Clinical outcomes of third-line chemotherapy prior to best supportive care in patients with stage IV colorectal cancer: a single-center study from Japan.

Background: Colorectal cancer (CRC) is a major cause of cancer-related mortality in Japan, and while first- and second-line regimens have improved outcomes, the optimal third-line strategy remains unclear. Modified regimens based on Narrative Evidence-Based Medicine (NEBM) and Minimally Effective Cytotoxic Dose (MECD) theory have shown promise in maintaining survival with fewer adverse events (AEs) in Japanese patients. This study aimed to retrospectively evaluate the survival outcomes, efficacy, and safety of third-line chemotherapy following standardized earlier treatments in stage IV CRC. Methods: This study retrospectively evaluated 37 patients, 12 with advanced recurrence following primary tumor resection and 25 with unresectable tumors with distant metastases, who had received at least three courses of chemotherapy (175 courses). The 12- and 36-month progression-free survival (PFS) and overall survival (OS) rates, along with median survival time (MST), were assessed. The number of courses (median), objective response rate (ORR), clinical benefit rate (CBR), and AEs were also examined. In addition, the 60-month (60M)-OS and MST were calculated from the initiation of first-line chemotherapy to assess the long-term efficacy of multidisciplinary treatment in advanced recurrent CRC. Results: The 12-month (12M)-PFS and 12M-OS were 18.9% (MST 4.1 months) and 52.9% (MST not reached), respectively. The 36-month (36M)-PFS and 36M-OS rates were 5.4 % (MST 4.1 months) and 13.9% (MST 13.3 months), respectively. Meanwhile, the 60M-OS rate was 27.8%, with an MST of 39.9 months. The median number of courses was 7.0 (4.0-9.0), with an ORR and CBR of 10.8% and 37.8%, respectively. AEs were mostly grade 1, while hematological side effects tended to be grade 2, but improved after adjusting the dose and dosing interval. Only two patients (5.4%) required granulocyte colony-stimulating factors. Grade 3 AEs included leukopenia (n=2, 5.4%), neutropenia (n=6, 16.2%), thrombocytopenia (n=2, 5.4%), and allergic reaction (n=1, 3.0%). After three courses, grade 3 hematological AEs included neutropenia (n=6, 16.2%), thrombocytopenia (n=2, 5.4%), and anemia (n=2, 5.4%). Conclusions: This study demonstrates that third-line chemotherapy incorporating oral anticancer drug and bevacizumab (B-mab) following standardized treatment is a safe and effective option for Japanese patients with stage IV CRC. The regimen was associated with a manageable safety profile and encouraging long-term outcomes and may contribute to improved quality of life and quality-adjusted life years prior to transition to best supportive care.