Capecitabine Should Replace 5-FU in Adjuvant Treatment of Dukes’ C Colon Cancer, Investigator Avers

September 1, 2004

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

NEW ORLEANS-Oral capecitabine(Xeloda) should supplant thecurrent standard intravenous fluorouracil/leucovorin (5-FU/LV) regimen,owing to its superior safety, and efficacythat is at least equivalent to thestandard of care, according to JamesCassidy, MD."At least in my opinion, capecitabineshould replace bolus 5-FU andleucovorin in the adjuvant treatmentof Dukes' C colon cancer patients,"said Dr. Cassidy, chair of the CancerResearch United Kingdom Departmentof Medical Oncology, GlasgowUniversity, at the 40th Annual Meetingof the American Society of ClinicalOncology.Dr. Cassidy reported new resultsfrom the X-ACT trial (Xeloda in AdjuvantColon Cancer Therapy) thatincluded nearly 2,000 patients with(stage III)/Dukes' C colon cancer whounderwent curative surgery followedby chemotherapy (abstract 3509) (Figure1).The study met its primary endpointof achieving disease-free survival atleast equivalent to standard 5-FU/leucovorin,while other clinical endpointssuggested superiority to the standardof care. In addition, capecitabine-treatedpatients had a significantly lowerincidence of the most severe toxicities."There is a trend to improved diseasefreesurvival, and almost superiorityin overall survival," Dr. Cassidy said.Relapse-free survival was superior."There is definitely improved safety.In every important side effect, capecitabineis better," Dr. Cassidy noted.Potential for Change
Findings of the X-ACT trial havethe "potential to bring a change to thecurrent standard of adjuvant treat-ment" for colon cancer, according toHoward A. Burris III, MD, of the SarahCannon Cancer Center, Nashville,Tennessee.

Dr. Burris, one of more than 160investigators in the X-ACT study, saidresults show that "a convenient oralregimen can be used in place of hoursof cumbersome chemotherapy."By intent-to-treat analysis, 3-yeardisease-free survival was 64.2% in thecapecitabine arm vs 60.6% for 5-FU/leucovorin (hazard ratio [HR] = 0.87,95% confidence interval [CI], 0.75-1.00, P = .0528, see Figure 2). "Certainly,I think one could interpret thisas showing at least equivalence-certainlynot inferiority, and almost certainlya degree of superiority," Dr.Cassidy said. These results show thattreatment with capecitabine produceda 13% reduction in the risk of diseaserelapse or death from any cause whencompared to IV 5-FU.The X-ACT trial is an "excellentequivalence trial" that has indeedachieved its primary objective of showingequivalence to 5-FU/LV, said EricVan Cutsem, MD, PhD, of the DigestiveOncology Unit, University HospitalGathuisberg; Leuven, Belgium."The conclusions of the X-ACT trialare that capecitabine is at least as effectiveas bolus 5-FU/folinic acid, with atrend to improved activity," Dr. VanCutsem said. "Also, Dr. Cassidy hasshown us that capecitabine is less toxicthan bolus 5-FU."

All Chemotherapy-Naive
All patients in X-ACT had chemotherapy-naive Dukes' C colon cancerwith curative resection and were randomizedto capecitabine or bolus 5-FU/leucovorin.Capecitabine was given at a dosageof 1,250 mg/m2 twice daily for 14 daysin a 21-day cycle. Alternatively, patientsreceived the Mayo Clinic regimenof 5-FU 425 mg/m2 and leucovorin20 mg/m2, given on days 1 to 5every 28 days. In total, both patientgroups received 24 weeks of treatment(eight cycles of capecitabine or six cycles of 5-FU/LV).Median age of patients in X-ACTwas approximately 62 years and 85%were Eastern Clinical Oncology Group(ECOG) performance status (PS) 0,with 15% having a PS of 1. More than80% of patients had normal carcinoembyronicantigen (CEA) and the majority(76%) had T3 disease. Medianfollow-up at the time of this analysiswas 3.8 years.While the primary endpoint ofequivalence in disease-free survival wasmet, relapse-free survival actually metstatistical criteria for superiority favoringcapecitabine. Three-year relapse-free survival was 65.5% forcapecitabine vs 61.9% for 5-FU/leucovorin(HR = 0.86, 95% CI 0.74-0.99, P = .0407). "At least for thisparticular endpoint, capecitabine isclearly superior to the Mayo Clinicregimen," Dr. Cassidy said. The differencetranslates into a 14% reductionin risk of relapse from colon can-cer among patients treated withcapecitabine.Overall survival also showed atrend in improvement favoringcapecitabine. Three-year overall survivalwas 81.3% for capecitabine and77.6% for 5-FU/leucovorin (HR =0.84, 95% CI 0.69-1.01, P = .0706).This difference translates into a 16%reduction in risk of death comparedto IV 5-FU. "We need to follow thepatients longer," Dr. Cassidy said,"[but] the separation [in survivalcurves] is in the direction of an advantagefor capecitabine."Capecitabine also offered an improvedside effect profile. Previouslypublishedsafety results (Ann Oncol14(12):1735-1743, 2003), show thatthere was significantly less diarrhea,stomatitis, neutropenia, nausea/vomiting,and alopecia in the capecitabinearm vs the 5-FU/leucovorin arm (P Potential Criticisms Addressed
According to Dr. Van Cutsem, onepoint of discussion for X-ACT is theuse of bolus 5-FU/leucovorin insteadof infusional 5-FU/leucovorin as a controlarm. "We have data from somestudies-an intergroup study in theUnited States and a French study-that show an identical activity of bolusvs infusional 5-FU regimen in the adjuvantsetting," he said.The X-ACT investigators also addressedanother potential criticism upfront-whether the performance ofthe Mayo Clinic regimen was inferiorto what has been observed in otherstudies. In fact, the Mayo arm inX-ACT had comparable efficacy withother trial data in Dukes' C patients.For example, the 3-year disease-freesurvival of 61% was comparable tofindings of 61%, 62%, and 63% inthree other trials comprising a total ofmore than 1,300 patients."There really is no difference here,so that potential explanation is notvalid," Dr. Cassidy said.One other potential criticism wasthat the desired chemotherapy durationor intensity may not have beenachieved in one or both arms. Therewas no difference, however, in thenumber of patients completing thefull course of treatment (84% forcapecitabine and 88% for bolus 5-FU/leucovorin), the number of patientsneeding dose reduction (42% and44%), or the number needing interruptionor delay (57% and 52%).FDA Approval Sought
This report on X-ACT was one oftwo suggesting an important role fororal fluoropyrimidines in the adjuvanttreatment of colon cancer. Alsoreported was a randomized trial oftegafur-uracil (UFT) vs 5-FU/leucovorin(see report on abstract 3508 onpage 13)."The data for capecitabine, basedon the trials that we have seen today,are more solid," Dr. Van Cutsem added.For the future, a major questionwill be whether capecitabine can replace5-FU/leucovorin in combinationregimens in the adjuvant setting.In particular, Dr. Van Cutsem suggestedpotential combinations can beexplored with oral fluoropyrimidinesplus oxaliplatin (Eloxatin) or irinotecan(CPT-11, Camptosar), or withnovel targeted agents such as bevacizumab(Avastin) and cetuximab(Erbitux)."We can conclude that the oralfluoropyrimidines are to be preferredto bolus intravenous 5-FU/folinic acidin the adjuvant treatment of coloncancer," he said.Capecitabine is currently indicatedas first-line treatment of metastaticcolorectal cancer when treatment withfluoropyrimidine therapy aloneis preferred. Results of the X-ACT trialwere submitted to the FDA in Augustto support the use of capecitabinefor adjuvant treatment of colon cancer.