Capecitabine Promises Convenience, Efficacy in LARC, Five Studies Show

March 2, 2005

This special “annual highlights” supplement to Oncology News International (ONI)is a compilation of selected news on important advances in the management ofgastrointestinal cancers over the past year, as reported in ONI. Guest Editor, Dr.James L. Abbruzzese, comments on the reports included herein and discussesdevelopments in the clinical management of GI cancers, with a look at the impactof targeted agents with cytotoxic chemotherapy, first-line and adjuvant therapies foradvanced disease, and the role of statins and COX-2 inhibitors in prevention.

NEW ORLEANS-Capecitabine(Xeloda) shows encouraging activitywhen given with preoperativeradiation for locally advanced rectalcancer, according to multiple investigations.Use of the oral agent couldalso avoid the need for daily intravenousinfusions and the associated inconvenienceand risks.Five separate phase II investigationsadded a considerable amount of supportfor using capecitabine preoperativelyin patients with locally advancedrectal cancer. Two of the investigationsevaluated capecitabine plus oxaliplatin(Eloxatin), while three othersevaluated single-agent capecitabine inthis setting.Capecitabine Plus Oxaliplatin"As an oral agent, capecitabine cangreatly simplify chemoradiation,avoiding the need for time-consumingand potentially complicated dailyintravenous infusions," according toRobert Glynne-Jones, MBBS.Dr. Glynne-Jones, consultant clinicaloncologist with Mount VernonHospital, Northwood, United Kingdom,is the principal investigator inone of the two trials suggesting thatcapecitabine/oxaliplatin has promisingefficacy and acceptable safety forpatients with locally advanced rectalcancer (abstract 3575). Capecitabine/oxaliplatin has already been shown tobe well tolerated and "highly effective"in first-line treatment of metastaticcolorectal cancer, Dr. Glynne-Jones and colleagues indicated in theirpresentation.The phase I/II trial, which is knownas SOCRATES (from the Scottish CancerRegistration System) is designedto evaluate the combination of oralcapecitabine, IV oxaliplatin, and standard radiotherapy to the pelvic region(XELOX-RT) followed by surgery inhistologically confirmed rectal adenocarcinoma.In the phase I portion of the trial,investigators determined the recommendeddoses of capecitabine (650mg/m2 twice daily for 5 weeks) andoxaliplatin (130 mg/m2 on days 1 and29). Data show that XELOX-RT enhancedsurgical resection, accordingto the investigators. Of 16 patientsundergoing surgery, an R0 resectionwas achieved in 14. Complete responseswere observed in five patients.In the phase II portion, 62 patientshave been enrolled. While pathologydata from phase II are not yet mature,safety data reported suggest the recommendeddose is well tolerated.Grade 3-4 adverse events were seen inonly 10 of 41 patients evaluable forsafety. Hand-foot syndrome (grade 1)was observed in only two patients.Belgian InvestigationIn a separate phase II study, Belgianinvestigators reported preliminaryresults suggesting that preoperativecapecitabine/oxaliplatin plusradiotherapy was feasible, with diarrheabeing the only clinically relevanttoxicity (abstract 3552).Lionel R. Duck, MD, UniversitCatholique de Louvain, Brussels, Belgium, reported that among 17 resectedrectal specimens, one specimen indicateda pathological complete remission,and five specimens had onlymicrofoci of residual tumor. All specimenswere reviewed by the same pathologist.Treatment in this trial consisted ofradiotherapy 5 days a week for 5 weeksfor a total dose of 45 Gy, plus oxaliplatin50 mg/m2 IV weekly, plus oralcapecitabine 825 mg/m2 twice daily.Patients received more than 90% ofthe planned dose of both oxaliplatinand capecitabine. In two patients, radiotherapywas interrupted becauseof diarrhea.German Study UpdateA German study group reportingat ASCO 2003 (abstract 1113) thatcapecitabine plus standard radiotherapywas "highly effective" as neoadjuvanttherapy for locally advanced rectalcancer, provided an update in 2004.The update confirmed that the oralagent is "an adequate substitute" forcontinuous infusion 5-FU in preoperativechemoradiation regimens."Oral capecitabine simplifieschemoradiation, avoiding the unwantedrisks and inconvenience associatedwith IV 5-FU," reported Juergen Dunstand colleagues from the departmentof radiotherapy at Martin-Luther-University, Halle, and other study sitesin Germany.The interim analysis of a phase IItrial included clinical response datafor 69 patients. By intent-to-treat analysis,capecitabine chemoradiation resultedin clinical complete or partialremissions in 42 patients (61%). Thisenabled R0 resections in 89% of patientsundergoing surgery. Tumordownstaging was achieved in 62%.A "low incidence" of grade 3-4 adverseevents was reported by the Germanresearchers. The most commonadverse event, diarrhea, occurred in46% of patients, but only four patients(7%) experienced diarrhea that was ofgrade 3-4 intensity.Italian and French TrialsItalian and French research groupsalso reported results for phase II investigationsof capecitabine chemoradiation.Encouraged by the positive resultspreviously reported by the Germans,the Italian group, led by Antonio DePaoli, MD, of the National CancerInstitute-CRO in Aviano, tested a similarregimen (abstract 3540).In 53 patients evaluable for safetyand efficacy, complete or partial clinicalresponse was seen in 31 (58%).Tumor downstaging was achieved in29 of 51 patients (57%). Only six ofthese patients had grade 3 toxicity andnone had grade 4.French researchers with the GERCOR(Oncology Multidisciplinary ResearchGroup) group also reportedtheir phase II experience with preoperativecapecitabine chemoradiation(abstract 3538). Among the 51 studypatients, 50 underwent surgery and 1refused. Histopathology showed that24% had complete response, while12% had persistence of minimal tumorcell foci and 23% had additionaltumor downstaging. Tumor-free resectionmargins were achieved in everypatient. Adverse events were mainlygastrointestinal, including three casesof grade 3 diarrhea."Capecitabine chemoradiotherapyis well tolerated, and the efficacysupports further exploration, as asingle agent and as part of new therapeuticstrategies with chemo- andbiological therapies," investigatorsconcluded.