Capecitabine/Irinotecan Active and Well-Tolerated as First-Line Therapy for Metastatic Colorectal Cancer

SEATTLE-The combination ofcapecitabine (Xeloda) and irinotecan(CPT-11, Camptosar) as first-line therapyfor metastatic colorectal cancer hasclinical activity with an acceptable toxicityprofile. Philip J. Gold, MD, director ofclinical research, Swedish Cancer Institute,Seattle, reported these preliminaryresults of a phase II study undertaken todevelop a regimen providing continuousfluoropyrimidine exposure without theinconvenience associated with infusionaltherapy (ASCO abstract 1158). The nationwidetrial was conducted at 16 centers.Neal Meropol, MD, of Fox ChaseCancer Center in Philadelphia served asprincipal investigator.Study DesignThere were two cohorts of patients inthe study. Cohort one (n = 15) receivedirinotecan 125 mg/m² and capecitabine1,000 mg/m² twice daily. Due to toxicityin the first cohort, the doses of capecitabineand irinotecan were reduced in a second cohort of patients. Cohort two (n =27) received irinotecan 100 mg/m² andcapecitabine 900 mg/m² twice daily.Treatment was administered every 21days in both cohorts: irinotecan on days 1and 8 over 90 minutes IV, and oral capecitabineon days 2 to 15 every 12 hours.Eligible patients had histologically confirmedmetastatic colorectal cancer; bidimensionallymeasurable disease; tumortissue available from the primary and atleast one metastatic site for molecularcorrelate studies; and a Karnofsky performancestatus (KPS) greater than or equalto 80. Any prior adjuvant fluorouracil (5-FU) therapy must have occurred morethan 12 months prior to the study. Patientswith prior chemotherapy treatmentfor metastatic/recurrent colorectal canceror prior therapy with capecitabine oririnotecan were also ineligible.The median age for patients in bothcohorts was 61. The median KPS was 100in cohort one and 90 in cohort two. Amongboth cohorts of patients, 14 had one metastaticsite, 19 had two sites, 6 had threesites, and 2 patients had four sites.

Evaluation and ResponsePatients were evaluated weekly for toxicityand then every 6 weeks for responseby magnetic resonance imaging (MRI),computed tomography (CT) scan/x-ray.Tumors were assessed based on theRECIST criteria (Response EvaluationCriteria in Solid Tumors) for response,and safety and survival status was evaluatedin all patients who receive at least onedose of study medication and had followupdata.The objective of the study was to evaluatethe overall objective response ratefor capecitabine plus irinotecan as firstlinetherapy for metastatic colorectal cancerpatients, and to evaluate the safetyprofile of the regimen. An additional objectivewas to describe expression of severalbio-markers-thymidylate synthase,thymidine phosphorylase, dihydropyrimidinedehydrogenase-that are potentially predictive of capecitabine activity.This final objective was based on a mandatorybiopsy of metastatic sites.Preliminary results are available forcohorts one and two, although cohort two will continue accrual until 50 patients areenrolled. In cohort one, complete responsewas seen in one patient (7%), partialresponse in six patients (40%), stabledisease in eight (53%), and progressivedisease in none. None of the patients incohort two had complete response, eight(35%) had partial response, 11 (48%) hadstable disease, and four (17%) had progressivedisease. Overall response was 47%(7 patients) for cohort one, and 35% (eightpatients) for cohort two (see Table 1).For cohort one, the median time toprogression was 8.1 months and medianduration of response was 7 months. Thesedata are not yet available for cohort two.Early Recognition ofAcceptable ToxicityIn cohort one, grade 3/4 toxicities werediarrhea (eight), dehydration (four), febrileneutropenia/sepsis (two), anorexia(one), depression (one), mucosal inflammation(one), renal failure (one), andcolitis (one). In cohort two, with reduceddoses but a larger number of patients,grade 3/4 toxicities were diarrhea (11),hand-foot syndrome (two), dehydration(two), deep vein thrombosis (two), andfebrile neutropenia/sepsis (one). Earlyrecognition of unacceptable toxicity incohort one highlights the importance andfeasibility of continuous adverse eventmonitoring in multicenter studies.In summarizing the preliminary resultsof the study, Dr. Gold said, "Thecombination of capecitabine and irinotecanhas activity in patients with metastaticcolorectal cancer. Once the startingdose was reduced, the combination waswell tolerated. After the study has accrued50 patients for cohort 2, then biomarkeranalysis will be performed. We will seekto determine whether biomarker assessmentmay be predictive of capecitabineactivity."