SEATTLE-The combination of capecitabine(Drug information on capecitabine) (Xeloda) and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) as first-line therapy for metastatic colorectal cancer has clinical activity with an acceptable toxicity profile. Philip J. Gold, MD, director of clinical research, Swedish Cancer Institute, Seattle, reported these preliminary results of a phase II study undertaken to develop a regimen providing continuous fluoropyrimidine exposure without the inconvenience associated with infusional therapy (ASCO abstract 1158). The nationwide trial was conducted at 16 centers. Neal Meropol, MD, of Fox Chase Cancer Center in Philadelphia served as principal investigator. Study Design There were two cohorts of patients in the study. Cohort one (n = 15) received irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 twice daily. Due to toxicity in the first cohort, the doses of capecitabine and irinotecan were reduced in a second cohort of patients. Cohort two (n = 27) received irinotecan 100 mg/m2 and capecitabine 900 mg/m2 twice daily. Treatment was administered every 21 days in both cohorts: irinotecan on days 1 and 8 over 90 minutes IV, and oral capecitabine on days 2 to 15 every 12 hours. Eligible patients had histologically confirmed metastatic colorectal cancer; bidimensionally measurable disease; tumor tissue available from the primary and at least one metastatic site for molecular correlate studies; and a Karnofsky performance status (KPS) greater than or equal to 80. Any prior adjuvant fluorouracil(Drug information on fluorouracil) (5- FU) therapy must have occurred more than 12 months prior to the study. Patients with prior chemotherapy treatment for metastatic/recurrent colorectal cancer or prior therapy with capecitabine or irinotecan were also ineligible. The median age for patients in both cohorts was 61. The median KPS was 100 in cohort one and 90 in cohort two. Among both cohorts of patients, 14 had one metastatic site, 19 had two sites, 6 had three sites, and 2 patients had four sites. Evaluation and Response Patients were evaluated weekly for toxicity and then every 6 weeks for response by magnetic resonance imaging (MRI), computed tomography (CT) scan/x-ray. Tumors were assessed based on the RECIST criteria (Response Evaluation Criteria in Solid Tumors) for response, and safety and survival status was evaluated in all patients who receive at least one dose of study medication and had followup data. The objective of the study was to evaluate the overall objective response rate for capecitabine plus irinotecan as firstline therapy for metastatic colorectal cancer patients, and to evaluate the safety profile of the regimen. An additional objective was to describe expression of several bio-markers-thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase-that are potentially predictive of capecitabine activity. This final objective was based on a mandatory biopsy of metastatic sites. Preliminary results are available for cohorts one and two, although cohort two will continue accrual until 50 patients are enrolled. In cohort one, complete response was seen in one patient (7%), partial response in six patients (40%), stable disease in eight (53%), and progressive disease in none. None of the patients in cohort two had complete response, eight (35%) had partial response, 11 (48%) had stable disease, and four (17%) had progressive disease. Overall response was 47% (7 patients) for cohort one, and 35% (eight patients) for cohort two (see Table 1). For cohort one, the median time to progression was 8.1 months and median duration of response was 7 months. These data are not yet available for cohort two. Early Recognition of Acceptable Toxicity In cohort one, grade 3/4 toxicities were diarrhea (eight), dehydration (four), febrile neutropenia/sepsis (two), anorexia (one), depression (one), mucosal inflammation (one), renal failure (one), and colitis (one). In cohort two, with reduced doses but a larger number of patients, grade 3/4 toxicities were diarrhea (11), hand-foot syndrome (two), dehydration (two), deep vein thrombosis (two), and febrile neutropenia/sepsis (one). Early recognition of unacceptable toxicity in cohort one highlights the importance and feasibility of continuous adverse event monitoring in multicenter studies. In summarizing the preliminary results of the study, Dr. Gold said, "The combination of capecitabine and irinotecan has activity in patients with metastatic colorectal cancer. Once the starting dose was reduced, the combination was well tolerated. After the study has accrued 50 patients for cohort 2, then biomarker analysis will be performed. We will seek to determine whether biomarker assessment may be predictive of capecitabine activity."