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Abstract

Objectives

Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab.

Methods

This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity.

Results

Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed.

Conclusions

Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Keywords

raltitrexed bevacizumab second-line mCRC

Introduction

Colorectal cancer (CRC) is one of the most common malignant tumors and the second leading cause of cancer death.¹ According to recent data, many newly diagnosed cases have metastatic disease at the time of initial diagnosis.² Systemic chemotherapy is the most common treatment for metastatic colorectal cancer (mCRC). Prior to the 21st century, fluorouracil and leucovorin were the primary regimens in the first-line setting for patients with mCRC. In the 21st century, the introduction of oxaliplatin and irinotecan has developed different combination chemotherapies.^3,4 FOLFIRI (fluorouracil and leucovorin plus irinotecan) and FOLFOX (fluorouracil and leucovorin plus oxaliplatin) significantly prolonged the survival of mCRC patients as first-line treatment.^5,6 However, most patients with mCRC experience disease progression or intolerable toxicity on first-line systemic therapy, which requires second-line treatment.⁷

The current problem, however, is that the basic chemotherapy regimen for mCRC first - and second-line palliative care is fluorouracil-based plus oxaliplatin or irinotecan, followed by targeted drugs. Repeated use of fluorouracil analogs resulted in cross-resistance and poor efficacy.^8,9 In addition to this, fluorouracil analogs have some cardiotoxicity, with ranging from 0.5% to 19%.¹⁰ Raltitrexed, a thymidylate synthase inhibitor, with proven efficacy in the treatment of mCRC as a single agent or in combination with oxaliplatin.^11,12 Therefore, for patients with mCRC who are receiving first-line treatment with FOLFOX or FOLFIRI, clinical decision-makers are considering replacing fluorouracil with raltitrexed in second-line treatment. However, there is a dearth of data on the combination of raltitrexed-based chemotherapy regimens with targeted agents. Clinical studies have shown that bevacizumab combined with chemotherapy can significantly improve the efficacy of mCRC.^13,14

In this study, we conducted an investigation into the efficacy and safety of a second-line raltitrexed-based chemotherapy regimen combined with bevacizumab in patients with mCRC who had failed first-line fluorouracil-based chemotherapy. According to current guidelines and specifications for the treatment of advanced colorectal cancer, both 2-week and 3-week regimens are considered appropriate. Our primary focus was on evaluating the efficacy and safety of the standard 3-week regimen of raltitrexed in this study. This regimen offers the advantage of reducing patient travel frequency to and from the hospital, thereby enhancing treatment convenience. In comparison with 5-FU, raltitrexed eliminates the need for calcium folinic acid sensitization and prolonged intravenous infusion (46-48 h), requiring only 15 min of intravenous infusion. Meanwhile, there is currently no reliable maintenance treatment option available for second-line mCRC therapy. The safety and convenience of raltitrexed make it a more suitable choice for maintenance treatment compared to fluorouracil drugs. Therefore, this study also explores the potential of using raltitrexed combined with bevacizumab as a maintenance treatment option. As per our study protocol, there will be three efficacy evaluations after six cycles of treatment. If the final efficacy evaluation still indicates stable disease (SD) or above, it is likely to suggest that the tumor has reached a relatively stable state. In such cases, maintenance therapy can minimize chemotherapy toxicity accumulation while ensuring treatment efficacy and improving overall safety when compared to continuing the original regimen or interrupting the treatment course. Our preliminary findings indicate that combining a raltitrexed-based regimen with targeted bevacizumab is more effective than routinely repeating second-line fluorouracil-based regimens combined with bevacizumab.

Methods

Study Schema

This is a prospective, open-lable, multicenter, phase II clinical study approved by the Ethics Association of Jiangsu Cancer Hospital under approval number 2016-057, and registered in ClinicalTrials.gov (NCT03126071). Study participants gave written consent, which was detailed in the informed consent form. Patient eligibility criteria included the following: (a) aged 18 to 70 years, no gender restriction; (b) histopathology and/or cytology confirmed locally advanced or metastatic colorectal cancer; (c) first-line chemotherapy with fluorouracil failed or disease recurred within 6 months after completion of adjuvant chemotherapy; (d) with 1 or more measurable lesions, the maximum diameter was at least 10 mm (spiral CT scan) or 20 mm (conventional CT scan) (RECIST criteria, 1.1 edition); (e) Eastern Cooperative Oncology Group performance status score of 0 to 1; (f) expected survival period≧3 months; (g) blood routine, liver and kidney function within 7 days before screening meet the following criteria: absolute neutrophil count≥1.5*10⁹/L; hemoglobin≥9.0 g/dl; platelet count≥80 *10⁹/L; total bilirubin≤1.5 times the upper limit of normal (ULN); alanine aminotransferase and aspartate aminotransferase≤2.5*ULN (≤5*ULN in patients with liver metastases); alkaline phosphatase≤3*ULN (≤5* ULN in patients with liver metastases); serum creatinine ≤1.5*ULN.

Main exclusion criteria were: (a) previously used raltitrexed; (b) symptomatic coronary artery disease or myocardial ischemia (myocardial infarction within the last 6 months), congestive heart failure exceeding grade III or IV (NYHA), stroke, or transient ischemic attack; (c) severe infection; (d) symptomatic brain or meningeal metastases; (e) undergoing renal dialysis; (f) history of additional malignancies within 5 years, except for cured carcinoma in situ of the cervix or basal cell carcinoma of the skin; (g) chronic tract diseases, infectious tract diseases, obstruction.

The willing patients provided written informed consent. A total of 100 mCRC patients were included. Enrolled patients after first-line oxaliplatin failed received SALIRI + Bev [bevacizumab (7.5 mg/kg, d1), raltitrexed (3 mg/m², d1) and irinotecan (200 mg⁄m²,d1)]. Patients after first-line irinotecan treatment received SALOX + Bev [bevacizumab (7.5 mg/kg, d1), raltitrexed (3 mg/m², d1) and oxaliplatin (130 mg ⁄m², d1)]. Both of two regimens repeated every 3 weeks. Patients treated for 6 cycles and efficacy evaluation over SD were followed by maintenance treatment of bevacizumab (7.5 mg/kg, d1) and raltitrexed (3 mg/m², d1)until disease progression or intolerable toxicity.

Study Endpoints and Definitions

The primary endpoint was progression-free survival (PFS), defined as the time from the date of enrollment to the date of confirmed progression or death from any cause, whichever occurred first. The secondary endpoints included the following: overall survival (OS, the time from the date of enrollment to the date of death from any cause), objective response rate (ORR, the proportion of eligible patients with measurable lesions reduction to a predefined value and able to maintain the minimum time requirement, as the sum of the proportion in complete response and partial response), disease control rate (DCR, the proportion of eligible patients with measurable lesions with a best overall response of complete response, partial response, or stable disease), toxicity and safety analysis (incidence of adverse events and adverse reactions).

Statistical Analysis

This is an exploratory Phase II clinical trial investigating the efficacy and safety of a regimen of raltitrexed chemotherapy in combination with bevacizumab for the second-line treatment of mCRC. Sample size calculation instructions: the sample size was calculated by the median PFS of the main index, with reference to the historical data of previous studies on mCRC, the second-line median PFS was around six months, assuming that the median PFS of the experimental group was eight months, in accordance with the design of superiority of the control historical data, the test efficacy of 1-β = 0.8, α = 0.05; The statistical analysis was performed using the One-Sample Log-rank Tests two-sided test with a sample size calculated to be 86 cases, requiring a sample size of 100 cases to take into account the 15% shedding rate. The treatment efficacy was assessed on an intent-to-treat basis. Demographic data and other fundamental indicators are described. Measurement data is statistically described by mean, median, standard deviation, maximum and minimum. Counting data or rank data is expressed in terms of frequencies.

The Cox proportional hazard model was fitted to the predefined subgroups, and all variables except the subgroup variables were included in the analysis. Pre-defined subgroups included age, sex, ECOG performance status, surgical history, family history, primary tumor location, number of metastatic sites, underlying disease, first-line chemotherapy regimen, second-line chemotherapy regimen, second-line chemotherapy cycle, and maintenance therapy. Survival curves were plotted using the Kaplan-Meier method, calculated median survival times (PFS, OS), and 95% confidence intervals. HRs with 95% CIs and P values were computed using the Cox proportional hazard model.

All statistical analyses were performed using SPSS (version-25.0) and R project (version-4.2.2).

Results

Study Patients

A total of 100 patients in China were enrolled in the study. In the per protocol population, the first-line chemotherapy regimens FOLFIRI/FOLFIRI plus bevacizumab/cetuximab were used in 5 cases and XELOX/FOLFOX plus bevacizumab/cetuximab in 95 cases. The second-line chemotherapy regimen was changed to SALIRI/SALOX plus bevacizumab (Figure 1). All patients who received study treatment were included in the safety evaluation. Treatment assignment was balanced by age, gender, ECOG performance status, and previous operation therapy exposure (Table 1).

Figure 1.

Trial profile.

Table 1.

Clinical data of 100 patients with mCRC treated with Raltitrexed chemotherapy regimen combined with Bevacizumab as second-line therapy

Clinical data	Frequency
Age
≥60	36
<60	64
Gender
Male	59
Female	41
ECOG score
1	88
0	12
Previous operation or not
Yes	93
No	7
Family history
Yes	1
No	99
Primary lesion
Colon	62
Rectum	38
Metastases cumulative number of organs
>2	6
≤2	94
Underlying disease
No	67
Yes	33
First-line chemotherapy regimens
FOLFIRI/FOLFIRI + Bevacizumab/Cetuximab	5
XELOX/FOLFOX + Bevacizumab/Cetuximab	95
Second-line chemotherapy regimens
SALIRI + bevacizumab	94
SALOX + bevacizumab	6
Number of cycles of second line chemotherapy (three drugs regimen period)
≥8	6
<8	94
Maintenance therapy or not
Yes	31
No	69

Efficacy

The mean number of cycles of protocol treatment was 6.3 (range 2-12) for SALOX plus bevacizumab group and 5.1 ((range 2-14) for SALIRI plus bevacizumab group. As of follow-up time, PFS and OS data collection were cut off, with 100 confirmed events [94 (SALIRI + bevacizumab) and 6 (SALOX + bevacizumab)] (Table 1). Ninety-seven patients [92 (SALIRI + bevacizumab) and 5 (SALOX + bevacizumab)] reached the PFS endpoint, with a median PFS of 8.4 (95% CI: 6.2-11.0) months (Supplemental Figure 1). Median PFS was 11.6 (95% CI: 3.1-NA) months in the SALOX plus bevacizumab group and 8.2 (95% CI: 6.2-11.0) months in the SALIRI plus bevacizumab group (Figure 2). Eighty-eight patients [83 (SALIRI + bevacizumab) and 5 (SALOX + bevacizumab)] reached the OS endpoint, with a median OS of 17.6 (95% CI: 15.2-22.0) months (Supplemental Figure 2). Median OS was 17.1 (95% CI: 4.1-NA) months in the SALOX plus bevacizumab group and 17.6 (95% CI: 15.2-22.0) months in the SALIRI plus bevacizumab group (Supplemental Figure 3). By the time of follow-up, a total of 69 patients did not receive maintenance therapy, of which 67 patients reached the PFS endpoint with a median PFS 5.6 (95% CI: 3.9-8.9) months and 60 patients reached the OS endpoint with a median OS 15.2 (95% CI: 11.9-20.5) months. A total of 31 patients received maintenance therapy, of which 30 reached the PFS endpoint with a median PFS of 12.3 (95% CI: 9.4-18.5) months and 28 reached the OS endpoint with a median OS of 21.7 (95% CI: 17.6-33.5) months (Figure 3 and Supplemental Figure 4). Log-rank tests were performed for all variables, and the differences for all variables were not statistically significant for both the PFS endpoint and the OS endpoint (Supplemental Table 1). Variables were screened stepwise based on AIC for the PFS endpoint. The final variables included were first-line chemotherapy regimens, second-line chemotherapy regimens, and maintenance therapy. FOFIRI/FOLFIRI plus bevacizumab/cetuximab in first-line chemotherapy regimens was a risk factor (HR = 17.68, P = 0.015); SALIRI plus bevacizumab in the second-line chemotherapy regimen was a risk factor (HR = 9.09, P = 0.035); No less than eight cycles of second-line three-drug chemotherapy was the protective factor (HR = 0.48, P = 0.037); Maintenance therapy was also a protective factor (HR = 0.58, P = 0.022) (Table 2). Thirty-one patients received maintenance therapy after 6 cycles of second-line treatment with an efficacy rating of SD or higher, the median time on maintenance treatment was 5.1 (95% CI: 4.7-6.1) months (Supplemental Figure 5), and a total of 30 patients reached the PFS endpoint with a median PFS of 5.9 (95% CI: 3.9-13.4) months (Supplemental Figure 6). For OS endpoint, the Cox model showed that all variables had no statistical significance on OS outcomes (Supplemental Table 2).

Figure 2.

PFS survival curves in 100 patients with mCRC treated with raltitrexed chemotherapy regimen plus bevacizumab in second-line. (SALOX + bevacizumab and SALIRI + bevacizumab).

Figure 3.

PFS survival curves in 100 patients with mCRC treated with raltitrexed chemotherapy regimen plus bevacizumab in second-line. (Maintenance treatment and No- Maintenance treatment).

Table 2.

Multivariate Cox Regression AIC Screening Results of 100 Patients With Advanced Colorectal Cancer Treated With Raltitrexed Chemotherapy Regimen Combined With Bevacizumab as Second-Line Therapy (PFS).

Clinical Data	HR (95% CI)	P-Value
First-line chemotherapy regimens
FOFIRI/FOLFIRI + Bevacizumab/Cetuximab	Ref	0.015
XELOX/FOLFOX + Bevacizumab/Cetuximab	17.68 (1.73,180.72)	0.015
Second-line chemotherapy regimens
SALIRI + bevacizumab	Ref	0.035
SALOX + bevacizumab	9.09 (1.16,70.92)	0.035
Number of cycles of second line chemotherapy
≥8	Ref	0.037
<8	0.48 (0.24,0.96)	0.037
Maintenance therapy or not
Yes	Ref	0.022
No	0.58 (0.37,0.92)	0.022

Short-term efficacy was evaluated in 100 patients, 26.0% reached ORR, and 87.0% reached DCR (Supplemental Table 3). In SALOX plus bevacizumab group, 33.3% reached ORR, and 83.3% reached DCR. In the SALIRI plus bevacizumab group, 25.5% reached ORR and 87.2% reached DCR. For 69 patients who did not receive maintenance therapy, 15.9% reached ORR, and 81.2% reached DCR (Supplemental Table 4). Of the 31 patients receiving maintenance therapy, 48.4% reached ORR, and 100.0% reached DCR. For the 69 patients who did not receive maintenance therapy, 15.9% reached ORR, and 81.2% reached DCR (Supplemental Table 5). Differences in the incidence of ORR and DCR were compared between the variables using the chi-square test or Fisher’s test (Supplemental Table 6). For ORR, the number of cycles of second-line three-drug chemotherapy greater than eight and whether maintenance therapy is administered are essential factors. For DCR, whether maintenance therapy is administered is a crucial factor.

Safety

Throughout treatment, adverse events in 86% (86/100) and adverse reactions in 86% (86/100) (Supplemental Table 7), one patient needed a dose delay or dose reduction, and two patients needed discontinued (Supplemental Table 8 lists major adverse events and adverse reactions). No discontinuations of treatment or deaths due to adverse events were recorded during the study period. Grade 3 or grade 4 adverse events were not present in the SALOX plus bevacizumab group (Supplemental Table 9). Patients in the SALIRI plus bevacizumab group experienced grade 3 or grade 4 hepatic insufficiencies (6 of 94 patients), thrombocytopenia (1 of 94 patients), and proteinuria (1 of 94 patients). The incidence of grade 3 or 4 adverse events during treatment was low (Supplemental Table 10). Grade 1 or grade 2 adverse events include leucopenia, neutropenia, thrombocytopenia, anemia, proteinuria, fever, and gastrointestinal adverse reactions (incidence rate over 5%). In addition, the incidence of adverse events was not significantly higher in the maintenance treatment group than in the non-maintenance treatment group [27 of 31 patients (87.1%) vs 59 of 69 patients (85.5%)] (Supplemental Table 11 and 12). Patients in the non-maintenance treatment group had a numerically higher incidence of grade 3 adverse events than those in the maintenance treatment group [7 of 69 patients (10.1%) vs 2 of 31 patients (6.4%)] (Supplemental Table 11 and 12).

Discussion

Chemotherapy is the cornerstone of mCRC treatment, and the optimal application of chemotherapy drugs has always been a focus of mCRC treatment. In the early stages, fluorouracil and leucovorin were used as the primary treatment for mCRC patients. The median OS of patients was only 8-12 months, and the efficacy was not satisfactory.¹⁵ The introduction of novel cytotoxic drugs, including oxaliplatin, irinotecan, further prolongs survival in mCRC patients.^16-19 Most mCRC patients experience disease progression on first-line systemic therapy and require second-line therapy. The choice of cytotoxic agent for second-line mCRC depends on the chemotherapy regimen chosen in the prior first-line therapy. The GERCOR study investigated the efficacy of two sequential chemotherapy regimens: first-line FOLFIRI followed by second-line FOLFOX, and first-line FOLFOX followed by second-line FOLFIRI. The results showed no significant difference in OS between the two groups, and the median OS of patients was more than 20 months.⁵ Therefore, patients who have previously received oxaliplatin-containing regimens should receive irinotecan-containing regimens in second-line therapy. It is important to note that while the first-line effective rate was approximately 50%, the second-line chemotherapy regimen of oxaliplatin and irinotecan exchange was only about 10% effective, and the reason for the significant reduction in the effective rate may be due to fluorouracil resistance. In contrast, patients who have previously received the irinotecan-containing regimen should be given the oxaliplatin-containing regimen in second-line therapy. In addition, analysis of data associated with the phase III mCRC studies showed that median OS reported in clinical studies was significantly positively correlated with the proportion of patients receiving all three cytotoxic agents (fluorouracil, irinotecan, and oxaliplatin) throughout the patient’s first-line and second-line treatment, but not with the proportion of patients receiving second-line treatment.²⁰ Therefore, cytotoxic agents should be used throughout the course of treatment when the patient’s condition permit, in order to maximize the survival of mCRC patients.

Targeted therapies has gained unprecedented momentum in recent years as a critical approach to treating malignancies. In mCRC treatment, the use of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) antibodies cetuximab and bevacizumab, as well as their combination with chemotherapeutic agents, have brought benefits to many patients. Studies have shown that patients with mCRC who have not previously received bevacizumab have significantly improved median OS and ORR after receiving bevacizumab in combination with FOLFOX in the second-line treatment.²¹ Second-line cross-line treatment with bevacizumab is also efficacious and safe in patients with mCRC who have failed previous first-line treatment containing bevacizumab.^22,23

Our study investigated the efficacy and safety of second-line treatment with a raltitrexed-based chemotherapy regimen plus bevacizumab in mCRC patients who had failed first-line treatment with a fluorouracil-based chemotherapy regimen. The cytotoxic drug raltitrexed, either alone or combined with oxaliplatin, is effective in mCRC.^24,25 In our study, SALOX plus bevacizumab showed a higher response rate compared to FOLFOX plus bevacizumab. Compared with FOLFOX/FOLFIRI/XELIRI plus bevacizumab treatment,^21,26 the SALOX/SALIRI plus bevacizumab group has more significant ORR, median PFS, and median OS benefits. Compared with irinotecan monotherapy and SALIRI/FOLFIRI chemotherapy regimens,^5,27,28 SALIRI plus bevacizumab significantly improved efficacy, with improvements in ORR, DCR, median PFS, and median OS. Of concern, the incidence of adverse events during treatment was low and dominated by grade 1 and grade 2 adverse events. In addition, there were no cases of cardiotoxicity associated with raltitrexed treatment in the study. During its use, raltitrexed takes only 15 minutes be administered, improving patient compliance and patient life during treatment, which is one of the advantages of raltitrexed. Finally, we also explore the role of maintenance therapy in second-line therapy. Strong induction therapy plus low-intensity maintenance therapy is currently the mainstream mode of first-line treatment for advanced colorectal cancer.²⁹ The maintenance treatment group of raltitrexed plus bevacizumab resulted in improved short-term efficacy (ORR, DCR) and long-term efficacy, and the maintenance treatment reduced the occurrence of grade 3-4 adverse reactions. However, there are limitations to our study; with only six patients in the SALOX + bevacizumab group, the data in all regions are not accurately representative and the efficacy needs to be further confirmed by studies with larger samples.

Conclusion

In our series, we provide evidence that the SALOX/SALIRI regimen plus bevacizumab as second-line therapy in mCRC patients with first-line treatment failure is associated with a significantly longer PFS and OS with manageable safety. This finding suggests that a raltitrexed-based chemotherapy regimen in combination with bevacizumab could be the standard backbone of second-line treatment for mCRC.

Supplemental Material

Supplemental Material - Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial

Supplemental Material for Raltitrexed Chemotherapy Regimen Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer: A Prospective Multicenter Phase II Trial by Sheng Li, Xiaoyou Li, Qianni Zhu, Jin Gao, Chunrong Zhu, and Liangjun Zhu Cancer Control

Footnotes

Acknowledgments

The authors express their gratitude to the patients and their families, the investigators, study coordinators, and operations staff for their contributions to this study.

Author Contributions

Sheng Li, Xiaoyou Li, Qianni Zhu, Jin Gao, Chunrong Zhu, and Liangjun Zhu wrote the main manuscript text and prepared figures and tables. All authors reviewed the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Statement

ORCID iD

Liangjun Zhu

Data Availability Statement

The datasets generated and/or analysed during the current study are not publicly available, but are available from the corresponding author on reasonable request.*

Supplemental Material

Supplemental material for this article is available online.

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