A single-center retrospective analysis of the efficacy and safety of a modified regimen of irinotecan plus S-1 (IRIS) with molecular targeting agents as second-line chemotherapy in Japanese patients with recurrent or nonresectable colorectal cancer

Abstract

Background: As the second-line chemotherapy for stage IV recurrent or nonresectable colorectal cancer, our hospital started a modified treatment regimen comprising of irinotecan plus S-1 (IRIS) [tegafur/gimeracil/oteracil (S-1)] plus molecular targeting agents (MTAs), i.e., an epidermal growth factor receptor (EGFR) inhibitor such as panitumumab (P-mab) or cetuximab (C-mab) or vascular endothelial growth factor (VEGF) inhibitor such as bevacizumab (B-mab) since October 2012. The purpose of this study is to evaluate the efficacy and safety of this modified regimen.

Methods: This retrospective study included 41 patients with advanced recurrent colorectal cancer at our hospital whom at least 3 courses of chemotherapy were conducted from January 2015 to December 2021. Based on the location of the primary tumor, patients were classified into two group (right-sided group, proximal to the splenic curve, and left-sided, distal to the splenic curve). We assessed archived data on RAS and BRAF status and UGT1A1 polymorphisms and use of the VEGF inhibitor bevacizumab (B-mab) and the EGFR inhibitors panitumumab (P-mab) and cetuximab (C-mab). In addition, progression-free survival rate (36M-PFS) and the overall survival rate (36M-OS) were calculated. Furthermore, the respective median survival time (MST), the median number of treatment courses; the objective response rate (ORR) and clinical benefit rate (CBR) and the incidence of adverse events (AEs) were assessed as well.

Results: There were 11 patients (26.8%) in the right-sided group, and 30 patients (73.2%) in the left-sided group. There were 19 patients with RAS wild type (46.3%) (1 in the right sided group and 18 in the left sided group). P-mab was used for 16 of these patients (84.2%), C-mab for 2 (10.5%), and B-mab for 1 (5.3%); the remaining 22 patients (53.7%). Ten patients in the right group and 12 patients in the left group were a mutated type and received B-mab. BRAF testing was performed in 17 patients (41.5%); as more than 50% of patients (58.5%) were included before the assay's introduction. Five patients in the right-sided group and 12 patients in the left-sided group had wild type. There was no mutated type. UGT1A1 polymorphism was tested in 16/41 patients: Eight were wild type (8/41 patients, 19.5%) and 8, mutated type. Regarding the *6/*28 double heterozygous type, there was only 1 patient in the right-sided group and the remaining 7 patients were in the left-sided group. The total number of chemotherapy courses was 299, and the median number, 6.0 (range, 3-20). PFS, OS, and MST were as follows: 36M-PFS (total/Rt/Lt), 6.2%/0.0%/8.5% (MST; 7.6/6.3/8.9 months); and 36M-OS (total/Rt/Lt), 32.1%/0.0%/44.0% (MST; 22.1/18.8/28.6 months). The ORR and CBR were 24.4% and 75.6%, respectively. The majority of AEs were grades 1 or 2 and were improved with conservative treatment. Grade 3 leukopenia was observed in 2 cases (4.9%), neutropenia in 4 cases (9.8%), and malaise/nausea/diarrhea/perforation in 1 case each (2.4%). Grade 3 leukopenia (2 patients) and neutropenia (3 patients) were more commonly observed in the left-sided group. Diarrhea and perforation were also common in the left-sided group.

Conclusions: This second-line modified IRIS regimen with MTAs is safe and effective and results in good PFS and OS.

Keywords: Colorectal cancer; chemotherapy; irinotecan plus S-1 (IRIS); molecular targeting therapy; recurrent/non-resectable cancer.

Figure 1

Modified IRIS regimen [irinotecan plus tegafur/gimeracil/oteracil (S-1)] with molecular targeting agents. Similar to FOLFOX 6, irinotecan (85 mg/m²) was administered via direct intravenous infusion at the outpatient clinic on day 1 and day 15 (4 weeks per course), and S-1 was administered orally according to the package insert (80–120 mg/m²; 2 weeks on/2 weeks off). IRIS, irinotecan plus S-1; BSA, body surface area; S-1, tegafur/gimeracil/oteracil.

Figure 2

Kaplan-Meyer curves. (A) 12M-PFS: 31.7%, 24M-PFS: 12.3%, and 36M-PFS: 6.2% (MST: 7.6 M). (B) 12M-OS: 70.6%, 24M-OS: 49.4%, and 36M-OS: 32.1% (MST: 22.1 M). The follow-up rate was 78.1%. PFS, progression-free survival; MST, median survival time; OS, overall survival.

Figure 3

Kaplan-Meyer curves. (A) 12M-PFS: Rt. 9.1% vs. Lt. 40.0% (P=0.037); 24M-PFS: Rt. 0.0% vs. Lt. 17.0% (P=0.016); and 36M-PFS: Rt. 0.0% vs. Lt. 8.5% (P=0.016) (MST: Rt. 6.3 M/Lt. 8.9 M). (B) 12M-OS: Rt. 54.5% vs. Lt. 76.5% (P=0.204); 24M-OS: Rt. 40.9% vs. Lt. 52.7% (P=0.360); and 36M-OS: Rt. 0.0% vs. Lt. 44.0% (P=0.070) (MST: Rt. 18.8 M/Lt. 28.6 M). PFS, progression-free survival; MST, median survival time; OS, overall survival.