Chemoradiation With Capecitabine Appears To Be Well-Tolerated and May Replace Infusional 5-FU in Locally Advanced Rectal Cancer

Oncology NEWS International Vol 12 No 8, Volume 12, Issue 8

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

HOUSTON-Preoperative radiotherapywith continuous infusion fluorouracil(5-FU) is known to improvesphincter preservation and producepathologically complete remissions in10% to 30% of patients with locally advancedrectal cancer. A preliminary safetyanalysis from a phase II study suggeststhat chemoradiation with capecitabineappears to be very well tolerated and mayreplace preoperative radiotherapy with5-FU in this setting.This interim analysis was reported byEdward H. Lin, MD, assistant professorgastrointestinal medical oncology, andNora Janjan, MD, professor of radiationoncology, at the M. D. Anderson CancerCenter, Houston (ASCO abstract 1152).Dr. Lin described how "randomizedstudies comparing preoperative vs postoperative5-FU-based chemoradiation inlocally advanced rectal cancer appearedto favor preoperative chemoradiation forlocal control because the intact tumor isbetter vascularized and oxygenated, allowingfor better drug delivery. The preoperativeapproach offers the potentialfor sphincter-sparing resection and it isbetter tolerated because of reduced radiationexposure to the small bowel. Furthermore,it produces evidence of 5-FU chemosensitivity in contrast to the postoperativeapproach."Additive EffectCapecitabine is preferentially convertedto 5-FU in tumor tissue by three enzymaticconversions. Thymidine phosphorylaseis responsible for the last step ofconversion and can be 70-fold higher intumor tissue than in normal tissue. TPactivation of capecitabine increases 5-FUconcentrations in the tumor.Radiotherapy also upregulates TP intumor tissue. The effect of capecitabine isat least additive when combined with radiotherapyin xenograft models. "Capecitabineis preferentially converted by thymidinephosphorylase, which is thenactivated up to 17-fold by radiation in thetumor," Dr. Lin explained. "This relationship may allow greater delivery of 5-FU tothe tumor tissue."Dr. Lin pointed out that capecitabinemimics continuous infusion 5-FU in itssuperior response rate and safety profilescompared to bolus 5-FU. Continuous infusion5-FU, however, "is cumbersome,expensive, and is associated with catheterand pump-related complications.Capecitabine simplifies chemoradiationby its oral administration and is highlyappealing to patients," Dr. Lin said.Phase II StudyBased on phase I data that capecitabineis safe and appears to be effective, "weinitiated a phase II study of oral capecitabine825 mg/m2 twice daily with radiotherapy45 Gy/25 fractions to the pelvisand 52.5 Gy/30 fractions to the primaryand perirectal nodes in 54 patients withlocally advanced rectal cancer," Dr. Linsaid. "All patients will have surgery, andan interim efficacy analysis for the first 19patients is planned. Eligible patients willalso receive 4 months of adjuvant capecitabinepostoperatively."The primary objective of the study isto determine the rate of pathologic response,and the secondary objectives aresafety, tolerability, overall survival, qualityof life, and biomarkers. Patients withT3 or T4, N0 or N1 disease on endoscopicultrasound are eligible.Preliminary Results"Preliminary results suggested thatcapecitabine provided many advantageswithout compromising efficacy, comparedwith the less convenient infusional5-FU plus radiation regimen," Dr. Linsaid."As of May 2003, 19 patients have beenenrolled in the study and completedchemoradiation, and all are evaluable fortoxicities. Fifteen of these patients underwentsurgery and are evaluable for pathologicresponse. Two patients have completedthe fourth 21-day cycle of adjuvanttreatment with capecitabine, and five additionalpatients are completing their thirdcycle," he reported.No reduction in capecitabine dose wasnecessary for 12 patients, and 4 patientsrequired only minor dose modificationdue to diarrhea or hand-foot syndrome.Clinical DownstagingEffective downstaging with capecitabineand radiation was observed (see Table1). The overall pathological response was87% (n = 15). Pathologic response ratesincluded complete response (20%), microscopicresidual tumor (27%), greaterthan 70% reduction in tumor volume(40%), and stable/progressive disease(13%). Overall pathologic downstagingwas seen in 73%: primary tumor (47%)and node (57%).Of the six patients with locally advancedrectal cancer who received capecitabinechemoradiation off protocol, all hadclinical downstaging, with three patientsachieving pathologic complete response."The results in terms of pathologicdownstaging (87%) with pathologic completeresponse (20%) and microscopicresidue (27%) suggest that this treatmentregimen is better or at least equivalent tothe historical M. D. Anderson experiencewith continuous infusion-5-FU plus radiationin this regard," Dr. Lin said.

The most common toxicities are ofgrade 1 in nature and include fatigue,radiation dermatitis, diarrhea, nausea andanorexia. Grade 2 toxicities are less common,about 10% to 15%, and includedthree cases of nausea/vomiting, two caseseach of radiation dermatitis, diarrhea, andhand-foot syndrome, and one case of fatigue.Serious grade 3 and 4 toxicities are rareat 5% to 6% and included two patientswith diarrhea and one patient each withnausea/vomiting, deep venous thrombosis,radiation enteritis, dehydration, andrenal failure. "Although grade 3/4 toxicitiesare rare, they do seem to cluster inelderly patients," Dr. Lin said. "Therefore,caution should be exercised for thosepatients who are 65 years or older andreceiving chemoradiation with capecitabine."