Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer

Gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) are active cytotoxic drugs against pancreatic cancer. Preclinical data evaluating the combination of gemcitabine and irinotecan suggest dose-dependent synergistic interactions in SCOG small-cell lung cancer and MCF-7 breast cancer cell lines. Two phase I trials of this combination have been reported to date: the day 1 and 8 every-3-week schedule (IrinoGem trial), and the day 1, 8, and 15 every-4-week schedule (MSKCC trial). Both trials aimed to determine the maximum tolerated dose of irinotecan when administered as a 90-minute i.v. infusion either immediately after (IrinoGem) or before or immediately after (MSKCC) gemcitabine at 1,000 mg/m2 by 30-minute i.v. infusion in patients with solid tumors. The achieved maximum tolerated dose of IrinoGem has a higher dose intensity of irinotecan (100 mg/m2 on days 1 and 8, every-3-week cycle) compared with the MSKCC schedule (60 mg/m2 on days 1, 8, and 15, every-4-week trial). In IrinoGem, two of three previously untreated metastatic pancreas cancer patients had durable radiologic partial responses. The third had stable disease with clinical benefit for eight cycles. In addition, a patient with metastatic adenocarcinoma of unknown primary--potentially pancreatic--has had a durable response and is alive more than 30 months after the diagnosis. Preliminary results of a 45-patient multicenter phase II trial with IrinoGem in advanced and metastatic pancreas cancer were recently reported. Toxicity was modest, with no toxic deaths or neutropenic fever. Radiologic response rate was 20% of patients (9 out of 45), and a CA 19-9 decrease of more than 50% from baseline values occurred in 32.5% of patients (13 out of 40). Median survival was 6 months (range: 0.9 to 12.2+ months) and median time to treatment failure was 2.9 months (range: 0.1 to 11.3+ months). A pivotal international multicenter phase III trial comparing IrinoGem to single-agent gemcitabine in advanced and metastatic pancreas cancer is ongoing.