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© 2000 American Society for Clinical Oncology
Phase I Study of Preoperative Oral Uracil and Tegafur Plus Leucovorin and Radiation Therapy in Rectal CancerFrom the Departments of Gastrointestinal Medical Oncology and Digestive Diseases, Radiation Oncology, Surgical Oncology, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ; and Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD. Address reprint requests to Paulo M. Hoff, MD, Department of Gastrointestinal Medical Oncology and Digestive Diseases, Box 78, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email phoff{at}mdanderson.org
PURPOSE: Preoperative combined-modality therapy for rectal cancermay allow for sphincter preservation, while decreasing recurrencerates and improving the overall prognosis. Oral chemotherapy withuracil and tegafur (UFT) plus leucovorin (LV) may reduce costs andcomplications associated with protracted infusions offluorouracil. Our goal was to evaluate the safety of UFT plus LVcombined with preoperative radiation and determine themaximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFTplus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectalcancer received escalating doses of UFT (starting at 250mg/m2/d, with50-mg/m2/d increments between consecutivecohorts) and fixed doses of LV (90 mg/d). The UFT and LV combinationwas given 5 days per week concurrently with a 5-week course ofpreoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery wasperformed 4 to 6 weeks after radiation and was followed by four 35-daycycles of fixed doses of UFT and LV (28 days of therapy eachcycle). RESULTS: Fifteen patients weretreated, and 13 received the full preoperative chemotherapy. Allplanned radiation was delivered successfully. The MTD of UFT withradiation was 350 mg/m2/d with 90 mg/d ofLV. Diarrhea was the DLT. Sphincter-preserving surgery was performedin 12 of 14 patients. One patient had progressive disease beforesurgery. Pathologic evaluation of 14 resected specimens showed acomplete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV isfeasible and well tolerated and should be furtherinvestigated.
ANESTIMATED 34,700 patients were diagnosed with rectal cancer in theUnited States in 1999.1 Themajority of these patients had surgical resection, and a significantpercentage were candidates for adjuvant treatments. Randomized trialsconducted in the 1980s found that patients with tumor-node-metastasis(TNM) stages II and III adenocarcinomas of the rectum that penetratedthrough the wall (T3 to T4) and/or invaded regional lymph nodes (N1 toN3) had improved rates of survival with adjuvant postoperative pelvicradiation and fluorouracil (5-FU)-based chemotherapy.2,3 Continuous 5-FU infusionduring the radiation therapy was superior to the use of bolus 5-FUschedules because of lower hematologic toxicity and improveddisease-free and overall survival rates.4 The modulation of bolus 5-FU byleucovorin (LV) increased response rates in metastatic colorectalcancer.5 However, thepreliminary results from an Intergroup trial showed that disease-freeand overall survival rates were similar when adjuvant postoperativeradiation was given with bolus 5-FU alone, with either LV orlevamisole, or with both LV and levamisole.6 Although adjuvant combined-modalitytherapy clearly benefits patients with TNM stages II and III rectalcancer, the optimal regimen remains unclear.7 At least half ofthe patients who receive postoperative chemoradiation for rectalcancer require a permanent colostomy.3,4,6,8 Preoperative (neoadjuvant)chemoradiation offers the potential for sphincter preservation whilestill aiming at decreasing local recurrence and improvingsurvival.9 On the basis ofencouraging results of preoperative chemoradiation withcontinuous-infusion 5-FU, this treatment modality is used at TheUniversity of Texas M. D. Anderson Cancer Center for patients with TNMstages II and III rectal cancer.10 Advantages of preoperative adjuvanttherapy include an in vivo evaluation of drug efficacy, an intactblood supply to the tumor, and a reduced amount of small bowel in theirradiated field. The main disadvantage of preoperative therapy is thelimited ability to stage the tumor pathologically, thus riskingovertreatment of patients with early-stage (T2) lesions.9 Over the pastseveral years, many new drugs with activity in colorectal cancer havebeen investigated or approved. Among them, oral fluoropyrimidinesconstitute an attractive alternative to intravenous 5-FU. Oralchemotherapy may represent a convenient and more acceptable modalityfor patients, an impression that has been confirmed in the palliativesetting.11 In addition, oralchemotherapy may circumvent the problems and costs associated withcentral venous lines and portable infusionpumps. UFT, one of the new oralfluoropyrimidines, combines uracil and tegafur in a fixed molar ratioof 4:1.12 Tegafur is aprodrug converted to 5-FU by the hepatic microsomal system. Uracilcompetitively inhibits dihydropyrimidine dehydrogenase, the chiefcatabolic enzyme of 5-FU, which results in elevated and maintainedconcentrations of 5-FU.13,14 In preclinical experiments, LV has beencombined with UFT in an attempt to enhance antitumoractivity.15 In patients withadvanced colorectal cancer, the combination of UFT and oral LVproduced objective response rates ranging from 25% to 42%.14 Preliminary results from two largerandomized studies in patients with metastatic colorectal cancersuggested that patients treated with UFT/LV and those receiving bolusintravenous 5-FU/LV may have equivalent response rates andsurvival.16,17 Inthe adjuvant setting, Japanese investigators compared postoperativeUFT to surgery alone; UFT led to a significantly improved 4-yeardisease-free survival, particularly in patients with rectalcancer.18 Like infusional5-FU, UFT is generally well tolerated, with diarrhea, nausea, andanorexia being the most frequent adverse effects. In reported trials,grade 3 or 4 diarrhea occurred in 4% to 21% of patients.14,16,17 UFT is notassociated with significant myelosuppression, mucositis, hand-footsyndrome, or alopecia. Pharmacokinetic studieshave shown that the 5-FU plasma levels in patients receivingprotracted infusions of 5-FU are similar to those found in patientsreceiving oral UFT, although peak levels of 5-FU are higher withUFT.14 Although a largenumber of patients have received UFT plus oral LV as adjuvantchemotherapy or to treat metastatic disease, relatively little isknown about the use of UFT/LV with radiation therapy in patients withrectal cancer. The primary objective of our present trial was toinvestigate the safety of a preoperative regimen of UFT plus oral LVcombined with radiation therapy for patients with rectal cancer. Thesecondary objective was to evaluate pathologic responses obtained withthisregimen.
Eligibility and PatientEvaluation Eligible patients had histologicallyconfirmed rectal cancer and evidence of a T3 or T4 lesion or nodalinvolvement by endoscopic ultrasonography or computed tomography(CT). Other eligibility criteria were the ability to tolerate majorsurgery, age over 18 years, Zubrod performance status of 0 to 2, lifeexpectancy of at least 3 months, absolute granulocyte count  1,500/mL, platelet count 100,000/mL, total bilirubin level  1.5 mg/dL, ALT level 70 IU/L, and serum creatinine level 1.5mg/dL. Patients with distant metastasis or prior malignancies(excluding localized epithelial skin or cervical cancer), majorsurgery within 3 weeks, or prior chemotherapy or pelvic irradiationwere excluded. Pregnant or breast-feeding women were not eligible, andsexually active fertile patients had to practice contraception. Theprotocol was approved by our institutional review board, and allpatients gave written informed consent beforeenrollment. Pretreatment evaluation included acomplete medical history and physical examination, complete bloodcount and chemistry profile, colonoscopy with endoscopicultrasonography, a chest radiogram, CT of the abdomen and pelvis, andan electrocardiogram. Women of childbearing potential underwent urineor serum pregnancy testing before treatment. Complete blood counts andserum chemistry profiles were obtained weekly during chemoradiationand before each course of adjuvant postoperativechemotherapy. Patients had repeat CT of the abdomen and pelvis andproctoscopy with biopsy 4 to 6 weeks after the completion ofchemoradiation. After the completion of all therapy, patients wereevaluated every 3 months with a physical examination, complete bloodcount and serum chemistry profile, and CT of the abdomen andpelvis.
TreatmentProgram
Radiation therapy was administered to the pelvis using a three-field technique with posterior, right lateral, and left lateral treatment fields. The superior border of the radiation field was placed at the L5-S1 interspace, and the inferior border was 4 to 5 cm distal to the rectal tumor; in all cases, the inferior border was at or distal to the obturator foramina. To encompass the iliac lymph node chain, the lateral borders of the posterior field were 1.5 to 2 cm lateral to the margins of the true bony pelvis. The lateral radiation fields included the sacrum and coccyx posteriorly and the femoral head anteriorly to include the obturator nodes. The external iliac nodes were not included in the treatment fields, unless there was evidence of external iliac adenopathy or direct invasion of adjacent structures. Dosimetric weighting of the fields was 2:1:1 for the posterior, right lateral, and left lateral fields, respectively; 45° wedges were used over the lateral fields. All fields were treated each day, and port films were taken every week for quality assurance. Surgical resection was performed 4 to 6 weeks after the completion of chemoradiation. Four to 6 weeks after surgery, patients received four courses of adjuvant oral chemotherapy. Each course consisted of fixed doses of UFT and LV, both given three times a day for 28 consecutive days, followed by a 7-day rest period. The UFT dose was 250 mg/m2/d in the first three patients; since no major toxic effects were observed, all the following patients received 300 mg/m2/d. The LV dose was 90 mg/d in all patients.
Evaluation of Toxicity
Standard antiemetic therapy was prescribed as required. Antidiarrheal drugs were not given prophylactically but could be used for the symptomatic treatment of diarrhea of grade 2 or higher. Chemotherapy was withheld upon development of a grade 2 or higher nonhematologic toxicity or grade 3 or higher hematologic toxicity, and resumed with a UFT dose reduction of 50 mg/m2/d when symptoms were grade
Pathologic Responses
Preoperative Therapy Between December 1996 and August 1999, 15 patients entered the study. Their demographic and clinical characteristics are shown in Table 2.
Preoperative chemoradiation therapy was completed in all patients. Table 3 shows the toxicity associated with the preoperative therapy. At the starting dose level of UFT (250 mg/m2/d), no grade 3 or 4 toxicity was observed in the three patients treated. In the three patients treated at dose level 1 (UFT 300 mg/m2/d), only one case of grade 3 diarrhea, not requiring parenteral support, occurred, allowing further escalation. Dose level 2 (UFT 350 mg/m2/d) produced no DLT in the first cohort of three patients, and escalation proceeded. Among three patients treated at dose level 3 (UFT 400 mg/m2/d), two patients had grade 3 diarrhea, and one of these patients also had grade 3 nausea and anorexia requiring prolonged parenteral fluids. Because two of three patients at this level had DLT, another cohort of three patients was entered at the previous dose level (level 2). The most severe toxic effects in these patients were grade 3 diarrhea not requiring fluids and rectal pain in one patient and grade 3 hyperbilirubinemia in another patient. Therefore, one of six patients at dose level 2 (UFT 350 mg/m2/d) developed DLT, and this was considered the MTD.
Overall, the most common side effects were diarrhea, anorexia, and nausea. All patients experienced grade 1 or 2 skin changes in the intergluteal region during radiation therapy. Grade 1 or 2 urinary symptoms were also expected because the bladder would receive 20 to 30 Gy. Laboratory test abnormalities were infrequent, with grade 3 hyperbilirubinemia occurring in the case described above. The goal of administering 25 days of UFT/LV concurrently with radiation therapy was accomplished in 13 patients (87%). Two patients treated at dose level 2 received only 20 and 23 days of chemotherapy because of toxic effects (grade 3 diarrhea and grade 3 hyperbilirubinemia). Radiation therapy was delivered at the planned dose of 45 Gy in 14 patients (93%). One patient underwent field modification because of grade 3 diarrhea and secondary dehydration.
Surgery Of the 14 patients undergoing resection, 12 had sphincter-preserving procedures, and only two had abdominal perineal resection. Five patients had delayed wound healing. Four patients who underwent low anterior resection had wound-healing complications in the anterior abdominal incision. One patient who had an abdominal perineal resection developed a perineal abscess. All five patients received 350 or 400 mg/m2/d of UFT. A rectal stricture that required intraoperative dilatation occurred in a 105-kg diabetic patient who received UFT 300 mg/m2/d. One patient developed urinary tract obstruction, acute renal failure, and urosepsis 50 days after undergoing low anterior resection and diverting ileostomy. The urinary retention was thought to be secondary to a neurogenic bladder. Pathologic evaluation of the surgical specimens showed a complete response in three (21.4%; 95% confidence interval, 5.7% to 52.4%) of the 14 resected cases. Ten patients had a partial pathologic response, and only one patient was thought to have had no pathologic response to preoperative therapy. In the 12 patients who underwent sphincter-preserving procedures, bowel function (including frequency, continence, and lack of pain with defecation) remained normal after preoperative UFT/LV plus radiation. Late toxic effects, consisting of mild, frequent bowel movements, have occurred in only two patients. No late radiation toxicities, such as telangiectasia or hyperpigmentation, have been observed over the cutaneous surfaces in the radiation fields. The one case of rectal stenosis requiring dilatation occurred shortly after completion of radiation; therefore, radiation fibrosis alone is not likely to account for this complication.
Postoperative Therapy One patient withdrew consent after one cycle of postoperative therapy. The patient, who developed a neurogenic bladder, acute renal failure, and urosepsis, had a prolonged recovery and was not considered fit for postoperative chemotherapy. This was one of the patients who had had a complete pathologic response. Of the remaining 11 patients, nine have completed their postoperative course of chemotherapy. One patient developed prolonged grade 3 hyperbilirubinemia after two cycles, was removed from the study, and completed treatment with two cycles of intravenous 5-FU and LV. This was the same patient who had developed grade 3 hyperbilirubinemia before surgery. One patient developed angioedema believed to be unrelated to study treatment but was removed from study because of the prolonged treatment delay. No grade 4 toxicity was observed during the postoperative part of the study. Other grade 1 or 2 toxic effects were consistent with those in previous studies of UFT/LV given to patients with advanced colorectal cancer. Follow-up is still limited at this point. Both patients with liver metastasis, described previously, have died, 12 and 19 months after enrollment. One patient developed metastatic disease 23 months after enrollment and is currently alive after salvage treatment.
The present study demonstrated the feasibility of a preoperative chemoradiation program containing oral UFT/LV in patients with rectal cancer. The treatment was well tolerated, with a toxicity profile that was predictable and relatively mild. All of our patients completed the preoperative component of the program, and full doses of radiation were delivered successfully to all patients, including the patient who required modification of the radiation treatment plan. The recommended dose of UFT/LV used in this schedule with radiation therapy is UFT up to 350 mg/m2/d along with LV 90 mg/d. Despite the addition of radiation therapy, the 5-day regimen with 2 days of rest allowed for a higher daily dose of UFT/LV than the one usually given for 28 days with 7 days of rest. Surgical resection was performed in all but one patient, who had metastatic disease diagnosed after chemoradiation was completed. Sphincter-preserving procedures were possible in 12 of 14 patients, and these results are comparable to those of other studies in which patients received preoperative chemoradiation with infusional 5-FU.10 Pathologic evaluation of surgical specimens showed a complete response in three of 14 cases. One additional patient showed only a few areas of microscopic residual tumor. A larger trial would be required to clarify the real magnitude of the response to preoperative chemoradiation. Postoperative chemotherapy with UFT and oral LV was well tolerated, a result consistent with the findings of previous trials in advanced disease.16,17 The lack of significant marrow suppression with this agent makes it safer in the postradiation setting than bolus regimens of intravenous 5-FU. Among the patients who did not receive all four postoperative cycles as planned, two had metastatic disease, one refused treatment, one had a complicated postoperative course that precluded additional treatment, one had prolonged hyperbilirubinemia, and one had a prolonged treatment delay due to angioedema, which was not thought to be related to study treatment. Hyperbilirubinemia has been demonstrated with UFT and other oral fluoropyrimidines.16,20,21 The elevated fraction is virtually always the indirect, and toxic effects are usually limited to grade 2 or 3. Bilirubin concentrations return to normal rapidly once the medication is suspended or discontinued. In our experience, other liver function test results are not altered. The patient with hyperbilirubinemia had previously experienced the same toxic effect in the preoperative setting and was removed from the study because the postoperative episode lasted longer and thus raised safety questions. The patient’s bilirubin level normalized 2 weeks after withdrawal from the agent. The main goal of our study was to find the dose of UFT/LV that could be safely combined with preoperative radiation therapy among patients with rectal cancer. We believe that we have achieved this goal and in the process have demonstrated the feasibility of using an oral fluoropyrimidine as a radiosensitizing agent instead of intravenous 5-FU. The superior toxicity profile of these oral agents, when compared with intravenous 5-FU, in the treatment of colorectal cancer has been demonstrated in recent phase III trials.16,17 The ability of UFT and LV to deliver protracted plasma levels of 5-FU without the need for intravenous access or an infusion pump makes them an attractive alternative in regimens combining chemotherapy and radiation. Further studies exploring these strategies are therefore warranted.
Supported by Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.
The views expressed are the result of independent work and do not represent the views of the United States Food and Drug Administration or the United States government. Work described herein was performed while Richard Pazdur was an employee of The University of Texas M.D. Anderson Cancer Center.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999 2. Douglas HO Jr, Moertel CG, Mayer RJ, et al: Survival after postoperative combination treatment of rectal cancer. N Engl J Med 315: 1294-1295, 1986[Medline] 3. 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]
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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 5. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rates. J Clin Oncol 10: 896-903, 1992[Abstract]
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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 7. Minsky BD: Adjuvant postoperative combined-modality therapy for rectal cancer. Oncology (Huntingt) 13: 132-135, 1999 (suppl 3)[Medline] 8. Gastrointestinal Tumor Study Group: Prolongation of disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312: 1465-1472, 1985[Abstract] 9. Minsky BD: Role of adjuvant therapy in adenocarcinoma of the rectum. Semin Surg Oncol 17: 189-198, 1999[Medline] 10. Janjan NA, Khoo VS, Abbruzzese J, et al: Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: The M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 44: 1027-1038, 1999[Medline]
11.
Liu G, Franssen E, Fitch MI, et al: Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15: 110-115, 1997 12. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs 9: 479-490, 1998[Medline] 13. Hirata K, Sasaki K, Yamamitsu S, et al: A comparison of 5-fluorouracil concentration of 5-fluorouracil drip infusion versus oral UFT in plasma of same patients (in Japanese). Gan To Kagaku Ryoho (Jpn J Cancer Chemother) 20: 1409-1411, 1993 14. Ho DH, Pazdur R, Covington W, et al: Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4: 2085-2088, 1998[Abstract] 15. Okabe H, Toko T, Saito H, et al: Augmentation of the chemotherapeutic effectiveness of UFT, a combination of tegafur [1-(2-tetrahydrofuryl)-5-fluorouracil] with uracil, by oral 1-leucovorin. Anticancer Res 17: 157-164, 1997[Medline] 16. Pazdur R, Douillard J-Y, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFTTM in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 263a, 1999 (abstr 1009) 17. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of ORZEL® (oral uracil/tegafur (UFTTM) plus leucovorin (LV)) versus parenteral 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 264a, 1999 (abstr 1015) 18. Nakazato H, Koike A, Saji S, et al: Efficacy of oral UFT as adjuvant chemotherapy to curative resection of colorectal cancer: A prospective randomized clinical trial. Proc Am Soc Clin Oncol 16: 279a, 1997 (abstr 990) 19. Meterissian S, Skibber J, Rich T, et al: Patterns of residual disease after preoperative chemoradiation in ultrasound T3 rectal carcinoma. Ann Surg Oncol 1: 111-116, 1994[Medline] 20. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer. Chemother Pharmacol 37: 581-586, 1996 21. Hoff PM, Wenske CA, Medgyesy DC, et al: Phase I and pharmacokinetic (PK) study of the novel oral fluoropyrimidine, S-1. Proc Am Soc Clin Oncol 18: 173a, 1999 (abstr 665) Submitted April 5, 2000; accepted June 12, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
