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Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Purpose

Fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab is the standard second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) who are refractory or intolerant to fluoropyrimidines and oxaliplatin. However, the benefits of incorporating fluoropyrimidines into second-line chemotherapy for patients with mCRC who are refractory to fluoropyrimidines are unknown.

Methods

We retrospectively evaluated patients with mCRC who were administered irinotecan plus bevacizumab or FOLFIRI plus bevacizumab as second-line chemotherapy at a single institution from January 2010 to April 2020. We compared the efficacy and safety of irinotecan plus bevacizumab (IRI group) with those of FOLFIRI plus bevacizumab (FOLFIRI group).

Results

Of the 255 enrolled patients, 107 (IRI/FOLFIRI group, 31/76 patients) were eligible for analysis. After a median follow-up of 13.1 months (range 1.2–48.4) and 14.3 months (range 0.9–46.5) for the IRI and FOLFIRI groups, respectively, the median progression-free survival was 6.4 months and 5.8 months [adjusted hazard ratio (aHR), 0.82; 95% confidence interval (CI) 0.50–1.34, p = 0.44] and the median overall survival was 16.6 months and 16.5 months (aHR, 1.01; 95% CI 0.59–1.69; p = 0.97) in the IRI and FOLFIRI groups, respectively. All-grade nausea, stomatitis, neutropenia, thrombocytopenia, Grade 3/4 neutropenia, and febrile neutropenia occurred more frequently in the FOLFIRI group than in the IRI group.

Conclusion

Our study suggests omitting fluorouracil from FOLFIRI plus bevacizumab as the second-line chemotherapy decreases adverse events without affecting the treatment efficacy in patients with mCRC who are refractory to fluoropyrimidines. Further randomized prospective studies are warranted to validate our result.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60(24):6921–6926

    CAS  PubMed  Google Scholar 

  • Becouarn Y, Gamelin E, Coudert B, Négrier S, Pierga JY, Raoul JL, Provençal J, Rixe O, Krisch C, Germa C, Bekradda M, Mignard D, Mousseau M (2001) Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 19(22):4195–4201

    Article  CAS  PubMed  Google Scholar 

  • Clarke SJ, Yip S, Brown C, van Hazel GA, Ransom DT, Goldstein D, Jeffrey GM, Tebbutt NC, Buck M, Lowenthal RM, Boland A, Gebski V, Zalcberg J, Simes RJ (2011) Single-agent irinotecan or FOLFIRI as second-line chemotherapy for advanced colorectal cancer; results of a randomised phase II study (DaVINCI) and meta-analysis [corrected]. Eur J Cancer 47(12):1826–1836

    Article  CAS  PubMed  Google Scholar 

  • Graeven U, Arnold D, Reinacher-Schick A, Heuer T, Nusch A, Porschen R, Schmiegel W (2007) A randomised phase II study of irinotecan in combination with 5-FU/FA compared with irinotecan alone as second-line treatment of patients with metastatic colorectal carcinoma. Onkologie 30(4):169–174

    CAS  PubMed  Google Scholar 

  • Kayhanian H, Goode E, Sclafani F, Ang JE, Gerlinger M, Gonzalez de Castro D, Shepherd S, Peckitt C, Rao S, Watkins D, Chau I, Cunningham D, Starling N (2018) Treatment and survival outcome of BRAF-mutated metastatic colorectal cancer: a retrospective matched case-control study. Clin Colorect Cancer 17(1):e69–e76

    Article  Google Scholar 

  • KohneKöhne CH, Cunningham D, Di Costanzo F, Glimelius B, Blijham G, Aranda E, Scheithauer W, Rougier P, Palmer M, Wils J, Baron B, Pignatti F, Schöffski P, Micheel S, Hecker H (2002) Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol 13(2):308–317

    Article  Google Scholar 

  • Kuramochi H, Ando M, Itabashi M, Nakajima G, Kawakami K, Hamano M et al (2017) Phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, and bevacizumab. Cancer Chemother Pharmacol 79(3):579–585

    Article  Google Scholar 

  • Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N, Shirao K, Yamada Y, Ohmatsu H, Kubota K, Yoshida T, Ohtsu A, Saijo N (2007) Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genom 17(7):497–504

    Article  CAS  Google Scholar 

  • Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK et al (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21(11):2059–2069

    Article  Google Scholar 

  • Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ, National Cancer Research Institute Colorectal Clinical Studies Group (2007) Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 370(9582):143–152

    Article  CAS  PubMed  Google Scholar 

  • Shitara K, Matsuo K, Yokota T, Takahari D, Shibata T, Ura T, Inaba Y, Yamaura H, Sato Y, Najima M, Muro K (2011) Prognostic factors for metastatic colorectal cancer patients undergoing irinotecan-based second-line chemotherapy. Gastrointest Cancer Res 4(5–6):168–172

    PubMed  PubMed Central  Google Scholar 

  • Shitara K, Yuki S, Yamazaki K, Naito Y, Fukushima H, Komatsu Y, Yasui H, Takano T, Muro K (2013) Validation study of a prognostic classification in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy. J Cancer Res Clin Oncol 139(4):595–603

    Article  CAS  PubMed  Google Scholar 

  • Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F, R. S. (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5):499–508

    Article  CAS  PubMed  Google Scholar 

  • Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, Agarwal A, Maru DM, Sieber O, Desai J (2011) Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 117(20):4623–4632

    Article  CAS  PubMed  Google Scholar 

  • Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237

    Article  CAS  PubMed  Google Scholar 

  • Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30(28):3499–3506

    Article  PubMed  Google Scholar 

  • Wulaningsih W, Wardhana A, Watkins J, Yoshuantari N, Repana D, Van Hemelrijck M (2016) Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and. Cochrane Database Syst Rev 2016(2):CD008593

    PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Enago (http://www.enago.jp) for the English language review.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Yuki Matsubara, Toshiki Masuishi, Takatsugu Ogata, Taiko Nakazawa, Kyoko Kato, Kazuki Nozawa, Yukiya Narita, Kazunori Honda, Hideaki Bando, Hiroya Taniguchi, Shigenori Kadowaki, Masashi Ando & Kei Muro

  2. Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan

    Masahiro Tajika

Authors
  1. Yuki Matsubara
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  2. Toshiki Masuishi
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  3. Takatsugu Ogata
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  6. Kazuki Nozawa
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by YM. The first draft of the manuscript was written by YM and TM, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshiki Masuishi.

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Conflict of interest

The authors declare the following conflicts of interest: YM received honorania from Takeda, Merck Bio Pharma, and Taiho. TM received honorania from Takeda, Chudai, Merck Bio Pharma, Taiho, Bayer, Eli Lilly, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol-myers squibb and research funding from MSD, Daiichi Sankyo, Ono, and Novartis. TO received honorania from Ono, Bristol-myers squibb, Taiho, MSD, and Eli Lilly. TN received honorania from Eli Lilly. YN received honorania from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, and AstraZeneca and research funding from Ono, and Bristol-myers squibb. YN was also a part of the advisory board of Daiichi Sankyo. HB received honorania from Eli Lilly and Taiho and research funding from Ono. HT received honorania from Taiho, Chugai, Takeda, Eli Lilly, Merck Biopharma, and Yakult Honsha. SK received honorania from Bristol-myers squibb, Chugai, Merck Bio Pharma, Daiichi Sankyo, MSD, Ono, Bayer, Taiho, and Esai and research funding from Ono, Taiho, MSD, Nobelpharma, Bristol-myers squibb, Eli Lilly, and Chugai. MT received honorania from EA Pharma. KM received honorania from Ono, Chugai, Takeda, Taiho, Sanofi, Bristol-myers squibb, Eli Lilly, and Bayer; research funding from Solasia Pharma, Merck Serono, Daiichi Sankyo, Parexel International, Pfizer, MSD, Amgen, ONO, Astellas, Sanofi, Taiho, and Esai; and consulting fees from AstraZeneca, Ono, and Amgen. KM was also a part of the advisory boards of Ono, MSD, AstraZeneca, Daiichi Sankyo, and Solasia Pharma.

Ethics approval

This study was approved by the institutional review board (Aichi Cancer Center Hospital IRB, ref, 2020-1-339). The institutional review board approved the waiving of informed consent because of the observational retrospective study design, with an optout opportunity provided on the institution’s website.

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Informed consent of participants was waived by the ethics committee as a substitute opt-out.

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Matsubara, Y., Masuishi, T., Ogata, T. et al. Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 149, 1123–1129 (2023). https://doi.org/10.1007/s00432-022-03979-2

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  • DOI: https://doi.org/10.1007/s00432-022-03979-2

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