Phase II study of irinotecan/S-1 combination chemotherapy for patients with oxaliplatin-refractory colorectal cancer

Abstract

To determine the efficacy and tolerance of irinotecan in combination with S-1 (IRIS) for patients whose disease progressed after treatment with an oxaliplatin-based therapy for colorectal cancer (CRC). Each patient's disease had progressed after the administration of a regimen containing oxaliplatin and 5-FU. S-1 was administered orally at a fixed dose of 40 mg/m(2) twice daily on days 1-14 and 21-35. Irinotecan (150 mg/m(2)) was administered via intravenous infusion on days 1, 15, and 29. Courses were repeated every 6 weeks. 20 patients were enrolled in this study between April 2006 and March 2008. The median age was 63 years (range: 34-74), and the dominant metastasis sites were the liver, lung, and lymph nodes. The objective response rate was 20%; 1 patient registered complete response and 3 patients registered partial responses; 7 patients were stabilized (35%); and 9 evidenced progression of disease (45%). Median progression-free survival was 3.0 months (95% CI, 2.1-3.9 months) and median overall survival was 9.8 months (95% CI, 6.3-13.3 months). For the 41 cycles analyzed, the most commonly detected hematologic toxicity was grade I-II anemia (63.4%). Leukopenia occurred in 18 cycles (41.5%), including eight cycles (19.5%) of grade 3-4 leukopenia. Frequently observed non-hematologic toxicities included the following: grade I vomiting was reported in 4 patients (20%), grade 2 neuropathy occurred in 3 patients (15%), and grade 2 mucositis was noted in 2 patients (10%). Two patients died from sepsis and hematemesis during treatment. Although the response rate in stage I reached the target (≥ 3/18, p0 = 10%) established for movement to stage II, this study had to be discontinued because two patients died during treatment. Additionally, the follow-up loss rate was higher (16.6%) than we had anticipated (<10%). Even though a regime consisting of irinotecan combined with S-1 (IRIS) has proven effective in oxaliplatin-pretreated patients with advanced CRC, treatment-related mortalities and the high follow-up loss rate suggested that this IRIS protocol should result in early closure and modification.

Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

“…8,9 We report that treatment with the chemotherapeutic agent irinotecan induces mucositis, which is in agreement with previous studies reporting this association in both humans and mice. 13,14,36 More importantly, we define the crucial role played by ASC/caspase-1 activation and consequent IL-1b and IL-18 production for establishment of the inflammatory response in irinotecan-induced mucositis. Furthermore, our results indicate the important participation of ROS in Figure 6 IL-1b and IL-18 play important but redundant roles in mucositis induced by irinotecan.…”