Research progress on drug therapy for metastatic colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

MA Ganqing ^1,2 , ZHANG Dan ^1,2 , LI Luyao ^1,2 , LIU Jixiang ^2,3 ,  FAN Ruifang ²

1. The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, P. R. China;
2. Department of General Surgery, The 940^th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, P. R. China;
3. Northwest Minzu University, Lanzhou 730030, P. R. China;

Corresponding author：

FAN Ruifang, Email: fanruif@163.com

Keywords：

colorectal cancer; metastatic colorectal cancer; chemotherapy; targeted therapy; immunotherapy

DOI：

10.7507/1007-9424.202303071

Video：

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Objective To understand the latest research progress of chemotherapy, targeted therapy and immunotherapy drugs in the treatment of metastatic colorectal cancer. Method The literature on the efficacy of different treatment drugs for metastatic colorectal cancer in recent years both domestically and internationally was retrieved and reviewed. Results There had been many clinical research progress in the treatment of metastatic colorectal cancer, new drugs had emerged, targeted drugs were particularly prominent, and more trials of therapeutic drugs and drug combination treatment regimens were also being carried out. Different treatment methods were applied to patients according to the mutation status of RAS/RAF and the expression of mismatch repair protein, the survival benefit varied greatly. Conclusion Precision medicine is becoming increasingly important, screening patients to choose appropriate treatment modality can further improve survival benefit.

Citation： MA Ganqing, ZHANG Dan, LI Luyao, LIU Jixiang, FAN Ruifang. Research progress on drug therapy for metastatic colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(7): 889-896. doi: 10.7507/1007-9424.202303071 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Kasper S, Foch C, Messinger D, et al. Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer. Eur J Cancer, 2021, 144: 291-301.
3.	Hernandez-Alejandro R, Ruffolo LI, Sasaki K, et al. Recipient and donor outcomes after living-donor liver transplant for unresectable colorectal liver metastases. JAMA Surg, 2022, 157(6): 524-530.
4.	Trinh T, Park SB, Murray J, et al. Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial. Support Care Cancer, 2021, 29(2): 1103-1110.
5.	Kawai S, Takeshima N, Hayasaka Y, et al. Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis. BMC Cancer, 2021, 21(1): 116. doi: 10.1186/s12885-021-07823-7.
6.	Ishibashi K, Aoyama T, Kotaka M, et al. PhaseⅡ study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study). Cancer Chemother Pharmacol, 2021, 87(5): 665-672.
7.	Yamazaki K, Yamanaka T, Shiozawa M, et al. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage Ⅱ colon cancer: the randomized phase Ⅲ ACHIEVE-2 trial. Ann Oncol, 2021, 32(1): 77-84.
8.	Li Y, Gan Y, Liu J, et al. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduct Target Ther, 2022, 7(1): 87. doi: 10.1038/s41392-022-00902-6.
9.	Wang L, Zhao L, Lin Z, et al. Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness. Clin Transl Med, 2022, 12(5): e743. doi: 10.1002/ctm2.743.
10.	Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(1): 29-42.
11.	Gholami S, Kemeny NE, Boucher TM, et al. Adjuvant hepatic artery infusion chemotherapy is associated with improved survival regardless of KRAS mutation status in patients with resected colorectal liver metastases: A retrospective analysis of 674 patients. Ann Surg, 2020, 272(2): 352-356.
12.	Pak LM, Kemeny NE, Capanu M, et al. Prospective phaseⅡ trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. J Surg Oncol, 2018, 117(4): 634-643.
13.	Boilève A, Maillard A, Wagner M, et al. Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy–a randomized phase Ⅱ study—SULTAN UCGI 30/PRODIGE 53 (NCT03164655)–study protocol. BMC Cancer, 2020, 20(1): 74. doi: 10.1186/s12885-020-6571-7.
14.	巴明臣, 崔书中, 骆福添, 等. 腹腔热灌注化疗治疗进展期结直肠癌临床疗效及安全性的Meta分析. 中国普外基础与临床杂志, 2010, 17(7): 725-730.
15.	Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(2): 256-266.
16.	Adams RA, Fisher DJ, Graham J, et al. Capecitabine versus active monitoring in stable or responding metastatic colorectal cancer after 16 weeks of first-line therapy: Results of the randomized FOCUS4-N trial. J Clin Oncol, 2021, 39(33): 3693-3704.
17.	Cruz-Duarte R, Rebelo de Almeida C, Negrão M, et al. Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer. Clin Cancer Res, 2022, 28(6): 1203-1216.
18.	Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer, 2021, 124(3): 587-594.
19.	Benavides M, Díaz-Rubio E, Carrato A, et al. Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase Ⅱ randomised Spanish TTD trials. ESMO Open, 2019, 4(6): e000599. doi: 10.1136/esmoopen-2019-000599.
20.	Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol, 2021, 39(4): 285-294.
21.	Terazawa T, Kato T, Goto M, et al. Phase Ⅱ study of pani-tumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable RAS wild-type colorectal cancer: OGSG 1602. Oncologist, 2021, 26(1): 17-e47. doi: 10.1002/onco.13523.
22.	Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF^V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol, 2021, 39(4): 273-284.
23.	Seligmann JF, Fisher DJ, Brown LC, et al. Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer: A randomized trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. J Clin Oncol, 2021, 39(33): 3705-3715.
24.	Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol, 2020, 21(3): 412-420.
25.	Liu Y, Xiao Q, He J, et al. PhaseⅡstudy of anlotinib in combination with oxaliplatin and capecitabine for patients with RAS/BRAF wild-type metastatic colorectal adenocarcinoma as the first-line therapy. BMC Med, 2022, 20(1): 155. doi: 10.1186/s12916-022-02357-6.
26.	Wang F, He MM, Yao YC, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phaseⅠ b/Ⅱ clinical trial and gut microbiome analysis. Cell Rep Med, 2021, 2(9): 100383. doi: 10.1016/j.xcrm.2021.100383.
27.	Iwasa S, Okita N, Kuchiba A, et al. Phase Ⅱ study of lenvatinib for metastatic colorectal cancer refractory to standard chemotherapy: the LEMON study (NCCH1503). ESMO Open, 2020, 5(4): e000776. doi: 10.1136/esmoopen-2020-000776.
28.	Liotti F, Kumar N, Prevete N, et al. PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells. J Exp Clin Cancer Res, 2021, 40(1): 22. doi: 10.1186/s13046-020-01818-1.
29.	Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol, 2022, 23(7): 876-887.
30.	Li J, Deng Y, Zhang W, et al. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol, 2021, 14(1): 95. doi: 10.1186/s13045-021-01095-1.
31.	André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med, 2020, 383(23): 2207-2218.
32.	Le DT, Kim TW, Van Cutsem E, et al. PhaseⅡ open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol, 2020, 38(1): 11-19.
33.	Picco G, Cattaneo CM, van Vliet EJ, et al. Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy, and immunotherapy. Cancer Discov, 2021, 11(8): 1923-1937.
34.	Jabbari N, Kenerson HL, Lausted C, et al. Modulation of immune checkpoints by chemotherapy in human colorectal liver metastases. Cell Rep Med, 2020, 1(9): 100160. doi: 10.1016/j.xcrm.2020.100160.
35.	Kim RD, Kovari BP, Martinez M, et al. A phaseⅠ / Ⅰ b study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer. Eur J Cancer, 2022, 169: 93-102.
36.	Kim DW, Tan E, Zhou JM, et al. A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer. Br J Cancer, 2021, 124(11): 1803-1808.
37.	Tomar MS, Kumar A, Srivastava C, et al. Elucidating the mechanisms of temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188616. doi: 10.1016/j.bbcan.2021.188616.
38.	Crisafulli G, Sartore-Bianchi A, Lazzari L, et al. Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients. Cancer Discov, 2022, 12(7): 1656-1675.
39.	Zhang C, Wang Z, Yang Z, et al. PhaseⅠ escalating-dose trial of CAR-T therapy targeting CEA⁺ metastatic colorectal cancers. Mol Ther, 2017, 25(5): 1248-1258.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Kasper S, Foch C, Messinger D, et al. Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer. Eur J Cancer, 2021, 144: 291-301.
3. Hernandez-Alejandro R, Ruffolo LI, Sasaki K, et al. Recipient and donor outcomes after living-donor liver transplant for unresectable colorectal liver metastases. JAMA Surg, 2022, 157(6): 524-530.
4. Trinh T, Park SB, Murray J, et al. Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial. Support Care Cancer, 2021, 29(2): 1103-1110.
5. Kawai S, Takeshima N, Hayasaka Y, et al. Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis. BMC Cancer, 2021, 21(1): 116. doi: 10.1186/s12885-021-07823-7.
6. Ishibashi K, Aoyama T, Kotaka M, et al. PhaseⅡ study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study). Cancer Chemother Pharmacol, 2021, 87(5): 665-672.
7. Yamazaki K, Yamanaka T, Shiozawa M, et al. Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage Ⅱ colon cancer: the randomized phase Ⅲ ACHIEVE-2 trial. Ann Oncol, 2021, 32(1): 77-84.
8. Li Y, Gan Y, Liu J, et al. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduct Target Ther, 2022, 7(1): 87. doi: 10.1038/s41392-022-00902-6.
9. Wang L, Zhao L, Lin Z, et al. Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness. Clin Transl Med, 2022, 12(5): e743. doi: 10.1002/ctm2.743.
10. Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(1): 29-42.
11. Gholami S, Kemeny NE, Boucher TM, et al. Adjuvant hepatic artery infusion chemotherapy is associated with improved survival regardless of KRAS mutation status in patients with resected colorectal liver metastases: A retrospective analysis of 674 patients. Ann Surg, 2020, 272(2): 352-356.
12. Pak LM, Kemeny NE, Capanu M, et al. Prospective phaseⅡ trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. J Surg Oncol, 2018, 117(4): 634-643.
13. Boilève A, Maillard A, Wagner M, et al. Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy–a randomized phase Ⅱ study—SULTAN UCGI 30/PRODIGE 53 (NCT03164655)–study protocol. BMC Cancer, 2020, 20(1): 74. doi: 10.1186/s12885-020-6571-7.
14. 巴明臣, 崔书中, 骆福添, 等. 腹腔热灌注化疗治疗进展期结直肠癌临床疗效及安全性的Meta分析. 中国普外基础与临床杂志, 2010, 17(7): 725-730.
15. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(2): 256-266.
16. Adams RA, Fisher DJ, Graham J, et al. Capecitabine versus active monitoring in stable or responding metastatic colorectal cancer after 16 weeks of first-line therapy: Results of the randomized FOCUS4-N trial. J Clin Oncol, 2021, 39(33): 3693-3704.
17. Cruz-Duarte R, Rebelo de Almeida C, Negrão M, et al. Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer. Clin Cancer Res, 2022, 28(6): 1203-1216.
18. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer, 2021, 124(3): 587-594.
19. Benavides M, Díaz-Rubio E, Carrato A, et al. Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase Ⅱ randomised Spanish TTD trials. ESMO Open, 2019, 4(6): e000599. doi: 10.1136/esmoopen-2019-000599.
20. Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol, 2021, 39(4): 285-294.
21. Terazawa T, Kato T, Goto M, et al. Phase Ⅱ study of pani-tumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable RAS wild-type colorectal cancer: OGSG 1602. Oncologist, 2021, 26(1): 17-e47. doi: 10.1002/onco.13523.
22. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF^V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol, 2021, 39(4): 273-284.
23. Seligmann JF, Fisher DJ, Brown LC, et al. Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer: A randomized trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. J Clin Oncol, 2021, 39(33): 3705-3715.
24. Pfeiffer P, Yilmaz M, Möller S, et al. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol, 2020, 21(3): 412-420.
25. Liu Y, Xiao Q, He J, et al. PhaseⅡstudy of anlotinib in combination with oxaliplatin and capecitabine for patients with RAS/BRAF wild-type metastatic colorectal adenocarcinoma as the first-line therapy. BMC Med, 2022, 20(1): 155. doi: 10.1186/s12916-022-02357-6.
26. Wang F, He MM, Yao YC, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phaseⅠ b/Ⅱ clinical trial and gut microbiome analysis. Cell Rep Med, 2021, 2(9): 100383. doi: 10.1016/j.xcrm.2021.100383.
27. Iwasa S, Okita N, Kuchiba A, et al. Phase Ⅱ study of lenvatinib for metastatic colorectal cancer refractory to standard chemotherapy: the LEMON study (NCCH1503). ESMO Open, 2020, 5(4): e000776. doi: 10.1136/esmoopen-2020-000776.
28. Liotti F, Kumar N, Prevete N, et al. PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells. J Exp Clin Cancer Res, 2021, 40(1): 22. doi: 10.1186/s13046-020-01818-1.
29. Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol, 2022, 23(7): 876-887.
30. Li J, Deng Y, Zhang W, et al. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol, 2021, 14(1): 95. doi: 10.1186/s13045-021-01095-1.
31. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med, 2020, 383(23): 2207-2218.
32. Le DT, Kim TW, Van Cutsem E, et al. PhaseⅡ open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol, 2020, 38(1): 11-19.
33. Picco G, Cattaneo CM, van Vliet EJ, et al. Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy, and immunotherapy. Cancer Discov, 2021, 11(8): 1923-1937.
34. Jabbari N, Kenerson HL, Lausted C, et al. Modulation of immune checkpoints by chemotherapy in human colorectal liver metastases. Cell Rep Med, 2020, 1(9): 100160. doi: 10.1016/j.xcrm.2020.100160.
35. Kim RD, Kovari BP, Martinez M, et al. A phaseⅠ / Ⅰ b study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer. Eur J Cancer, 2022, 169: 93-102.
36. Kim DW, Tan E, Zhou JM, et al. A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer. Br J Cancer, 2021, 124(11): 1803-1808.
37. Tomar MS, Kumar A, Srivastava C, et al. Elucidating the mechanisms of temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188616. doi: 10.1016/j.bbcan.2021.188616.
38. Crisafulli G, Sartore-Bianchi A, Lazzari L, et al. Temozolomide treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients. Cancer Discov, 2022, 12(7): 1656-1675.
39. Zhang C, Wang Z, Yang Z, et al. PhaseⅠ escalating-dose trial of CAR-T therapy targeting CEA⁺ metastatic colorectal cancers. Mol Ther, 2017, 25(5): 1248-1258.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on drug therapy for metastatic colorectal cancer

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