Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry

. 2023 Dec 15;13(12):6333-6345.

eCollection 2023.

Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry

Chou-Chen Chen¹, Shih-Ching Chang², Yu-Yao Chang^{3

4}, Bo-Wen Lin⁵, Hong-Hwa Chen⁶, Yao-Yu Hsieh^{7

8}, Hung-Chih Hsu^{9

10}, Meng-Che Hsieh¹¹, Tao-Wei Ke¹², Feng-Che Kuan¹³, Chih-Chien Wu^{14

15}, Wei-Chen Lu¹⁶, Yu-Li Su¹⁷, Yi-Hsin Liang¹⁸, Joe-Bin Chen¹⁹, Hsuan-Yuan Huang³, Hsiang-Lin Tsai^{20

21}, Jaw-Yuan Wang^{20

21

22

23

24}

Affiliations

¹ Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.
² Division of Colon and Rectal Surgery, Department of Surgery, Veterans General Hospital Taipei, Taiwan.
³ Department of Colorectal Surgery, Changhua Christian Hospital Changhua, Taiwan.
⁴ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University Taichung, Taiwan.
⁵ Division of Colon and Rectal Surgery, Department of Surgery, National Cheng Kung University Hospital Tainan, Taiwan.
⁶ Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital Kaohsiung, Taiwan.
⁷ Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University New Taipei City, Taiwan.
⁸ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University Taipei, Taiwan.
⁹ Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou Taoyuan, Taiwan.
¹⁰ College of Medicine, Chang Gung University Taoyuan, Taiwan.
¹¹ Division of Hematology Oncology, Department of Internal Medicine, E-Da Hospital, I-Shou University Kaohsiung, Taiwan.
¹² Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital Taichung, Taiwan.
¹³ Department of Hematology and Oncology, Chang Gung Memorial Hospital Chiayi, Taiwan.
¹⁴ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital Kaohsiung, Taiwan.
¹⁵ School of Medicine, National Yang Ming Chiao Tung University Taipei, Taiwan.
¹⁶ Department of Oncology, National Taiwan University Hospital Yunlin Branch Yunlin, Taiwan.
¹⁷ Division of Hematology Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung, Taiwan.
¹⁸ Department of Oncology, National Taiwan University Hospital Taipei, Taiwan.
¹⁹ Department of Surgery, Chung Shan Medical University Hospital Taichung, Taiwan.
²⁰ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University Kaohsiung, Taiwan.
²¹ Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²² Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²³ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²⁴ Center for Cancer Research, Kaohsiung Medical University Kaohsiung, Taiwan.

PMID: 38187069
PMCID: PMC10767339

Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry

Chou-Chen Chen et al. Am J Cancer Res. 2023.

. 2023 Dec 15;13(12):6333-6345.

eCollection 2023.

Authors

Affiliations

¹ Department of Surgery, Taichung Veterans General Hospital Taichung, Taiwan.
² Division of Colon and Rectal Surgery, Department of Surgery, Veterans General Hospital Taipei, Taiwan.
³ Department of Colorectal Surgery, Changhua Christian Hospital Changhua, Taiwan.
⁴ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University Taichung, Taiwan.
⁵ Division of Colon and Rectal Surgery, Department of Surgery, National Cheng Kung University Hospital Tainan, Taiwan.
⁶ Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital Kaohsiung, Taiwan.
⁷ Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University New Taipei City, Taiwan.
⁸ Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University Taipei, Taiwan.
⁹ Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou Taoyuan, Taiwan.
¹⁰ College of Medicine, Chang Gung University Taoyuan, Taiwan.
¹¹ Division of Hematology Oncology, Department of Internal Medicine, E-Da Hospital, I-Shou University Kaohsiung, Taiwan.
¹² Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital Taichung, Taiwan.
¹³ Department of Hematology and Oncology, Chang Gung Memorial Hospital Chiayi, Taiwan.
¹⁴ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital Kaohsiung, Taiwan.
¹⁵ School of Medicine, National Yang Ming Chiao Tung University Taipei, Taiwan.
¹⁶ Department of Oncology, National Taiwan University Hospital Yunlin Branch Yunlin, Taiwan.
¹⁷ Division of Hematology Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung, Taiwan.
¹⁸ Department of Oncology, National Taiwan University Hospital Taipei, Taiwan.
¹⁹ Department of Surgery, Chung Shan Medical University Hospital Taichung, Taiwan.
²⁰ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University Kaohsiung, Taiwan.
²¹ Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²² Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²³ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung, Taiwan.
²⁴ Center for Cancer Research, Kaohsiung Medical University Kaohsiung, Taiwan.

PMID: 38187069
PMCID: PMC10767339

Abstract

This multicenter study aimed to explore the survival benefit of metastasectomy by first-line cetuximab-based chemotherapy in real-world patients with RAS wild-type metastatic colorectal cancer (mCRC). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and metastasectomy rate. The exploratory endpoint was the optimal treatment cycle for better OS and PFS. Receiver operating characteristic curve with the area under curve (AUC) was used to identify the optimal cut-off cycle for survival outcomes. A total of 758 mCRC patients were enrolled in this study, with a median OS of 35.1 months, median PFS of 14.6 months, and metastasectomy rate of 21.4%. Left-sided mCRC had a significantly higher DCR (88.9% vs. 73.1%, P<0.001) and better OS (36.4 vs. 19.6 months, P<0.001). There were no significant differences in PFS and metastasectomy rate between left-sided and right-sided mCRC. However, mCRC patients who underwent metastasectomy over the course of treatment had better OS (54.9 vs. 28.6 months, P<0.001) and PFS (21.0 vs. 13.1 months, P<0.001) than those who did not. Notably, right-sided mCRC who benefited from first-line cetuximab-based chemotherapy to underwent metastasectomy also had favorable outcomes, on a par with left-sided mCRC. The optimal treatment cycle was 14 cycles (AUC: 0.779, P<0.001). Patients who received ≥14 cycles had higher metastasectomy rates (27.5% vs. 13.5%, P<0.001), favorable OS (42.6 vs. 23.4 months, P<0.001) and PFS (18.1 vs. 8.6 months, P<0.001), and, importantly, had comparable adverse events compared with patients who received <14 cycles of treatment. Patients who underwent metastasectomy after or during first-line cetuximab therapy have an improved OS in both left-sided and right-sided mCRC. Furthermore, patients receive ≥14 cycles of treatment whenever possible to achieve a higher likelihood of metastasectomy was associated with favorable survival outcomes.

Keywords: RAS wild-type metastatic colorectal cancer; cetuximab; metastasectomy; optimal treatment cycle; overall survival; progression-free survival.

PubMed Disclaimer

Conflict of interest statement

None.

Figures

**Figure 1**
Survival outcomes of patients with *RAS* wild-type mCRC. Kaplan-Meier survival plots of OS (A) and PFS (B) for total population (N=758). Kaplan-Meier survival plots of OS (C) and PFS (D) accrdoing to the right- and left-sided mCRC. Kaplan-Meier survival plots of OS (E) and PFS (F) accrdoing to metastasectomy. The Log-Rank test was used to assess the survival difference between groups. A p-value less than 0.05 was considered statistically significant.

**Figure 2**
Subgroup analysis of survival outcomes of patients with RAS wild-type mCRC based on metastasectomy across overall population. Kaplan-Meier survival plots of OS (A) and PFS (B) for patients with left-sided mCRC according to whether they underwent metastasectomy. Kaplan-Meier survival plots of OS (C) and PFS (D) for patients with right-sided mCRC according to whether they underwent metastasectomy. Kaplan-Meier survival plots of OS (E) and PFS (F) stratified by lef-sided and right-sided mCRC in patients who underwent metastasectomy during first-line cetuximab-based chemotherapy. The Log-Rank test was used to assess the survival difference between groups. A p-value less than 0.05 was considered to be statistically significant.

**Figure 3**
First-line cetuximab-based chemotherapy ≥14 cycles associated with better survival outcomes in mCRC. A. The ROC curve analysis of optimal cut-off value of treatment cycle. The optimal cycle of first-line cetuximab-based chemotherapy was 14 cycles, with an AUC of 0.779 (P<0.001; Sensitivity =71.8%, Specificity =75.1%). B. Kaplan-Meier survival plot of OS according to optimal cycle of first-line cetuximab-based chemotherapy. C. Kaplan-Meier survival plot of PFS according to optimal cycle of first-line cetuximab-based chemotherapy. The Log-Rank test was used to assess the survival difference between groups. A p-value less than 0.05 was considered to be statistically significant.

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[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. - PubMed

[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. - PubMed

[3] Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:329–359. - PubMed

[4] Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:329–359. - PubMed

[5] Benson AB, Venook AP, Al-Hawary MM, Azad N, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Jeck W, Johung KL, Kirilcuk N, Krishnamurthi S, Maratt JK, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stotsky-Himelfarb E, Tavakkoli A, Willett CG, Gregory K, Gurski L. Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20:1139–1167. - PubMed

[6] Benson AB, Venook AP, Al-Hawary MM, Azad N, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Jeck W, Johung KL, Kirilcuk N, Krishnamurthi S, Maratt JK, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stotsky-Himelfarb E, Tavakkoli A, Willett CG, Gregory K, Gurski L. Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20:1139–1167. - PubMed

[7] Zarour LR, Anand S, Billingsley KG, Bisson WH, Cercek A, Clarke MF, Coussens LM, Gast CE, Geltzeiler CB, Hansen L, Kelley KA, Lopez CD, Rana SR, Ruhl R, Tsikitis VL, Vaccaro GM, Wong MH, Mayo SC. Colorectal cancer liver metastasis: evolving paradigms and future directions. Cell Mol Gastroenterol Hepatol. 2017;3:163–173. - PMC - PubMed

[8] Zarour LR, Anand S, Billingsley KG, Bisson WH, Cercek A, Clarke MF, Coussens LM, Gast CE, Geltzeiler CB, Hansen L, Kelley KA, Lopez CD, Rana SR, Ruhl R, Tsikitis VL, Vaccaro GM, Wong MH, Mayo SC. Colorectal cancer liver metastasis: evolving paradigms and future directions. Cell Mol Gastroenterol Hepatol. 2017;3:163–173. - PMC - PubMed

[9] Cremolini C, Antoniotti C, Moretto R, Masi G, Falcone A. First-line therapy for mCRC - the influence of primary tumour location on the therapeutic algorithm. Nat Rev Clin Oncol. 2017;14:113. - PubMed

[10] Cremolini C, Antoniotti C, Moretto R, Masi G, Falcone A. First-line therapy for mCRC - the influence of primary tumour location on the therapeutic algorithm. Nat Rev Clin Oncol. 2017;14:113. - PubMed

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Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry

Affiliations

Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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Abstract

Conflict of interest statement

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