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© 2002 American Society for Clinical Oncology Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal CancerByFrom the Clinic of Radiotherapy and Clinic of General Surgery, Martin-Luther-Universität, Halle; Paul-Gerhardt-Hospital, Wittenberg; and WiSP Research Institute, Langenfeld, Germany; and Hoffmann- La Roche, Inc, Nutley, NJ. Address reprint requests to Jürgen Dunst, MD, Department of Radiotherapy, Martin-Luther-Universität, Dryanderstrasse 4, D-06097 Halle, Germany; email: juergen.dunst{at}medizin.uni-halle.de
PURPOSE: To establish the feasibility of concurrent radiotherapy and capecitabine and define the maximum-tolerated dose (MTD) in patients with rectal cancer. PATIENTS AND METHODS: Thirty-six patients with rectal cancer received treatment in the adjuvant, neoadjuvant, or palliative setting with a total irradiation dose of 50.4 Gy with 1.8 Gy/d in approximately 6 weeks. Capecitabine was administered at escalating doses from 250 to 1,250 mg/m2 bid (including weekends) for the duration of radiotherapy. The MTD was defined when two or more patients in a cohort of three or six patients experienced dose-limiting toxicities. RESULTS: Dose-limiting grade 3 hand-foot syndrome was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 bid. Other toxicities were generally rare and/or mild, with only one case of non–dose-limiting grade 3 diarrhea and a single patient with grade 3 skin toxicity. Myelosuppression consisted mainly of leukocytopenia, with a maximum severity of grade 2. Thus, a dosage of 825 mg/m2 bid is the recommended dose level for further evaluation. One pathologic complete remission of a T3N1 tumor and nine partial remissions were observed in 10 patients treated in the neoadjuvant setting. CONCLUSION: The recommended dose for phase II evaluation is capecitabine 825 mg/m2 bid, administered without break during a conventional radiotherapy period of about 6 weeks. This combined-modality approach proved to be a feasible and well-tolerated treatment option with promising preliminary efficacy results in rectal cancer.
CURATIVE SURGICAL resection of primary rectal cancer is typically associated with a high rate of relapse, with up to 30% of patients developing recurrent disease. However, local tumor control and overall survival in patients with stage II and III rectal cancer is improved by the administration, before or after surgery, of radiation therapy in combination with fluorouracil (5-FU) chemotherapy.1,2 Following the recommendation of the National Institutes of Health Consensus Development Conference, this strategy has become the standard therapy for patients with rectal cancer.3 Attempts have been made to improve the efficacy of chemoradiotherapy through the inclusion of other agents such as leucovorin, levamisole, or nitrosourea, and modulation of the 5-FU administration schedule. Most of these strategies have failed to significantly improve the outcomes achieved with standard chemoradiotherapy. However, a randomized trial has shown that infusion of 5-FU throughout the entire course of radiotherapy prolongs both overall and disease-free survival and significantly decreases the rate of development of distant metastases compared with bolus 5-FU.3 Nevertheless, this schedule requires indwelling catheters and ambulatory pumps and is more difficult to administer on an outpatient basis. Capecitabine (Xeloda, Hoffmann-La Roche, Inc, Nutley, NJ) is an oral fluoropyrimidine that generates 5-FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with healthy tissue.4,5 The tumor-selective activation of capecitabine potentially enhances safety by minimizing systemic exposure to 5-FU. In clinical trials, capecitabine monotherapy has demonstrated a favorable safety profile that is typical of infused fluoropyrimidines.6-12 The majority of adverse events were mild to moderate in severity, with a low incidence of alopecia and myelosuppression. As an oral agent, capecitabine can be administered in the outpatient setting while, as a result of rapid and almost complete absorption in the upper gastrointestinal tract, potentially providing fluorouracil exposure similar to a low-dose continuous infusion of 5-FU.13 This offers a more convenient therapy for patients, avoiding the complications and pain associated with intravenous (IV) therapies. Two different administration schedules were explored in phase I studies14,15: the intermittent schedule (2 weeks of treatment followed by 1 week of rest) with a dosage of 1,250 mg/m2 bid, which was used for further phase III development of capecitabine in colorectal and breast cancer; and a 21-day continuous regimen. The latter study reached a maximum-tolerated dose (MTD) of capecitabine 829 mg/m2 bid, with hand-foot syndrome, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia reported as dose-limiting toxicities.14 Capecitabine is highly active in colorectal cancer. Data from two large, phase III trials9,11 have demonstrated that as first-line therapy for metastatic colorectal cancer, capecitabine achieves significantly superior response rates (P < .0002, integrated analysis), equivalent time to disease progression, and equivalent survival with an improved safety profile compared with IV bolus 5-FU/leucovorin (Mayo Clinic regimen).12 The majority of rectal cancers are adenocarcinomas, which share similar biologic characteristics with colon cancer and show similar responses to chemotherapy.16 As an oral agent that mimics continuous-infusion 5-FU, capecitabine has the potential to replace IV 5-FU and simplify chemoradiation for rectal cancer. Preclinical studies using human colon and breast tumor xenograft models show that radiotherapy selectively increases the activity of thymidine phosphorylase in tumor tissue but not in surrounding tissue.17 Furthermore, the combination of capecitabine and radiotherapy demonstrated highly enhanced antitumor activity compared with either therapy alone, whereas 5-FU/radiotherapy combination treatment showed no clear additive effect. We report the results of a phase I, dose-escalation study conducted to determine the MTD of oral capecitabine administered concurrently with standard pelvic radiotherapy in patients with rectal cancer. In order to optimally exploit any potential synergistic effect of radiotherapy and capecitabine, the drug was planned to be administered continuously for the duration of irradiation.
The study was conducted according to the principles of the Declaration of Helsinki as amended in Somerset West in 1996, and to good clinical practice guidelines. Approval was gained from the institutional review board, and each patient gave written informed consent before being recruited onto the trial.
Eligibility Criteria Exclusion criteria included previous radiotherapy of the pelvic region or a planned course of radiotherapy with a total dose of less than 45 Gy or a high dose (more than 2 Gy) per fraction. The following patients were also excluded: pregnant or lactating patients; women with childbearing potential who lacked a reliable contraceptive method; patients with organ allografts; patients with significant cardiac disease; and patients with CNS metastases or a history of uncontrolled seizures, CNS disorders, or psychological disability thought to be clinically significant, precluding informed consent, or adversely affecting patient compliance. Patients were also excluded if they had serious, uncontrolled infections, malabsorption syndrome, or if they lacked physical integrity of the upper gastrointestinal tract ensuring rapid and reproducible absorption of the drug. Patients with known sensitivity to fluoropyrimidines and patients who had received cytotoxic chemotherapy (except for one or two previous cycles of 5-FU/leucovorin immediately before recruitment onto the trial) or participated in another clinical trial within 4 weeks of the start of treatment were ineligible. Patients with hemoglobin less than 9 g/dL, absolute neutrophil count less than 2.5 x 109/L, and platelet count less than 125 x 109/L were excluded, as were those with creatinine concentrations more than 1.5 times the upper limit of normal, total bilirubin concentrations more than 2.0 times the upper limit of normal, calcium concentrations more than 11.5 mg/dL, or transaminase or alkaline phosphatase concentrations more than 2.5 times the upper limit of normal or, in patients with liver or bone metastases, more than 5 times the upper limit of normal.
Study Design and Treatment Study treatment was started within 14 days after screening assessment and, in the case of adjuvant therapy, within 6 to 8 weeks after curative surgery. A total irradiation dose of 50.4 Gy was delivered in 1.8-Gy daily fractions, Monday through Friday over a period of approximately 6 weeks. Patients were irradiated in a prone position using a belly board to minimize exposure of the small bowel. A three- or four-field box technique with high-energy photons (10 to 15 MV) was used. In this protocol, three-dimensional planning with measurements of planning target volume and the volume of small bowel in the planning target volume was mandatory. The clinical target volume, according to the International Commission on Radiation Units and Measurements guidelines, included the sacrum, the presacral space, the posterior walls of the bladder and prostate/vagina, and the regional lymph nodes extending to the common iliac artery. The upper border of the field was the interspace between L5/S1 or between L4/L5, depending on the extent of regional lymph node involvement (pN0 to 1 v pN2 to 3 or macroscopically involved nodes in patients with preoperative radiochemotherapy). Ventral extension of the lateral fields to include the external iliac nodes was permitted in the case of clinically detectable or pathologically extensive lymph node involvement. The lower border of the radiation field included the perineum in patients with a local recurrence and/or who had undergone abdominoperineal resection. In patients who had undergone an anterior resection of the primary tumor, the lower border of the field was within the anal canal. For patients treated with preoperative radiochemotherapy, the lower field border was 5 cm below the macroscopic tumor. Capecitabine was to be administered at planned escalating doses of 250, 375, 500, 650, 825, 1,000, and 1,250 mg/m2 bid continuously for the duration of radiotherapy. The first daily dose was administered approximately 2 hours before radiotherapy, with the second dose given 12 hours after the first. The following recommendations for dose reductions were applied: if a patient experienced a grade 2 or 3 toxicity that was considered possibly related to capecitabine treatment or clearly not related solely to radiation, capecitabine treatment was interrupted and appropriate prophylactic treatment administered, if available. When the toxicity resolved to grade 0 to 1, treatment was resumed without dose adjustment. However, in the case of grade 3 nausea/vomiting or diarrhea not resolving to grade 0 to 1 within 2 days of interruption despite symptomatic treatment, capecitabine treatment was resumed at the preceding dose level without prophylactic treatment. On the recurrence of a toxicity at grade 2 or more severe intensity, treatment was interrupted until the toxicity had resolved to grade 0 to 1. Treatment was resumed at the preceding capecitabine dose level (or at the same dose level in patients treated at the lowest dose level). The radiotherapy schedule was not modified unless the severity of the toxicity worsened or a new toxicity of grade 2 or more severe intensity occurred. If a toxicity considered to be clearly related to radiotherapy, such as local skin toxicity, occurred at grade 2 or more severe intensity, radiotherapy was interrupted until the toxicity had resolved to grade 0 to 1 and then resumed with appropriate prophylactic treatment, if required. If the toxicity recurred at grade 2 or more severe intensity, radiotherapy was interrupted until the toxicity had resolved to grade 0 to 1. The administration of capecitabine was not modified unless the severity of the toxicity worsened or a new grade 2 or more severe toxicity developed. If grade 4 toxicities developed, the combination treatment was discontinued, unless the investigator considered it to be in the best interest of the patient to continue treatment with radiation alone or in combination with a reduced dose of capecitabine.
Evaluation of Safety and Efficacy Three patients each were recruited to dose levels 1 and 2 (capecitabine 250 and 375 mg/m2 bid). The capecitabine dose was escalated when all three patients had completed a minimum of 4 weeks’ treatment without DLTs, with at least one patient completing the entire treatment course. If one patient experienced a DLT, an additional three patients were recruited to the same dose level. At dose levels 3 to 7 (500, 650, 825, 1,000, and 1,250 mg/m2 bid), six patients were recruited to each dose level and at least three patients were treated for the entire treatment period before dose escalation. The MTD was defined as the dose below that causing DLTs in at least two patients in a cohort of six patients. To confirm the safety of the MTD (recommended dose level), a total of 12 patients were treated at this dose level. The safety analysis included all patients who received at least one dose of capecitabine in combination with one dose of irradiation. All adverse events were monitored continuously during treatment and for 6 weeks after the end of treatment. Hematology and clinical chemistry was performed weekly during treatment and thereafter on days 45, 52, 66, and 80 from the start of therapy. In neoadjuvant and palliative cases, tumors were evaluated on the basis of World Health Organization criteria at baseline, within 14 days before the start of treatment, and after the end of the combined treatment. Responses were assessed on the basis of World Health Organization criteria. In the neoadjuvant setting, tumors were additionally evaluated on the basis of histopathologic findings after surgery.
Statistical Aspects
A total of 36 patients were accrued onto the study at Halle University between November 1998 and October 2000. The patient characteristics are listed in Table 1. The vast majority of the cases (92%) had newly diagnosed rectal cancer, with only three cases of relapsed disease, previously treated with surgery and also with chemotherapy in two patients. Most of the adjuvantly treated patients had received one or two cycles of 5-FU/leucovorin before being referred to the university center and recruited onto the study.
There were major deviations from the protocol in three patients: two patients (dose levels of 250 and 1,000 mg/m2 bid) withdrew their consent during therapy. In the first case, a sufficient radiotherapy dose could be applied by shortening the treatment period with increased doses. The second patient required termination of drug therapy on day 27 because of abdominal pain (not considered a DLT). A third patient (825 mg/m2 bid) was withdrawn by the investigator from capecitabine but not radiotherapy because of a psycho-organic syndrome (not considered a DLT).
Dose Escalation and DLTs
Hematologic Toxicity
Nonhematologic Toxicity Adverse events according to maximum NCIC CTC are presented for the whole patient group (Table 3) and for the 12 patients treated with capecitabine 825 mg/m2 bid (Table 4). Figure 1 presents the frequency and NCIC severity grade of adverse events by body/organ system. Gastrointestinal toxicities occurred in approximately half of all patients, consisting primarily of grade 1 nausea and vomiting. Diarrhea occurred in three patients at grade 2 (8%) and in one patient at grade 3 (3%), the latter being observed at the highest dose level (1,000 mg/m2 bid). According to the study protocol, this event was not considered to be a DLT, as it resolved quickly. (However, the same patient experienced dose-limiting hand-foot syndrome.) Neurologic toxicities consisted primarily of perianal pain, obstipation, and minor mood disorders. Peripheral paresthesia occurred in only one patient. Skin toxicity was observed in approximately 60% of patients and was more pronounced in 28%, but occurred mainly in the irradiated regions and was attributable in most cases to radiotherapy. Therefore, grade 3 rash/itch in one patient on the 375-mg/m2 bid dose level was not considered to be dose-limiting. Increased values of bilirubin without clinical relevance, common in other capecitabine trials, were recorded in 12 patents, three of which already showed abnormal values at baseline. Except for the observed DLT (hand-foot syndrome), no clear-cut dose/toxicity relationship was evident.
Antitumor Activity In the majority of the patients (n = 23) treated postoperatively, no information on antineoplastic efficacy can be derived. However, the effect of therapy on the primary tumor could be observed in 10 patients treated in the neoadjuvant setting. On the basis of tumor imaging, a clinical partial response was reported in nine of 10 patients, with the remaining patient achieving stable disease. Pathologic examination of the surgical specimen revealed a histologic complete remission in one patient treated at the third dose level (capecitabine 500 mg/m2 bid). In addition, among the three patients treated in the palliative setting, with tumor relapses after initial surgery, there was one partial remission in a patient treated with the recommended dose level of 825 mg/m2 bid and one case each of stable and progressive disease in patients receiving the second dose level (capecitabine 375 mg/m2 bid).
Combined radiation and chemotherapy is recommended as adjuvant treatment for high-risk rectal cancer and is also increasingly used as preoperative treatment for locally advanced rectal tumors. The consensus of the National Institutes of Health19 and the current guidelines of the German Cancer Society20 recommend bolus 5-FU during pelvic radiotherapy or protracted venous infusion (PVI) 5-FU. Infused 5-FU yielded higher response rates compared with bolus 5-FU in metastatic colorectal cancer.21 Moreover, PVI 5-FU plus radiotherapy has demonstrated efficacy superior to bolus 5-FU in combination with radiotherapy in the adjuvant treatment of rectal cancer.3 The superior efficacy of PVI 5-FU is possibly because of radiosensitization of 5-FU, which has been observed in vitro if cells are exposed to the drug for prolonged periods (24 hours) after irradiation.22,23 Thus, more recent United States guidelines (eg, National Comprehensive Cancer Network) generally recommend infusion schedules. Capecitabine is an oral fluoropyrimidine. It is converted to the active moiety by means of a three-step enzymatic pathway.4,5 The last step in this activation cascade requires the enzyme thymidine phosphorylase, which is significantly more active in tumor tissues compared with normal tissues for a range of tumor types. This may lead to preferential activation of capecitabine to active 5-FU in tumor cells compared with normal tissue. Moreover, the oral administration of capecitabine pharmacologically mimics PVI 5-FU. The drug therefore offers an attractive alternative to infused 5-FU, especially in combination with radiotherapy. The objective of this phase I study was to determine the DLTs of capecitabine in combination with radiotherapy and the most appropriate capecitabine dose for administration with concurrent curative radiation therapy in patients with rectal cancer. Therefore, patients with different stages of the disease were apt for recruitment, with limitations consequent on this heterogeneity (resulting from variability in planned radiotherapy) considered to be of only minor relevance. According to the findings of this study, a capecitabine dose of 825 mg/m2 bid throughout radiotherapy is recommended. Dose-limiting hand-foot syndrome occurred at a capecitabine dose of 1,000 mg/m2 bid. The only other toxicity considered to be possibly, probably, or definitely related to capecitabine was grade 3 diarrhea in one patient. One case of grade 3 rash/itch in the irradiated region was considered to be solely related to radiation (although a synergistic contribution of the drug might be argued). All other side effects were mild to moderate. The safety profile of capecitabine in this investigation was similar to that seen in other studies in which capecitabine has been administered without concurrent radiotherapy. The DLT in our study was hand-foot syndrome, as in other studies of capecitabine monotherapy for solid tumors.13,14 Furthermore, the recommended dose (825 mg/m2 bid for 6 to 7 weeks without a drug-free period) is identical to the total 6-weekly cumulative dose that is recommended for capecitabine as a single agent in metastatic colorectal and breast cancer (and to the bid dose of 829 mg/m2 in a 42-day continuous regimen). The recommended single-agent capecitabine regimen is 1,250 mg/m2 bid for 2 weeks followed by 1 week’s rest. The total dose of the drug administered over a period of 6 weeks equals 70 g/m2 with both schedules. According to these data, the observed toxicities in our study can be attributed almost exclusively to capecitabine. Acute side effects of radiotherapy, especially bowel and skin toxicity in the radiation field, were not increased and were not dose limiting. Thus, specific interactions between pelvic radiation therapy and capecitabine in terms of potentially enhanced acute radiation toxicity seem unlikely on the basis of this phase I study. In contrast, the main toxicity of radiotherapy and concurrent standard 5-FU is bowel toxicity, probably because of a 5-FU–induced increase in acute radiation toxicity, especially if 5-FU is administered as an IV bolus. Transient acute grade 3 diarrhea has been reported in up to one third of patients treated with adjuvant radiation and concurrent 5-FU.24 The safety profile of capecitabine suggests that this drug might be an ideal compound for combination with radiotherapy. Most of the patients on this phase I study were treated after curative resection in the adjuvant setting. Thus, no conclusions can be drawn about the antitumor efficacy of capecitabine in combination with radiotherapy. Only a limited number of patients were treated preoperatively. The response rate in these few patients is promising. Furthermore, the data are in accordance with a recent finding of Yoon et al.25 In their study, patients with locally advanced rectal cancer were treated with preoperative irradiation (45 Gy) and concurrent chemotherapy with either bolus 5-FU or two courses of capecitabine (1,250 mg bid for 2 weeks), plus leucovorin in both groups. The response rate was significantly higher in 32 patients receiving radiotherapy and simultaneous capecitabine compared with 44 patients treated with radiotherapy plus concurrent IV 5-FU and leucovorin (pathologically confirmed complete remission, 31% v 5%, respectively; sphincter preservation, 91% v 64%, respectively). A theoretical explanation for the enhanced tumor activity of radiation plus capecitabine comes from animal tumor models in which the key enzyme for the activation of capecitabine, thymidine phosphorylase, was upregulated by irradiation. In colon and mammary human cancer xenograft models, this upregulation was associated with an increased antitumor effect of irradiation in combination with capecitabine, but not in combination with 5-FU.17 On the basis of the recommended dose of this phase I trial, a multicenter phase II study has been initiated in Germany to evaluate this combined-modality approach in the neoadjuvant setting. In addition, the treatment schedule developed in this phase I trial has been adopted by the National Surgical Adjuvant Breast and Bowel Project to design a large-scale confirmatory trial in the preoperative setting comparing capecitabine plus radiotherapy versus protracted 5-FU plus radiotherapy.
Supported in part by a grant from Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany.
Presented in part at the Forty-Fifth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
1. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312: 1465-1472, 1985[Abstract] 2. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324: 709-715, 1991[Abstract]
3. O’Connell MJ, Martenson JA, Weiand HS, et al: Improving adjuvant therapy by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331: 502-507, 1994 4. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectivity in tumors by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34: 1274-1281, 1998[CrossRef][Medline] 5. Schüller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45: 291-297, 2000[CrossRef][Medline]
6. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17: 485-493, 1999 7. Blum JL, Dieras V, Lo Russo PM, et al: Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92: 1759-1768, 2001[CrossRef][Medline]
8. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: Results of a randomized phase II study. J Clin Oncol 18: 1337-1345, 2000
9. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous 5-fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19: 4097-4106, 2001 10. Hoff P, Abbruzzese JL, Medgysey D, et al: A phase II study of Xeloda (capecitabine) in patients with metastatic colorectal cancer demonstrating progression on 5-FU therapy. Proc Am Soc Clin Oncol 19: 993, 2000 (abstr)
11. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19: 2282-2292, 2001 12. Twelves C, on behalf of the Xeloda Colorectal Cancer Group: Capecitabine as first-line treatment in colorectal cancer: Pooled data from two large, phase III trials. Eur J Cancer 38: S15-S20, 2002 13. Judson IR, Beale PJ, Trigo JM, et al: A human capecitabine excretion balance and pharmacokinetic study after administration of a single dose of 14C-labelled drug. Invest New Drugs 17: 49-56, 1999[CrossRef][Medline] 14. Budman D, Meropol NG, Creaven P, et al: Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine. J Clin Oncol 16: 1795-1802, 1998[Abstract]
15. Mackean M, Planting A, Twelves C, et al: Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16: 2977-2985, 1998
16. Tepper JE, O’Connell MJ, Petroni GR, et al: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: Initial results of intergroup 0114. J Clin Oncol 15: 2030-2039, 1997
17. Sawada N, Ishikawa T, Sekiguchi F, et al: X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5: 2948-2953, 1999 18. Piantadosi S: Clinical Trials: A Methodologic Perspective. New York NY, John Wiley, 1997, pp 151-155 19. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990 20. Rödel C, Hohenberger W, Sauer R: Adjuvant and neoadjuvant therapy of rectal carcinoma: The current status. Strahlenther Onkol 175: 133, 1999[Medline]
21. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16: 301-308, 1998 22. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and X rays. Int J Radiat Oncol Biol Phys 8: 1923-1933, 1982[Medline] 23. Byfield JE, Sharp TR, Frankel SS, et al: Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck. J Clin Oncol 2: 406-413, 1984[Abstract] 24. Rödel C, Fietkau R, Keilholz L, et al: The acute toxicity of the simultaneous radiochemotherapy of rectal carcinoma. Strahlenther Onkol 173: 415-421, 1997[Medline] 25. Yoon W, Choi J, Kim T, et al: Enhanced tumor response and sphincter preservation with preoperative chemoradiation (CXRT) using capecitabine for locally advanced rectal cancer. Eur J Cancer 37: S258, 2001 (suppl 6, abstr) Submitted February 11, 2002; accepted June 18, 2002.
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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
45 Gy) of the pelvic region in the adjuvant, neoadjuvant, or palliative setting were eligible for this study (the trial was extended to the recruitment of patients in a neoadjuvant situation by a protocol amendment implemented in February 2000). Further inclusion criteria were Karnofsky performance status 
