectal excision, has reduced local recurrence rates.22 In our study, all patients underwent total mesorectal excision and most received postoperative radiotherapy. The locoregional recurrence rate was 4% at a median follow-up duration of 37.4 months: 2% in early radiotherapy group and 6% in late radiotherapy group. This is similar to the results of a recent study using total mesorectal excision in which the local recurrence rate was 5% at 2 years.23 The study showed that radiotherapy could reduce the risk of local recurrence even when administered to patients who underwent total mesorectal excision.23 It is likely that residual tumor clones remain after surgical resection of rectal cancer. Early eradication of these tumor clones can reduce the possibility of local recurrence and can also prevent tumor clones spreading outside the pelvis and metastasizing systemically. Thus, the administration of pelvic irradiation during the early postoperative period may have the benefit of decreasing both locoregional and systemic recurrences compared with the delayed administration of irradiation. Although statistically not significant, both locoregional and distant recurrence rates were lower in the early radiotherapy group than in the late radiotherapy group. These combined effects may result in improving disease-free survival of the patients who were randomized to the early radiotherapy group. Similar findings have been observed in several clinical trials of lung cancer.24-27 Three randomized trials of thoracic irradiation timing in limited-stage small-cell lung cancer showed the superiority of early thoracic irradiation compared with delayed thoracic irradiation.24-26 The importance of early thoracic irradiation timing was also reported for stage III non–small-cell lung cancer.27 In studies of lung cancer and in our study, the earlier reduction of the residual tumor stem-cell population by irradiation may decrease the probability that a chemo- or radioresistant tumor will evolve during adjuvant treatment. We were concerned about the decreased dose-intensity of fluorouracil during the early postoperative period in patients who were assigned to the early radiotherapy group. However, our results of less frequent systemic recurrences in the early radiotherapy group suggest that early application of combined chemotherapy and radiotherapy might be more important than the dose-intensity of fluorouracil during the early postoperative period. Fluorouracil is a well-known radiosensitizer, and irradiation may also potentiate the effect of fluorouracil in tumor cells because irradiation is known to upregulate the level of intracellular thymidine phosphorylase, which is an enzyme that converts fluorouracil into an active metabolite.28 Thus, radiotherapy, plus fluorouracil, can exert synergistic effects in eradicating residual local tumor cells after surgical resection. These effects may be more important during the early postoperative period in rectal cancer patients. Seven percent of the patients received less than 40 Gy of radiotherapy, and 12% of the patients received less than four cycles of chemotherapy. The main reason for incomplete treatment was patients’ refusal of further treatment. The proportion of patients who received inadequate pelvic irradiation was larger in the late radiotherapy group than in the early radiotherapy group. However, this difference of treatment compliance did not influence the overall results of our study. We analyzed our data after the patients who received inadequate pelvic irradiation had been excluded. The patients assigned to the early radiotherapy group still showed superior disease-free survival compared with those assigned to the late radiotherapy group (4-year disease-free survival of 80.1% in the early radiotherapy group v 68.4% in the late radiotherapy group, P = .039). Recently, randomized trials have tested the value of preoperative radiotherapy versus surgery alone for initially resectable rectal cancers.29-37 These studies indicate that preoperative irradiation alone could reduce the incidence of local recurrence and time to recurrence compared with surgery alone. One of these studies also showed survival improvement with preoperative radiotherapy.37 Given the advantage of the addition of concurrent chemotherapy to radiotherapy in the postoperative setting, a variety of preoperative combined-modality treatment programs have been developed.38-40 Preoperative versus postoperative radiotherapy was compared in a randomized trial, in which a significant decrease was noted in local recurrence with preoperative irradiation, but no difference was found in survival.41 However, this study used a suboptimal radiation technique and chemotherapy was not included. Whether the preoperative approach is more effective than postoperative combined therapy remains to be defined. In conclusion, early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.
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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
