Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

doi:10.1016/j.tranon.2018.12.003

. 2019 Mar;12(3):502-512.

doi: 10.1016/j.tranon.2018.12.003. Epub 2018 Dec 27.

Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

Cheng-Jen Ma¹, Ching-Wen Huang², Tsung-Kun Chang³, Hsiang-Lin Tsai⁴, Wei-Chih Su⁵, Yung-Sung Yeh⁶, Po-Jung Chen⁷, Jaw-Yuan Wang⁸

Affiliations

¹ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Digestive and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Colorectal Surgery, Department of Surgery, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan.
⁸ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Center for Biomarkers and Biotech Drugs, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: cy614112@ms14.hinet.net.

PMID: 30594039
PMCID: PMC6307535
DOI: 10.1016/j.tranon.2018.12.003

Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

Cheng-Jen Ma et al. Transl Oncol. 2019 Mar.

. 2019 Mar;12(3):502-512.

doi: 10.1016/j.tranon.2018.12.003. Epub 2018 Dec 27.

Authors

Cheng-Jen Ma¹, Ching-Wen Huang², Tsung-Kun Chang³, Hsiang-Lin Tsai⁴, Wei-Chih Su⁵, Yung-Sung Yeh⁶, Po-Jung Chen⁷, Jaw-Yuan Wang⁸

Affiliations

¹ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Digestive and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Colorectal Surgery, Department of Surgery, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan.
⁸ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Center for Biomarkers and Biotech Drugs, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: cy614112@ms14.hinet.net.

PMID: 30594039
PMCID: PMC6307535
DOI: 10.1016/j.tranon.2018.12.003

Abstract

Background: To evaluate the efficacy and toxicities of regorafenib plus irinotecan, dose-escalated on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping, in previously heavily treated metastatic colorectal cancer (mCRC) and the prognostic values of EGFR expression, KRAS mutations, and tumor sidedness.

Methods: Forty-one patients with mCRC with disease progression after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR MoAbs were subjected to UGT1A1 genotyping and received regorafenib combined with FOLFIRI with dose-escalated irinotecan.

Results: The median follow-up period was 10.0 months (1.3-23.5 months). The overall disease control rate was 58.5%, whereas the median progression-free survival (PFS) and overall survival (OS) were 6.0 months and 12.0 months, respectively. KRAS mutations were significantly associated with positive EGFR expression (P = .026). KRAS mutations significantly correlated with a shorter OS than KRAS wild-type (6.0 vs. 14.4 months, P = .014) but had no significant association with PFS. Positive EGFR expression had an inverse correlation with PFS (2.5 vs. 14.0 months, P = .039) and OS (9.6 vs. 19.7 months, P = .044). Moreover, left-sided tumors associated with superior PFS (2.0 vs. 7.0 months, P < .0001) and OS (4.0 vs. 13.0 months, P < .0001), and tumor sidedness was an independent prognostic factor by the multivariate analysis.

Conclusion: Regorafenib and FOLFIRI concomitant therapy with dose-escalated irinotecan seemed to be potentially practicable with satisfactory oncological results. KRAS mutations and EGFR expression might be predictors of poor oncological outcomes; however, left-sided mCRCs would be more beneficial for concomitant regorafenib and FOLFIRI therapy.

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Figures

**Figure 1**
The study scheme of the present study.

**Figure 2**
Kaplan-Meier survival analysis of all patients with metastatic colorectal cancer. (A) Progression-free survival and (B) overall survival.

**Figure 3**
Kaplan-Meier survival analysis of *KRAS* subgroups. (A) Progression-free survival and (B) overall survival.

**Figure 4**
Kaplan-Meier survival analysis of EGFR expression subgroups. (A) Progression-free survival and (B) overall survival.

**Figure 5**
Kaplan-Meier survival analysis of tumor sidedness subgroups. (A) Progression-free survival and (B) overall survival.

See this image and copyright information in PMC

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References

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[1] Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–1403. - PubMed

[2] Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–1403. - PubMed

[3] Arnold D, Stein A. New developments in the second-line treatment of metastatic colorectal cancer: potential place in therapy. Drugs. 2013;73:883–891. - PubMed

[4] Arnold D, Stein A. New developments in the second-line treatment of metastatic colorectal cancer: potential place in therapy. Drugs. 2013;73:883–891. - PubMed

[5] Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–255. - PubMed

[6] Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–255. - PubMed

[7] Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312. - PubMed

[8] Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312. - PubMed

[9] Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–629. - PubMed

[10] Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–629. - PubMed

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Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

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Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

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