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Originally published as JCO Early Release 10.1200/JCO.2004.11.124 on June 21 2004 © 2004 American Society of Clinical Oncology. Preoperative Uracil, Tegafur, and Concomitant Radiotherapy in Operable Rectal Cancer: A Phase II Multicenter Study With 3 Years' Follow-UpFrom the Departments of Medical Oncology, Radiation Oncology, and Surgery, Fundación Instituto Valenciano de Oncología; Hospital Universiatrio La Fe; Hospital Peset Aleixandre; Hospital Arnau de Vilanova, Valencia; Hospital Luis Alcañiz, Xativa-Valencia; Hospital de la Ribera, Alcira-Valencia; Hospital General Universitario; and Hospital Virgen de los Lirios, Alcoy-Alicante, Spain Address reprint requests to Carlos Fernández-Martos, MD, Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, c/o Professor Beltrán Báguena 8 y 19, 46009 Valencia, Spain; e-mail: carlosfmartos{at}mx2.redestb.es
PURPOSE: To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. PATIENTS AND METHODS: Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. RESULTS: All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. CONCLUSION: UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.
Patients with cancer of the distal rectum in stage II and III are a group at risk of local and distant relapse. In these patients, the postoperative treatment with fluorouracil (FU) combined with radiotherapy (RT) diminishes the rate of local relapse and increases survival. Preclinical studies demonstrate that the radiosensitization efficacy of the FU depends on the continued exposure of the tumor cells to the FU following the irradiation.1,2 Because of the short half-life of FU, the drug needs to be administered as a continuous infusion (CI) to achieve a prolonged exposure of the tumor cells to effective levels of FU. The study of the North Central Cancer Treatment Group 86-47-51 demonstrated an improvement in local control and of survival in patients who received CI FU during RT than those who received the bolus FU following surgery.3 Although the Intergroup 0144 study did not confirm the survival advantage of continuous infusion FU versus bolus, it did, however, show a significant decrease in hematologic toxicity.4 The possible advantages of preoperative treatment of rectal cancer include a lower toxicity, an increased resectability and an increased level of conservative surgery of the anal sphincter. Further, the intact anatomy of the treated zone offers an ideal in vivo model for the evaluation of treatment efficacy. Several groups have, over the past decade, reported the effects of combining RT with FU in bolus or CI, and with or without leucovorin (LV). The levels of pathologic complete response (pCR) have been between 8% and 33%.5-9 Although the data are limited and there are no studies comparing bolus versus CI, the results of efficacy (pCR, downstaging, and sphincter preservation) appear to favor the CI schemes. However, the need for indwelling catheters and infusion pumps can limit the use of CI FU schemes. Oral fluoropyrimidines, because of their ease of administration, constitute an attractive alternative to FU. UFT is one of the oral formulations of the fluoropyrimidines that combines uracil and tegafur in a fixed molar ration of 4:1. Tegagur is a prodrug that is converted to FU by the mitochondrial system of the liver. Uracil competitively inhibits dihydropyrimidine dehydrogenase; the principal enzyme responsible for the catabolism of FU. Pharmacokinetic studies have demonstrated that UFT administered orally reaches plasma concentrations of FU similar to when FU is administered in CI.10 In advanced colorectal cancer, UFT and LV has been demonstrated, in two randomized studies, to have an efficacy comparable with bolus FU bolus + LV (schedule of the Mayo clinic) but with a better safety profile.11,12 In preoperative treatment of rectal cancer, a phase I study has been conducted to determine the maximum tolerable dose of UFT + LV and RT.13 In that study, the UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation dose, totaling 45 Gy (1.8 Gy/fraction). The maximum tolerable dose of UFT with radiation was 350 mg/m2/d with 90 mg/d of LV. Diarrhea was the dose-limiting toxicity. This study demonstrated that UFT/LV and RT could be combined in dose intensity similar to that usually used in advanced disease.13 In postoperative treatment, the data of the Intergroup-0114 study did not demonstrate any advantage in the regimens that combined LV or levamisol with FU and RT over the scheme of bolus FU with RT.14 Based on these observations, we initiated a multicentered phase II trial to test the combination of UFT without LV and with RT. The principal objective was to know the efficacy (downstaging, pCR, sphincter-preserving surgery) and the toxicity. The secondary objective was to assess the relapse-free survival (RFS) and the overall survival (OS). In our initial report, we presented preliminary data on toxicity and efficacy in 68 patients.15 In the current report, we present the final data on 94 patients with respect to downstaging, sphincter preservation, acute toxicity, local control, and survival over a median follow-up of 36 months.
The study was performed in complete conformity with the principles of the Declaration of Helsinki, Good Clinical Practice, and the Spanish statutes regulating clinical trials. The study was approved by the ethics committee of the eight participating centers of the Autonomous Government of Valencia, and each patient signed an informed consent before inclusion in the study.
Patients and Eligibility
Preoperative Treatment
Chemotherapy
Radiotherapy
Treatment was delivered through three to four fields via the axial beam technique, shaped with multileaf collimator, and high-energy photons
Surgery
Toxicity Assessment and Dose Attenuation
UFT was suspended if diarrhea or hematologic toxicity grade 3 or worse occurred. Loperamide was prescribed for diarrhea grade 2 or higher. UFT administration was started over again with a dose reduction of 50 mg/m2 when the diarrhea grade was no greater than 1 or when neutrophils were
Definition of Response Resected tumors were classified pathologically according to the tumor-node-metastasis system staging system, version 5.16 A pCR was considered when no malignant cells were observed. We performed a second pathology evaluation on sections obtained from surgery and, in which, the criteria of cell viability were incorporated into the definitions. Sections for this evaluation were available from five of the participating centers. As such, only 63% (59 of 93 patients) of patients were assessed using the resected samples obtained from surgery, and only in these samples were the criteria of cellular viability applied, as described by Meterisian et al.17 pCR was considered when the sample contained nonviable cells, or only large acellular pools of mucin. Nonviable cells were those that showed pyknosis, karyorrhexis, karyolysis, cytolysis, or extreme distortion and hyperchromasia of the nucleus.
Postoperative Treatment
Follow-Up
Patterns-of-Failure Analysis and Survival
Statistical Considerations
Between April 1999 and August 2001, 94 patients were recruited onto the trial after providing fully informed written consent. Their clinical and demographic characteristics are presented in Table 1.
Toxicity and Treatment Adherence Preoperative treatment. The toxicity observed in the 94 patients during the preoperative segment was mainly gastrointestinal, of which 13 patients developed toxicity grade G3-4. Diarrhea was the reason for UFT dose reduction in 13 of 15 patients. Radiotherapy was administered at 100% of the planned dose in all the patients although there was a need for dose delay in 15 patients (mean delay, 5 days; range, 1 to 12 days). Individual toxicities of G3+ are presented in Table 2.
At surgery. Of the 94 patients that completed the preoperative treatment, 93 were operated on. One patient died of a stroke (cerebrovascular accident) unrelated to the treatment and which occurred in the time between the preoperative treatment and the schedule surgery. Of the 93 patients undergoing surgery, 38 had the tumor in the middle third of the rectum (6 to 8 cm of the pectineal line) and 56 in the distal third (1 to 5 cm of pectineal line). In two patients, we were unable to resect the primary tumor because of an existing local progression (tumor that had infiltrated the sacrum). Of the 91 patients who had the primary tumor resected, 48 had abdominoperineal resection (APR) and 43 had low anterior resection or coloanal anastomosis. The surgery was considered radical in only 83 patients because eight patients had disseminated disease; seven had an appearance of hepatic metastases during the surgery, and one had been diagnosed with bone metastases in the femur 1 week before the surgery. One patient 85 years of age died in the postoperative recovery period as a result of respiratory insufficiency. Morbidities in the 48 patients having APR were delays in wound healing in 33% (16 of 48 patients) and two patients with perineal abscess. There were five patients with anastomotic leak in the group of patients undergoing low anterior resection. At postoperative treatment. Of the 82 patients having radical surgery and who were candidates for adjuvant chemotherapy, only 71% (58 of 82 patients) received 100% of the planned doses. Six patients did not receive complementary treatment: three because of protracted time required for recovery from surgery and three because the patients chose not to continue. The other 76 patients received postoperative chemotherapy, and 18 (24%) required dose reduction of the FU because of diarrhea (six patients), mucositis (seven patients) and leukopenia (five patients). There were no deaths attributable to the postoperative treatment.
Efficacy: Downstaging, Pathologic Response, and Sphincter Preservation
According to the cellular viability criteria of Meterissian, the level of pCR was 15% (nine of 59 patients); six sections were T0N0 according to the classical criteria, one pT1N0 (presence of nonviable cells) and two pT3N0 (presence of large acellular pools of mucin). In 13 additional patients (23%) only residual microscopic foci were observed. In 14 patients (15%) there was disease progression; in six because pT more than uT (however, we were able to radically resect the primary tumor in four of these six) and in eight because of relapse at distance.
In 56 patients the tumor was sited in the distal third of the rectum; 13 patients had a tumor less than 1 cm from the pectineal line or that had infiltrated the sphincter muscles and, as such, these patients were candidates for APR. The other 43 patients (37 with uT3 and six with uT4) had a tumor distance of
Patterns of Failure: RFS and OS and Its Relationship With Response to Preoperative Treatment Nineteen patients died—five from intercurrent causes and 14 from tumor-related causes. Of these 14 patients, 10 died of extrapelvic progression of disease, and four died of relapse complications of the pelvis. The actuarial rate of survival free of relapse at 3 years was 72% (Fig 1). The actuarial rate of survival at 3 years was 75% (Fig 2). The rate of RFS was 92% for downstaging patients and 51% for patients who had not responded (P < .00001). OS was significantly higher (P = .002) for patients with downstaging following preoperative treatment than for patients who had not responded (Fig 3).
The combination of UFT (with or without LV) with RT has been the focus of studies in cancer of the head and neck, non–small-cell lung cancer, gastric cancer, cancer of the pancreas, and cancer of the rectum.18 With respect to cancer of the rectum, the present study is one in which this combination has been evaluated in the greatest number of patients and with longest follow-up to date. Furthermore, it is the only study that combines UFT without LV and RT in preoperative treatment. The scheme used was based on the data available from phase I studies.13,19 In advanced disease, the recommended dose of UFT without LV is 360 mg/m2 over 28 of 35 days; this achieves a dose intensity of 2,016 mg/m2/wk. In the study by Hoff et al, the recommended dose for the combination of RT and UFT/LV was similar to that used in advanced disease. Hence, we used a scheme of dose of UFT of 400 mg/m2/5 days per week during the days on which the RT was administered. This schedule achieves treatment dose intensity of 2,000 mg/m2/wk. The primary objective of the present study was to determine the tolerance and efficacy of this combination. As expected, the toxicity G3-4 most frequently encountered was diarrhea (14%). UFT has a toxicity that is scheme-dependent, with neutropenia being the DLT in schemes of 5 of 21 days and diarrhea in schemes of 28 of 35 days.19 Diarrhea was the most frequent toxicity in other studies of the combination of UFT/LV plus RT. There was only one patient with neutropenia G3. The hematologic toxicity is similar to that observed in the CI FU combination and compares favorably with the schemes of bolus FU/LV in that the incidence of neutropenia G3-4 is higher.8 Combining the results of the other series published on preoperative combined FU in bolus or CI, the toxicity G3+ during the preoperative period is 15% to 25%.20 In the present study, downstaging was 54%, and the level of pCR was 9%. When morphologic criteria of cellular viability are taken into account, the rate of pCR was 15%. This activity is the same as that observed in other studies with UFT/LV and RT21,22 and similar to that observed in other studies of FU/LV combined with RT. The rate of sphincter preservation following the combined treatment was 25%, which is lower that other series in which surgery was performed by a single surgical unit but similar to that reported in multicentered studies.8,9 The secondary objective of our study was the RFS and OS. Following a median follow-up of 36 months, the level of local relapse was 5% in the patients with radical resection. A level of local control of 93% in the overall patients operated on is similar to that obtained in other studies with a similar follow-up time.7 Systemic disease is the most usual cause of death in patients operated on for cancer of the rectum in modern series.23 In this context, the dose intensity of the chemotherapy employed needs to be evaluated in further studies. In our study, 83% (10 of 12 deaths) of the deaths from tumor cause were by progression of metastases at distance. Furthermore, in only 55% (58 of 93 patients) of the overall patients, and 70% of the patients operated on with curative intent, was the dose of therapy administered the same as that planned for the postoperative period. Other groups have report similar findings.8 The most frequent causes are progression, toxicity, and the patient's decision to abandon treatment because of the fatigue following the aggressive therapy schedule. The administration of the combined treatment following surgery had a similar level of patients in whom it was not possible to administer the planned treatment.24 New strategies, including the administration of chemotherapies before chemoradiotherapy may improve this situation. Analyzing the outcomes as a function of response indicates an improved RFS and OS for those patients who respond to the preoperative treatment. This observation has been communicated by other investigators.5,25,26 Furthermore, the response to preoperative treatment increases the possibility of conservative surgery.27 Newer strategies in preoperative treatment of cancer of the rectum should seek a higher number of responses. One way of achieving this is to combine RT with the new pharmaceutical agents known to be active in the treatment of colorectal cancer. The combination of fluoropyrimidine with irinotecan or oxaliplatinum has demonstrated a significant increment in the number of responses in advanced disease. Several phase I-II trials evaluating the combination of RT with fluoropyrimidine and oxaliplatinum or irinotecan are currently underway and preliminary results are becoming available. The results of our phase I study of the combination UFT/oxaliplatinum, as with other phase I/II studies, demonstrate that the combination is possible with dose intensities equal to, or marginally lower than, that used in advanced disease. Although the levels of response obtained are high, there is a need for randomized studies comparing the outcomes with those obtained with fluoropyrimidines RT.28-30 In summary, UFT with RT reproduces the results of efficacy that have been obtained with FU but with better tolerance and fewer complications associated with the oral treatment scheme. Distance failure is the major problem in this patient population. Further investigation into the benefit of other forms of administration of the chemotherapy (ie, previous to the combined therapy) that may deliver higher dose intensity is warranted. The combinations of fluoropyrimidines with the new drugs and RT can offer a higher number of patients the option of benefiting from response (ie, the possibilities of conservative surgery and survival).
The authors indicated no potential conflicts of interest.
Presented in part at the 37th American Society of Clinical Oncology meeting, San Francisco, CA, May 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. 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] 2. Smalley SR, Kimler BF, Evans RG: 5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells. Int J Radiat Oncol Biol Phys 20:207-211, 1991[Medline]
3. O'Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502-507, 1994 4. Smalley SR, Benedetti J, Williamson S, et al: Intergroup 0144—phase III trial of 5-FU based chemotherapy regimens plus radiotherapy (XRT) in postoperative adjuvant rectal cancer: Bolus 5-FU vs prolonged venous infusion (PVI) before and after XRT + PVI vs bolus 5-FU + leucovorin (LV) + levamisole (LEV) before and after XRT + bolus 5-FU + LV. Proc Am Soc Clin Oncol 22:251, 2003 (abstr 1006) 5. Rich TA, Skibber JM, Ajani JA, et al: Pre-operative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 32:1025-1029, 1995[CrossRef][Medline] 6. Mehta VK, Poen J, Ford J, et al: Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 or T4 rectal cancer. Dis Colon Rectum 44:52-58, 2001[CrossRef][Medline] 7. Bosset JF, Magnin V, Maingon P, et al: Preoperative radiochemotherapy in rectal cancer: Long-term results of a phase II trial. Int J Radiat Oncol Biol Phys 46:323-327, 2000[CrossRef][Medline] 8. Grann A, Feng C, Wong D, et al: Pre-operative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 49:987-995, 2001[CrossRef][Medline] 9. Hyams DM, Mamounas EP, Petrelli N, et al: A clinical trial to evaluate the worth of pre-operative multimodality therapy in patients with operable carcinoma of the rectum: A progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 40:131-139, 1997[CrossRef][Medline] 10. Ho DH, Pazdur R, Covington W, et al: Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4:2085-2088, 1998[Abstract]
11. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605-3616, 2002
12. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617-3627, 2002
13. Hoff PM, Janjan N, Saad ED, et al: Phase I study of pre-operative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer. J Clin Oncol 18:3529-3534, 2000
14. Tepper JE, O'Connell M, Niedzwiecki D, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744-1750, 2002 15. Fernandez-Martos C, Aparicio J, Bosch C, et al: Pre-operative therapy (PT) with oral uracil and tegafur (UFT) and concomitant irradiation (RT) in operable rectal cancer (RC): Preliminary results of a multicenter phase II study. Proc Am Soc Clin Oncol 20:148a, 2001 (abstr 590) 16. Sobin LH, Wittekind Ch: UICC: TNM Classification of Malignant Tumors (ed 5). New York, NY, Wiley-Liss, 1997 17. Meterissian S, Skibber J, Rich T, et al: Patterns of residual disease after pre-operative chemoradiation in ultrasound T3 rectal carcinoma. Ann Surg Oncol 1:111-116, 1994[Abstract] 18. Minsky B: UFT plus oral leucovorin calcium (Orzel) and radiation in combined modality therapy: A comprehensive review. Int J Cancer 96:1-10, 2001 19. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trials of uracil-tegafur (UFT) using 5 and 28 day administration schedules: Demonstration of schedule-dependent toxicities. Anticancer Drugs 7:728-733, 1996[Medline] 20. Minsky BD: Primary treatment of rectal cancer: Present and future. Crit Rev Oncol Hematol 32:19-30, 1999[Medline] 21. de la Torre A, Ramos S, Valcarcel FJ, et al: Phase II study of radiochemotherapy with UFT and low-dose oral leucovorin in patients with unresectable rectal cancer. Int J Radiat Oncol Biol Phys 45:629-634, 1999[CrossRef][Medline]
22. Feliu J, Calvilio J, Escribano A, et al: Neoadjuvant therapy of rectal carcinoma with UFT-leucovorin plus radiotherapy. Ann Oncol 13:730-736, 2002
23. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Pre-operative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001
24. Tepper JE, O'Connell MJ, Petroni GR, et al: Adjuvant post-operative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: Initial results of Intergroup 0114. J Clin Oncol 15:2030-2039, 1997 25. Janjan NA, Abbruzzese J, Pazdur R, et al: Prognostic implications of response to pre-operative infusional chemoradiation in locally advanced rectal cancer. Radiother Oncol 51:153-160, 1999[CrossRef][Medline] 26. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664-674, 2002[CrossRef][Medline] 27. Crane CH, Skibber JM, Feig BW, et al: Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer 97:517-524, 2003[CrossRef][Medline] 28. Fernandez-Martos C, Aparicio, J, Bosch C, et al: Combined modality treatment with oxaliplatin, oral uracil and tegafur (UFT) and concomitant irradiation (RT) in rectal cancer: A dose-finding study. Proc Am Soc Clin Oncol 22:322, 2003 (abstr 1293)
29. Rodel C, Grabenbauer GG, Papadopoulos T, et al: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 21:3098-3104, 2003 30. Mehta VK, Cho C, Ford JM, et al: Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 55:132-137, 2003[CrossRef][Medline] Submitted November 20, 2003; accepted March 15, 2004. Related Editorial
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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
10 MV (this being possible using photons of 6 MV in the PA). The total dose administered was 45 Gy with conventional fractions of 1.8 Gy/d, five times per week. The prescribed dose was specified at the International Commission on Radiation Units and Measurements point (intersection of the central axes of the 3-4 beams) and isodose distribution to the PTV (95% to 105%). 
1 or when neutrophils were 
