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

Introduction

According to the International Agency for Research on Cancer, approximately two million cases of colorectal cancer (CRC) were diagnosed in 2020, making it the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide (1). In recent years, the incidence of CRC is increasing in Asia, with approximately 50,000 new cases reported annually in Japan, making it the second leading cause of cancer-related mortality (2). The number of new cases and deaths due to CRC is expected to continue to increase in the future, and the importance of its prevention and treatment is being emphasized globally. The multidisciplinary treatment of CRC has made remarkable progress over the past two decades. In particular, the approval of molecular targeted therapies identified through genetic testing, such as cetuximab and panitumumab (epidermal growth factor receptor antibodies), and bevacizumab (B-mab) (vascular endothelial growth factor antibody), marked a significant advancement. Additionally, agents such as encorafenib (3), dabrafenib (B-Raf proto-oncogene, serine/threonine kinase; BRAF inhibitors) (4), trifluridine/tipiracil (FTD/TPI) (5), and immune checkpoint inhibitors (ICIs), including pembrolizumab and nivolumab [programmed cell death-1 (PD-1) antibodies], as well as ipilimumab [cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] (6-8), have been introduced into clinical practice, contributing to prolonged overall survival (OS) in patients with metastatic CRC. Furthermore, the use of total neoadjuvant therapy (TNT) for unresectable, locally advanced lower rectal cancer has been increasingly reported. In patients achieving pathological complete response (CR), the ‘watch and wait’ strategy, which potentially allows for the omission of surgery, has become an emerging concept, particularly in Western countries (9). TNT can be classified into two approaches: consolidation chemotherapy, in which systemic chemotherapy is administered after chemoradiation therapy (CRT), and induction chemotherapy, wherein systemic chemotherapy precedes CRT in cases with distant organ metastases (e.g., liver or lungs) (10-12). In radiation therapy (RT), approximately 1 month of radiation is followed by a rest interval of approximately 6–8weeks. Similarly, induction chemotherapy using neoadjuvant chemotherapy (NAC) with B-mab requires a rest interval of approximately 6–8weeks following chemotherapy. Thus, either approach generally requires approximately 6 months of treatment (13). However, surgery can potentially be omitted among patients deemed to have achieved pathological CR. This includes the avoidance of a permanent colostomy, suggesting substantial clinical benefits. Nevertheless, in Japan, the national guidelines describe the current application as limited owing to insufficient evaluation of preoperative treatment regimens, lack of standardized definitions of clinical CR, absence of established diagnostic methods for disease monitoring, and inadequate surveillance strategies (14).

Although treatment options have expanded, the wide range of available therapies presents a challenge by creating a broad and sometimes complex spectrum of choices for each patient. Meanwhile, based on Narrative Evidence-Based Medicine (NEBM), we have reported modified regimens with optimized dosing strategies tailored for Japanese patients, who generally have smaller body frames than the Western counterparts (15-18). These regimens prioritize average relative dose intensity (DI)—the amount of drug administered over a defined period, rather than DI, which reflects the amount administered per unit time. Based on this concept, we proposed the Theory for Minimally Effective Cytotoxic Dose Chemotherapy (MECD theory), specifically for Japanese patients (16-18). These theories fundamentally aimed at administering outpatient chemotherapy to achieve a high quality of life (QOL), while also prolonging progression-free survival (PFS) and OS in cancer patients. We adopted capecitabine + oxaliplatin [L-OHP (CAPOX)] + molecular targeting agent (MTA) as first-line chemotherapy, which can be initiated as early as the day following initial diagnosis of stage IV disease at the first outpatient visit. However, the original regimen of L-OHP 130 mg/m² administered every 3 weeks often proves clinically unsustainable. Therefore, similar to FOLFOX4/6 (5-fluorouracil, leucovorin, and oxaliplatin), we adopted a modified schedule using L-OHP at 85 mg/m² every 2 weeks, enabling safe and reliable administration of over 1,000 mg over a 6-month period with minimal adverse events (AEs). As a result, we achieved favorable outcomes, with a 36-month OS rate of 26.4% and a median survival time (MST) of 25.2 months (16). As second-line chemotherapy, we adopted irinotecan (CPT-11) + tegafur/gimeracil/oteracil (S-1) (IRIS) + MTAs. In the second-line setting, various dosing regimens of CPT-11 have been used (100, 125, and 150 mg/m²), although none of these doses are clinically sustainable in many cases. Therefore, similar to L-OHP, we recommended a biweekly schedule at a dose of 85 mg/m². Consequently, we achieved a 36-month OS rate of 32.1% and an MST of 22.1 months (17). Although the patients’ backgrounds were not identical, favorable outcomes with reduced AEs were observed. We have been tested molecular markers before 1st- and 2nd-line chemotherapy. As previously reported, based on these results, the first- and second-line regimens are determined by selecting MTA (16,17).

Thus, this study aimed to retrospectively evaluate the survival outcomes, efficacy, and safety of standardized third-line chemotherapy following unified treatments for stage IV CRC at a single institution and to assess the usefulness of a multidisciplinary treatment approach throughout the treatment period based on the principles of NEBM and MECD theory. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-479/rc).

Methods

First-line and second-line therapy

At Tokai University Hachioji Hospital, surgical resection is the first-line therapy for stage IV CRC with liver or lung metastases, provided the tumor is macroscopically resectable with a negative margin (R0). Following surgery, intensive therapy is administered, including chemotherapy and RT. If R0 resection is not possible, chemotherapy is used as the first- and second-line therapies to achieve conversion surgery (CS)-R0. Treatment responses were assessed using ultrasonography (US) or computed tomography (CT) approximately 3–4 months after initiating chemotherapy. Primary resection in stage IV CRC is performed when clinically indicated, such as in cases of bleeding or bowel obstruction, or at the patient’s requests. If progressive disease (PD) is diagnosed, we promptly transition to third-line chemotherapy.

Third-line therapy

Oral anticancer agents, with or without MTA, are used. Since May 2018, we have initiated the use of various regimens combining MTA (B-mab) for third-line systemic chemotherapy in patients with stage IV CRC.

In January 2019, we standardized and changed to oral anticancer drugs [FTD/TPI, capecitabine, S-1, tegafur/uracil (UFT)/oral leucovorin (UZEL)] + B-mab, with a total of 175 treatment courses administered to 37 patients to date. All the patients had histologically confirmed primary CRC via colonoscopic biopsy. Recurrent or metastasis lesions involving the liver, lungs, and distant lymph nodes were diagnosed by US, CT scan, magnetic resonance imaging, and positron emission tomography. Of the 37 patients, 25 (67.6%) presented with unresectable distant metastases in liver, lung, and distant lymph nodes at the time of initial diagnosis. Twelve patients (32.4%) developed metastatic or recurrent CRC after resection of the primary tumor (Table 1). Tumor staging was assessed using the Union for International Cancer Control TNM classification stage of CRC, 8^th Edition (19).

Third-line chemotherapy was administered on an outpatient, with B-mab (5 mg/kg) administered intravenously on days 1 and 15, in combination with oral anticancer drugs. The regimen included FTD/TPI (administered as 5 days on/2 days off for two cycles), and capecitabine/S-1/UFT/UZEL (administered as 2 weeks on followed by 2 weeks off). All patients had RAS, BRAF, and microsatellite-instability (MSI) testing performed before first- and second-line chemotherapy, as reported in our previously reports, while third-line regimens were protocol based regardless of molecular markers (16,17,20,21).

Evaluation of efficacy and safety

We calculated PFS, OS, and MST at 12 and 36 months [12-month (12M)-PFS, 12M-OS, 36-month (36M)-PFS, and 36M-OS]. As an additional efficacy assessment, we evaluated the objective tumor response as the objective response rate (ORR), defined as CR or partial response (PR), and the clinical benefit rate (CBR), defined as CR, PR, or stable disease (SD) at 6 months or later. Furthermore, the dose reduction and dose-interval prolongation rates were analyzed. AEs during and after the three chemotherapy courses were evaluated according to the Common Terminology Criteria of Adverse Events version 5.0. In addition, we calculated 60-month (60M)-OS to evaluate multidisciplinary treatment of advanced recurrent CRC from the start of first-line chemotherapy.

Statistical analysis

The Kaplan-Meier method was used to calculate 12M-PFS, 12M-OS, 36M-PFS, 36M-OS, MST, and their respective 95% confidence intervals (95% CIs). PFS was calculated from the start date of the first course of the third-line to the date when the patient was diagnosed to have PD from SD on CT images. OS was measured from the first day of third-line chemotherapy until death. The 60M-OS was calculated from the start of first-line chemotherapy until death. Statistical analyses were conducted using IBM SPSS Statistics for Windows Version 28.0 (IBM Corp., Armonk, NY, USA).

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Chemotherapy Committee of the Tokai University Hachioji Hospital (IRB No. 24R184-HH001) and the Institutional Review Board for Clinical Research of the Tokai University Medical School (IRB No. 24R184-HH001), and informed consent was taken from all the patients.

Results

Patient characteristics and prior treatments

The cohort included more men than women, with a predominance of left-sided tumors (64.9%). The clinical stages were as follows: stage I, 1/37 (2.7%); stage II, 3/37 (8.1%); stage III, 8/37 (21.6%); and stage IV, 25/37 (67.6%). No notable difference exists in the distribution of primary tumor location by clinical stage (Table 1). Treatment before third-line chemotherapy was unified into CAPOX + MTA and IRIS + MTAs. All 37 patients underwent first-line treatment with CAPOX + B-mab, followed by second-line treatment with IRIS + MTAs [B-mab (n=21), panitumumab (n=14) and cetuximab (n=2)]. The median number of treatment courses was 9.0 for CAPOX and 8.0 for IRIS + MTAs (Table 2). The molecular marker results were as follows: RAS mutation 19 patients and wild-type 18 patients; BRAF mutation 1 patient, wild-type 24 patients, and not tested in 12 patients; MSI, with no MSI-high case and not tested in 8 patents. Among the 25 patients with initially unresected stage IV, the treatment strategies were as follows: chemotherapy alone (n=10, 40.0%); primary tumor resection (PTR) + chemotherapy + metastatic tumor resection (MTR) (n=4, 16.0%); PTR + chemotherapy + MTR + radiofrequency ablation (n=4, 16.0%); PTR + chemotherapy + MTR + RT (n=3, 12.0%); PTR + chemotherapy (n=3, 12.0%); and chemotherapy + RT (n=1, 4.0%).

CS, including procedures for postoperative recurrent disease, was performed in 18 of the 37 patients (48.6%). Specifically, CS was conducted after firs-line chemotherapy in 11 patients (29.7%), after second-line chemotherapy in 9 patients (24.3%), and after third-line treatment in 4 patients (10.8%) (Table 2).

Third-line chemotherapy regimens and survival outcomes

A total of 175 third-line procedures were administered to the 37 patients, with a median of 6.0 (3.0–8.3) courses. As oral anticancer drug, FTD/TPI was used in 23 patients (62.2%). The regimens included FTD/TPI + B-mab (n=17, 45.9%); FTD/TPI (n=6, 16.2%); capecitabine + B-mab (n=3, 8.1%); UFT/UZEL + B-mab, S-1 + B-mab, S-1, FOLFIRI (folinic acid, fluorouracil, irinotecan) + ramucirumab (RAM; n=2, 5.4%); and CAPOX + B-mab, TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) + B-mab, regorafenib (REG; n=1, 2.7%). Oral anticancer drugs + B-mab were used in 24 (64.9%) patients and oral anticancer drugs alone in 9 (24.3%) patients (Table 2). There is no difference in OS between the FTD/TPI with B-mab and without B-mab. The 12M-PFS was 18.9% (MST 4.1 M) (Figure 1A), and the 12M-OS was 52.9% (MST not reached) (Figure 1B); the 36M-PFS was 5.4% (MST, 4.1 M) (Figure 2A), and the 36M-OS was 13.9% (MST 13.3M) (Figure 2B). The 60M-OS was 27.8% (MST 39.9M) (Figure 3).

Figure 1 Kaplan-Meyer curves. (A) 12M-PFS: 18.9% (MST: 4.1 months). (B) 12M-OS: 52.9% (MST: not reached). The follow-up rate was 97.3%. 12M, 12-month; CI, confidence interval; MST, median survival time; OS, overall survival; PFS, progression-free survival.

Figure 2 Kaplan-Meyer curves. (A) 36M-PFS: 5.4% (MST: 4.1 months). (B) 36M-OS: 13.9% (MST: 13.3 months). The follow-up rate was 94.6%. 36M, 36-month; CI, confidence interval; MST, median survival time; OS, overall survival; PFS, progression-free survival.

Figure 3 Kaplan-Meyer curves. 60M-OS: 27.8% (MST: 39.9 months). The follow-up rate was 94.6%. 60M, 60-month; CI, confidence interval; MST, median survival time; OS, overall survival.

Tumor response and treatment modifications

The most common objective response was PD (59.5%), followed by SD (29.7%), and PR (10.8%) (Table 3). No patient achieved CR. The ORR was 10.8% (n=4) and the CBR was 37.8% (n=14). Dose reduction and dose interval prolongation were implemented in 6 (16.2%) and 17 (45.9%) patients, respectively. Among those who received dose reductions, the ORR was 0% and the CBR was 33.3%. In patients with extended dose interval, the ORR was 11.8%, and the CBR was 41.2% (Table 3). Overall, 18 (48.6%) patients underwent CS, including 4 (10.8%) patients who received it following third-line chemotherapy. Each patient was counted once in the conversion rate calculations (Table 2).

Performance status and AEs

At the initiation of third-line chemotherapy, 36 (97.3%) patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–1 (PS 0, n=18; PS 1, n=18). After three treatment courses, 33 (89.2%) maintained PS 0–1 (PS 0, n=16; PS 1, n=17), and by the end of treatment, 29 (78.4%) retained PS 0–1 (PS 0, n=15; PS 1, n=14), suggesting that most patients were able to complete third-line chemotherapy without marked PS decline (Table 2).

Common AEs include leukopenia (n=11, 29.7%) followed by neutropenia (n=12, 32.4%), thrombocytopenia (n=7, 18.9%), anemia (n=1, 2.7%), malaise (n=16, 43.2%), nausea (n=14, 37.8%), anorexia (n=13, 35.1%), diarrhea (n=6, 16.2%), peripheral neuropathy (n=13, 35.1%), stomatitis (n=7, 18.9%), dysgeusia (n=4, 10.8%), dermatitis (n=4, 10.8%), and allergic reaction (n=2, 5.4%) (Table 4).

Most AEs were grades 1 and 2, and were managed conservatively. However, hematological toxicities increased over time, including neutropenia (grade 3: 6 cases), thrombocytopenia (grade 3: 2 cases), and anemia (grade 2: 3 cases; grade 3: 2 cases). Grade 3 anemia increased from 0 to 2. Only two (5.4%) patients required granulocyte colony-stimulating factors, and none had febrile neutropenia. Grade 3 hematologic toxicities occurred predominantly in patients receiving FTD/TPI, except for one case of thrombocytopenia associated with regorafenib. One patient treated with CAPOX + B-mab developed a grade 3 allergic reaction, and one treated with UFT/UZEL + B-mab experienced grade 2 cholecystitis. No treatment-related deaths occurred during the study (Table 4).

Discussion

Cetuximab/encorafenib/binimetinib (CEB therapy) has been approved in Japan since November 2020 for use in patients harboring BRAF V600E mutation from the second-line onward (3,22). However, the prevalence of BRAF V600E mutation remains low—5.4% in Japan and <10% globally (4,22,23). Several studies have highlighted the potential efficacy of ICIs, with notable responses in recurrent peritoneal dissemination and extensive intraperitoneal lymph node metastases, drawing attention to the interplay between the host and immune environment, both systemically and locally (6-8). In Japan, pembrolizumab was approved in August 2021 for first-line treatment of MSI-high stage IV CRC; however, MSI-high cases remain rare, with only eight patients at our institution having received ICI therapy (24,25). Thus, ICI therapies were excluded from the current analysis. Although the concept of rechallenge and treatment rotation has been reported, the toxicity burden of intravenous chemotherapy in practice discourages many patients from reinitiating previous regimens. Consequently, oral anticancer drugs are often proffered (26). Combinations such as FTD/TPI + B-mab and UFT/UZEL + B-mab have emerged as relevant third-line options, particularly in patients prioritizing outpatient-based regimens (20,21).

Since 2018, we have standardized third-line regimen in our institution to include oral anticancer drug + B-mab. While the 2022 Japanese guidelines endorse FTD/TPI + B-mab and its clinical use has been expanding, patients in our cohort had initiated treatment with S-1, UFT/UZEL, and capecitabine. Regimen selection was ultimately based on patient background and clinician judgment. As a result, heterogeneity in the third-line regimens precluded a comparative assessment of the efficacy of B-mab add-on or between different oral regimens. Nonetheless, we demonstrated the feasibility and outcomes of a multidisciplinary approach in patients with advanced recurrent CRC who received standardized pre-treatment.

We adapted outpatient chemotherapy protocols in accordance with NEBM (15,27) optimizing dosing and administration methods for Japanese patients. These regimens aimed to minimize high-grade toxicities while improving patient’s QOL, PFS, and OS. We previously reported that third-line outpatient chemotherapy contributed to prolonged PFS and OS, with a favorable toxicity profile, and improved OS, consistent with previous studies (16,17). This aligns with the disease trajectory concept, where patients with cancer benefit from maintaining a stable condition for as long as possible gradually decreases with time, while in malignant diseases/cancers, it is how long a patient can survive stably in a flat and disease-stable state (28). The result of this study demonstrates that third-line chemotherapy as administered with sequential treatment contributed to well controlled slow disease progression and prolonged OS. In some cases, long-term survival without recurrence was achieved, underscoring the effectiveness of strategic, multimodal treatment.

In our cohort, pretreatment was standardized as CAPOX + MTA or IRIS + MTAs, administering both L-OHP and CPT-11 at 85 mg/m² until the start of the third-line regimen, with a median dose of 9.0 and 8.0 courses, respectively. The cumulative doses administered were 1,530 mg L-OHP and 1,360 mg CPT-11, indicating adequate drug exposure. Notably, 97.3% of patients maintained an ECOG PS of 0–1 at the start of the third-line therapy and after first- and second-line chemotherapy, which reflects the efficacy of multidisciplinary treatment guided by the NEBM theory.

In the SUNLIGHT study, the incidence of severe AEs (grade ≥3) was 72.4% for FTD/TPI + B-mab, and 69.5% for FTD/TPI alone (20). In this study, among 17 and 6 patients who received FTD/TPI + B-mab and FTD/TPI, respectively, grade ≥3 AEs occurred in 6 (35.3%) and 5 (83.3%) patients. Across all regimens, 11 of 23 patients (47.8%) experienced severe AEs. Although direct comparisons are limited by the small sample size and differing patient backgrounds, our findings suggest a lower incidence of severe AEs than previously reported (20).

The ORR was modest at 10.8%; however, the CBR of 40.5% was acceptable, particularly as treatment preceded transition to best supportive care. In comparison with national data from the Japanese CRC treatment guidelines [2008–2013], the 60M-OS of stage IV CRC for Cur B + Cur C was 26.7% (Cur B; 49.2%, 1,483/5,511 cases, and Cur C; 17.7%, 4,028/5,511 cases). In our study, after excluding 11 patients (29.7%) without PTR, among the remaining 26 patients, Cur A, B, and C were observed in 10 (38.5%), 11 (42.3%), and 5 (19.2%) patients, respectively (14). The Cur classification was defined as follows: Cur A indicates curative resection with no residual tumor and negative surgical margins; Cur B refers to cases that do not fulfill the criteria for either Cur A or Cur C; and Cur C indicates non-curative resection with macroscopic residual disease remaining after surgery. The overall 60M-OS for Cur B + Cur C in our study was 31.3% (MST, 50.8 months), which is a favorable outcome compared to the national data (data not shown). In patients with advanced recurrent CRC treated with standardized pretreatment through the third-line, a 60M-OS rate of 27.8% (MST 39.9 months) was achieved. The low incidence of AEs and favorable OS indicate that multimodal treatment based on the NEBM/MECD theory yields promising outcomes in advanced recurrent CRC. While this long-term survival likely reflects cumulative effects of sequential therapies, third-line chemotherapy contributed by maintaining disease stability with low toxicity. The high cost of cancer treatment affects QOL of patients. Within the NEBM/MECD theory, this remains an important challenge that warrants further attention in both clinical practice and research (29).

This study is limited by a single-institution design, small sample size, and variation in third-line regimen, which prevented robust comparative analyses. In future studies, we plan to unify third-line treatment strategies and evaluate the additive effect of B-mab. In addition, as hematological AEs were more frequent in patients receiving FTD/TPI, especially among those with smaller body sizes common in Asian populations, further investigation into optimal dosing is warranted. As treatment options for stage IV advanced recurrent CRC continue to expand, treatment with fewer AEs and long-term prognosis based on the NEBM/MECD theory is a useful option for multidisciplinary CRC treatment. Further research on the optimal dosage/optimal schedules for more selected drugs is warranted.

Conclusions

This study reports the outcomes of third-line regimens following the first- and second-line treatments at a single center. The findings demonstrate that third-line therapy for CRC, guided by the NEBM/MECD theory, can achieve favorable long-term PFS, extended OS, and maintain high QOL.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-479/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-479/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-479/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-479/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Chemotherapy Committee of the Tokai University Hachioji Hospital (IRB No. 24R184-HH001) and the Institutional Review Board for Clinical Research of the Tokai University Medical School (IRB No. 24R184-HH001), and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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