Research ArticleClinical Studies

Risk–benefit Analysis of FOLFIRI Plus Ramucirumab/Aflibercept as a Third-line Treatment in Metastatic Colorectal Cancer

MICHIO KIMURA, EISEKI USAMI, HITOMI TERAMACHI and TOMOAKI YOSHIMURA
Anticancer Research June 2021, 41 (6) 3091-3097; DOI: https://doi.org/10.21873/anticanres.15093

Abstract

Background/Aim: The efficacy of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (F-RAM) or aflibercept (F-AFL) as a second-line treatment in metastatic colorectal cancer (mCRC) is established. In this study, the risks and benefits of F-RAM/AFL as a third-line treatment after first- and second-line bevacizumab for mCRC were evaluated. Patients and Methods: Overall survival (OS) and adverse events (AEs) were compared between groups treated with F-RAM/AFL (n=17) and trifluridine/tipiracil combination tablet (TAS-102) (n=26). Results: Median OS was longer in the third-line F-RAM/AFL group (379 days; 95%CI=157-458 days) than in the TAS-102 group (183 days; 95%CI=80-204 days) (log-rank test, p=0.015). Discontinuation due to AEs was only observed in the F-RAM/AFL group (3 cases). Conclusion: As a third-line treatment for mCRC, F-RAM/AFL should be prioritized over TAS-102 in terms of efficacy; however, the risk of AEs should be considered.

Key Words:

Angiogenesis is an important therapeutic target in colorectal cancer (CRC) (1). Currently, three products are approved in Japan as angiogenesis inhibitors (VEGF inhibitors), bevacizumab (BV), ramucirumab (RAM), and aflibercept (AFL). In CRC, a larger number of phase III clinical trials have proven the effectiveness of BV compared to RAM and AFL (2-9). These trials support the use of BV in combination with any treatment line or concomitant drug. Phase III clinical trials have only demonstrated the effectiveness of RAM and AFL as a second-line treatment, and the concomitant drug is FOLFIRI therapy (F-RAM/AFL) (10, 11).

For the first-line treatment of metastatic colorectal cancer (mCRC), the combination of fluorouracil/leucovorin and oxaliplatin (FOLFOX) or fluorouracil/leucovorin and irinotecan (FOLFIRI) with BV, cetuximab, or panitumumab molecularly targeted therapeutic agents is recommended (3, 12-16). For cases with Ras mutations, the combination of FOLFIRI and BV/RAM/AFL is recommended as the second-line treatment after using FOLFOX plus BV as the first-line treatment (10, 11, 17, 18). BV is often used as a second-line treatment in clinical practice. As third-line treatment in cases that are refractory or intolerant to fluoropyrimidine, oxaliplatin, or irinotecan, the American Society of Clinical Oncology and the National Comprehensive Cancer Center Network recommends the regorafenib or trifluridine/tipiracil combination tablet (TAS-102) as the third-line and later-line treatment for mCRC (19, 20).

In short, there is evidence for the efficacy of F-RAM/AFL as a second-line treatment and for regorafenib and TAS-102 as third-line and later-line treatments. In clinical practice, F-RAM/AFL is often used as a third-line treatment after the use of BV as a second-line treatment; however, the efficacy and safety of F-RAM/AFL in the third-line setting is not clearly established. Therefore, clarifying the risk–benefit of F-RAM/AFL for third-line treatment of mCRC as well as its efficacy and safety will improve treatment selection. In this study, F-RAM/AFL (human IgG-1 monoclonal antibodies targeting the extracellular domain of VEGF receptor 2) and TAS-102 (containing trifluridine, which inhibits thymidylate synthase and tumour growth) have been compared for third-line treatment of mCRC, as there is no difference between F-AFL and F-RAM for second-line treatment (10, 11, 18). The aim of this study was to clarify the risk benefits of F-RAM/AFL with respect to overall survival (OS) and adverse events (AEs) in comparison with those of TAS-102 as a third-line treatment after using BV as first-line and second-line treatment for mCRC.

Patients and Methods

Patients and evaluations. In total, 44 patients treated with F-RAM/AFL or TAS-102 as a third-line treatment after using BV as the first-line and second-line treatment for mCRC at Ogaki Municipal Hospital (Ogaki, Japan) between October 2016 and December 2020 were retrospectively evaluated. However, we excluded one patient who had been transferred to another hospital. Thus, 43 patients were considered eligible for this study. Patient characteristics, OS, AEs, treatment period, and reasons for treatment discontinuation were analyzed using data collected from electronic charts and pharmacy service records. OS was defined as the interval between the initiation of F-RAM/AFL or TAS-102 administration and the date of death from any cause. AEs were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0 (21), and the most severe grades during chemotherapy were reported. Personal information was protected in aggregated data. This study was approved by the Institutional Review Board of Ogaki Municipal Hospital (Ogaki, Japan; approval number 20210325-2). The need for informed consent was waived owing to the retrospective nature of the study.

Treatment protocol. In the F-RAM/AFL group, patients received 8 mg/kg RAM/4 mg/kg AFL as a 60-min intravenous infusion, followed by FOLFIRI (150 mg/m2 irinotecan and 200 mg/m2 1-leucovorin were concurrently infused intravenously over 120 min, followed by 400 mg/m2 fluorouracil administered as an intravenous bolus over 2-4 min, and then 2,400 mg/m2 of fluorouracil as a continuous infusion over 48 h on day 1 every 2 weeks). Oral TAS-102 (35 mg/m2 per dose) was administered twice daily (after morning and evening meals) for 5 consecutive days, followed by 2 days of rest, for 2 weeks, followed by a 14-day rest period; this constituted one treatment cycle.

Statistical analysis. Between-group comparisons were performed using the F-test. Mann–Whitney U-tests or chi-squared tests of independence (Fisher’s exact probability tests) were used for comparisons of patient characteristics, AEs, and reasons for discontinuation. The Kaplan–Meier log-rank test was used to compare OS. Significance was defined as p<0.05, and all statistical analyses were performed using EZR (v1.30, Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (22).

Results

Patient characteristics. The F-RAM/AFL and TAS-102 groups included 17 (F-RAM: 12, F-AFL: 5) and 26 patients, respectively. The characteristics of patients are summarized in Table I. After the third line, TAS-102 (7 cases) was often used in the F-RAM/AFL group (p=0.017). In the TAS-102 group, regorafenib (6 cases) was frequently used (p<0.001).

View this table:
Table I.

Patient characteristics.

Hazard ratio for overall survival after third-line treatment. Univariate and multivariate analyses of the prognostic value of baseline and clinical characteristics are presented in Tables II and III. In the univariate analysis, body surface area (>1.50), use of F-RAM/AFL as a third-line treatment (yes), and subsequent treatment (after third-line treatment) (yes) were significantly associated with survival. In the multivariate analysis, the use of F-RAM/AFL in third-line treatment (yes) was independently and significantly associated with survival. Patients who received the F-RAM/AFL regimen on third-line treatment had a death hazard ratio of 0.379 (95%CI=0.164-0.876; p=0.023), which was lower than that of patients who received the TAS-102 regimen as a third-line treatment.

View this table:
Table II.

Univariate analysis of prognostic factors associated with OS in patients with advanced and recurrent colorectal receiving chemotherapy.

View this table:
Table III.

Multivariate analysis of prognostic factors associated with OS in patients with advanced and recurrent colorectal receiving chemotherapy.

Effect of the third-line treatment on overall survival. Kaplan– Meier survival curves according to third-line treatment for all patients are shown in Figure 1. The median OS of patients who received F-RAM/AFL on third-line treatment (n=17) and those who received TAS-102 (n=26) were 379 days (95%CI=157-458 days) and 183 days (95%CI=80-204 days), respectively (log-rank test, p=0.015) (Figure 1).

Figure 1.
Figure 1.

Kaplan–Meier survival curves of overall survival following third-line therapy with FOLFIRI plus ramucirumab/aflibercept and trifluridine/tipiracil combination tablet. No significant difference in survival was observed between the two groups. The FOLFIRI plus ramucirumab/aflibercept group had a longer survival compared with the rifluridine/tipiracil combination tablet group.

Reasons for discontinuation. The discontinuation of treatment due to AEs was more common in F-RAM/AFL (20 cases) than in TAS-102 (26 cases) (p=0.026). Reasons for the discontinuation of F-RAM/AFL or TAS-102 are summarized in Table IV. Treatment was discontinued due to progressive disease, AEs, deterioration of condition, and deterioration in performance status in 6, 3, 2, and 2 patients in the F-RAM/AFL group and in 10, 0, 4, and 10 patients in the TAS-102 group, respectively. The AEs in the F-RAM/AFL group included proteinuria, fatigue, and anorexia.

View this table:
Table IV.

Reasons for third-line treatment discontinuation.

Analysis of adverse events. The AEs for the F-RAM/AFL group included diarrhoea (n=9, 34.6%), anorexia (n=9, 34.6%), peripheral sensory neuropathy (n=9, 34.6%), and nausea (n=8, 30.8%). The AEs for the TAS-102 group included neutropenia (n=14, 82.4%), anaemia (n=12, 70.6%), and fatigue (n=11, 64.7%). The AEs for the F-RAM/AFL and TAS-102 groups are summarized in Table V. Grade 3 or higher AEs in the F-RAM/AFL group included leucopenia (n=1), neutropenia (n=2), diarrhoea (n=1), fatigue (n=1), proteinuria (n=1), and anorexia (n=1), while those in the TAS-102 group included leucopenia (n=2), neutropenia (n=7), decreased platelet count (n=1), and anaemia (n=2).

View this table:
Table V.

Treatment-related adverse events reported in 10% or more of treated patients in either group.

Discussion

In this study, we clarified the risks and benefits of F-RAM/AFL as a third-line treatment after the use of BV as the first-line and second-line treatment for mCRC in comparison with those of TAS-102. We observed a longer OS in F-RAM/AFL than in TAS-102. However, F-RAM/AFL yielded more frequent AEs, such as stomatitis and proteinuria, and was discontinued due to AEs, unlike TAS-102.

For the third-line and later treatment of mCRC, Yoshihiro et al. reported that F-RAM results in a median OS of 13.0 months (23). F-AFL has not been investigated after the third-line treatment in mCRC. However, in a local phase II trial of TAS-102, the OS was only 9.0 months (19). OS for patients treated with regorafenib is 6.4 months (24). These reports are broadly focused on third-line and later treatment and are not limited to third-line treatment. In our study, the OS estimates for F-RAM/AFL and TAS-102 were 379 days (12.6 months) and 183 days (6.1 months), respectively. Furthermore, the use of F-RAM/AFL as a third-line treatment was identified as a prognostic factor. Accordingly, it is possible that a similar OS can be obtained using F-RAM/AFL or TAS-102 as third-line treatment or third-line and later treatment. In fact, Kimura et al. reported that F-RAM and TAS-102 have the same effect on OS. However, comparisons between studies are limited by the previous focus on both third-line and later treatment as well as differences in drugs used as first- and second-line treatments, demographic factors, and the number of cases. In summary, these findings demonstrate the beneficial effect of F-RAM/AFL on prognosis after the use of BV for first- and second-line treatments.

Treatment discontinuation due to urinary protein, malaise, and loss of appetite was observed with F-RAM/AFL, whereas TAS-102 could be continued without discontinuation due to AEs in all cases. AEs in F-RAM included myelosuppression, gastrointestinal toxicity (e.g., nausea and diarrhoea), mouth ulcers, and proteinuria. AE management is important because diarrhoea and mouth ulcers reduce quality of life (24). Grade 3 or higher neutropenia and anaemia were observed in TAS-102; however, treatment was continued by temporarily stopping the drug. In addition, although the frequencies of nausea and malaise were high, these symptoms were mild and did not affect the continuation of treatment. Taken together, F-RAM/AFL frequently produces severe AEs and therefore patient quality of life may be lower for F-RAM/AFL than for TAS-102.

Our findings provide new insights into the potential of F-RAM/AFL and TAS-102 as third-line treatments after using BV as first- and second-line treatments in patients with mCRC. These results can guide the selection of an appropriate third-line therapeutic agent. However, the number of cases was limited, and patient backgrounds differed between groups. Thus, further well-designed studies are needed to resolve these issues and validate our results. The high cost of cancer treatment is a highly debated issue (26). Given the high cost, availability of alternative options, and minimal improvement in survival, the usefulness of RAM in clinical practice has been questioned (27). The estimated annual cost of F-RAM is significantly higher than the estimated cost of TAS-102 (24, 28). The cost-effectiveness ratios for AFL and RAM are JPY 19,836,504 (US $ 179,678) and JPY 41,947,989 (US $ 379,964) per QALY, respectively. AFL is more cost-effective than RAM. However, the addition of AFL or RAM to FOLFIRI as a second-line treatment for mCRC is not cost-effective in the Japanese healthcare system (29). In the future, it will be necessary to calculate the cost-effectiveness of RAM and AFL, including TAS-102. The results of this study suggest that F-RAM/AFL is superior to TAS-102 in terms of efficacy in the third-line setting. Furthermore, biomarkers may be used to predict the effect. Various potential prognostic biomarkers after F-AFL have been associated with efficacy endpoints (30).

In conclusion, as a third-line treatment after using BV as a first-line and second-line treatment for mCRC, F-RAM/AFL should be prioritized over TAS-102 in terms of efficacy; however, it is necessary to pay attention to the occurrence of AEs, such as stomatitis and proteinuria.

Footnotes

  • Authors’ Contributions

    MK contributed to the case report design, collected and provided data, was the principal author of the article, and is the guarantor of the article and all data. EU, HT, and TY contributed to the clinical study design, reviewed the article, and supervised the report and publication process. All the Authors approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received April 8, 2021.
  • Revision received April 19, 2021.
  • Accepted April 20, 2021.

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Risk–benefit Analysis of FOLFIRI Plus Ramucirumab/Aflibercept as a Third-line Treatment in Metastatic Colorectal Cancer
MICHIO KIMURA, EISEKI USAMI, HITOMI TERAMACHI, TOMOAKI YOSHIMURA
Anticancer Research Jun 2021, 41 (6) 3091-3097; DOI: 10.21873/anticanres.15093
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