A prospective phase II study of raltitrexed combined with S-1 as salvage treatment for patients with refractory metastatic colorectal cancer

Abstract

Aim: A third-line chemotherapy regimen for metastatic colorectal cancer (mCRC) is not available in China. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with fluorouracil (5-FU). In this phase II study, we prospectively analyzed the efficacy and safety of raltitrexed combined with S-1 (RS regimen) in the treatment of mCRC after the failure of conventional chemotherapy.

Methods: A total of 105 patients with mCRC with progression following treatment with 5-FU, oxaliplatin, and irinotecan were enrolled between November 2015 and May 2019. Patients received intravenous infusion of raltitrexed (3 mg/m2 from day 1 every 3 weeks) and oral S-1 (80-120 mg for 14 days every 3 weeks). Tumor evaluations were performed every two cycles according to the RECIST 1.1 guidelines.

Results: In the intention-to-treat patients, the objective response and disease control rates were 7.62% and 48.57%, respectively. The median progression-free survival and median overall survival were 2.5 and 8.0 months, respectively. Common adverse events included neutropenia, anemia, thrombocytopenia, and nausea, while neutropenia, anemia, thrombocytopenia nausea, diarrhea, skin eruption, and oral ulceration had grade 3 or higher adverse events. Subgroup analysis revealed that primary site or gene mutation status had little influence on the RS regimen efficacy, while the baseline albumin level, 5-FU administration in second-line therapy, and number of previous treatment regimens affected the efficacy.

Conclusion: The RS regimen demonstrated favorable effects in patients with mCRC following failure of standard chemotherapy, and could be a new choice for third-line treatment, and must be verified in future randomized clinical trials (Clinical trial: NCT02618356).

Keywords: metastatic colorectal cancer; prospective phase II study; raltitrexed-S-1 combination; subgroup survival analysis; third-line chemotherapy regimen.

Conflict of interest statement

AUTHOR CONTRIBUTIONS

Conceptualization: Weijian Guo. Project administration and resource: WeiJian Guo Mingzhu Huang, Yusheng Wang, Xiaodong Zhu, Zhiyu Chen, Wen Zhang, Chenchen Wang, Xiaowei Zhang, LixinQiu, Zhe Zhang, Xiaoying Zhao, and Wenhua Li. Data curation: Mingzhu Huang, Yusheng Wang, and Yue Yang. Data analysis: Yue Yang. Writing‐original draft: Mingzhu Huang and Yue Yang. Writing‐review and editing: Weijian Guo.

ETHICS STATEMENT

This study is registered with ClinicalTrials.gov, number: NCT02618356. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Fudan University Shanghai Cancer Center and Shanxi Cancer Hospital, and a signed informed consent was obtained from all the participants.

© 2021 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.

Figures

FIGURE 1

Survival analysis of intention‐to‐treat (ITT) group and per‐protocol (PP) group. A, Overall survival (OS) analysis of ITT group, medium progression‐free survival (PFS) months (95% CI): 2.5 (1.5‐3.0). B, PFS analysis of ITT group, medium OS months (95% CI): 8.0 (7.0‐10.0). C, OS analysis of PP group, medium PFS months (95% CI): 2.5 (1.8‐3.0). D, PFS analysis of PP group, medium OS months (95% CI): 8.0 (7.0‐10.0) [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Univariable survival analysis of primary site, gene status, metastatic site number baseline Alb, chemotherapy line and usage of 5‐FU in second‐line chemotherapy in intention‐to‐treat (ITT) group. A, Kaplan‐Meier survival curve of progression‐free survival (PFS) and overall survival (OS) according to primary site (P = .044, P = .65). B, Kaplan‐Meier survival curve of PFS and OS according to gene status (P = .46, P = .46). C, Kaplan‐Meier survival curve of PFS and OS according to number of metastatic sites (P = .81, P = .053). D, Kaplan‐Meier survival curve of PFS and OS according to baseline Alb level (P = .0022, P = .014). E, Kaplan‐Meier survival curve of PFS and OS according to line of chemotherapy (P < .0001, P = .051). F, Kaplan‐Meier survival curve of PFS and OS according to usage of 5‐FU in second‐line chemotherapy (P = .05, P = .75) [Colour figure can be viewed at wileyonlinelibrary.com]