Цетуксимаб в терапии метастатического колоректального рака: история вопроса и клиническое наблюдение

В настоящее время продолжается поиск наиболее оптимальных режимов лекарственной терапии метастатического колоректального рака (мКРР), в результате использования которых предполагаются увеличение выживаемости без прогрессирования (ВБП) и общей выживаемости (ОВ); улучшение качества жизни пациентов. Благодаря значительному прогрессу в химиотерапии (ХТ) и хирургическом лечении мКРР, использованию мультидисциплинарного подхода алгоритмы лечения больных изменились. Увеличение продолжительности жизни пациентов наблюдается при использовании всех трех наиболее активных при данном заболевании химиопрепаратов: оксалиплатина (Oxa), иринотекана (Iri), фторпиримидинов. Включение таргетного препарата цетуксимаба в современные режимы лечения мКРР привело к статистически достоверному увеличению частоты объективных ответов (ЧОО), медианы ВБП и ОВ. В статье приводятся результаты наиболее значимых клинических исследований, посвященных изучению эффективности анти-EGFR препарата цетуксимаба в комбинации со стандартными режимами ХТ в I и II линиях лекарственного лечения мКРР, а также представлено клиническое наблюдение успешного использования цетуксимаба в терапии мКРР.

1. Goldstein N et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res, 1995, 1: 1311-1318.

2. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res. 2001, 7: 2958–2970.

3. Arteaga C. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J. Clin. Oncol., 2001, 19(Suppl. 18): 32S-40S.

4. Lenz H-J. Cetuximab in the management of colorectal cancer. Biol Targ Ther, 2007, 1(2): 77–91.

5. Mendelsohn J et al. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 2003, 21: 2787-2799.

6. Moosmann N, Heinemann V. Cetuximab in the treatment of metastatic colorectal cancer. Exp Opin Biol Ther, 2007, 7(2): 243–256.

7. Vallbohmer D et al. Molecular determinants of cetuximab efficacy. J. Clin. Oncol., 2005, 23: 3536-3544.

8. Vincenzi B et al. Angiogenesis modifications related with cetuximab plus irinotecan as anticancer treatment in advanced colorectal cancer patients. Ann. Oncol., 2006, 17: 835-841.

9. Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinitecanrefractory metastatic colorectal cancer. N. Engl. J. Med., 2004, 351(4): 337-345.

10. Sobrero AF et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J. Clin. Oncol., 2008, 26(14).

11. Komatsu Y et al. Phase II trial of irinotecan plus s-1 (IRIS) with cetuximab (IRIS/Cet) as second-line treatment in patients with KRAS wild-type metastatic colorectal cancer (mCRC): HGCSG0902—Comparison of administration interval in cetuximab treatment. J. Clin. Oncol. (Meeting Abstracts), 2015, 33(Suppl. 3): 746 p.

12. Diaz-Rubio E et al. Cetuximab in combination with oxaliplatin|5-fluorouracil(5-FU)/folinic acid (Fa) (FOLFOX-4) in first-line treatment of patients with epidermal growth factor receptor (EGFR) – expressing metastatic colorectal cancer: An intenational phase 2 study. Proc Am Soc Clin Oncol, 2005, abstr. 3535.

13. Van Cutsem E et al. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Ann Oncol, 2004, 15(Suppl. 3): abstr. 339P.

14. Seufferlein T, Dittrich C et al. A phase I/II study of cetuximab with 5-fluorouracil plus weekly oxliplatin in first – line treatment of patients with metastatic colorectal cancer expressing epidermal growth factor receptor. ASCO, 2005, abstr. 3644.

15. Borner M, Mingrone W, Koeberle D et al. The impact of cetuximab on the capecitabine plus oxaliplatin (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC): A randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK) Proc. ASCO, 2006, 3551.

16. Tabernero J, Van Cutsem E, Diaz-Rubio E et al. Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer. J Clin Oncol, 2007, 25: 5225– 5232.

17. Tveit K, Guren T, Glimelius B et al. Randomized phase III study of 5-flurouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line therapy of metastatic colorectal cancer: the NORDIC VII study (NCT0014314), by the Nordic Colorectal Cancer Biomodulation Group. J Clin Oncol, 2011, 29(Suppl. 4): abstr. 365.

18. Van Cutsem E, Nowacki M et al. Randomized phase III study of irinotecan and 5FU/FA with or without cetuximab in the first-line treatment of pts with metastatic colorectal cancer. CRYSTAL trial. ASCO, 2007, abstr. 4000.

19. Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the firstline treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. Journal of Clinical Oncology, 2007, 25(Suppl. 18): 164S.

20. Bokemeyer C et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol., 2009, 27(5): 663-671.

21. De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol, 2008, 19: 508–515.

22. Di Fiore F, Blanchard F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer, 2007, 96: 1166–1169.

23. Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol, 2008, 26: 374– 379.

24. Custodio A, Feliu J. Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: beyond KRAS mutations. Critic Rev Oncol Hematol, 2013, 85: 45–81.

25. Горбунова В.А. Необходимость углубленного анализа RAS-мутаций для стратегии лекарственной терапии колоректального рака. Онкологическая колопроктология, 2014, 1: 7-13.

26. Семенов Н.Н. Высокая активность вектибикса у больных метастатическим колоректальным раком с диким типом гена RAS. Онкологическая колопроктология, 2014, 2: 18–21.

27. Lambrechts D. The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer. J. Clin. Oncol. (Meeting Abstracts), 2009, 27(15S): 4020 p.

28. De Roock W et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy ofcetuximab plus chemotherapy in chemotherapyrefractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol, 2010, 11(8): 753-762.

29. Di Nicolantonio F et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol., 2008, 26(35): 5705-5712.

30. Douillard JY, Oliner KS, Siena S et al. Panitumumab FOLFOX-4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 2013, 369: 1023–1034.

31. Moosmann N, von Weikersthal LF, VehlingKaiser U et al. Final analysis of the randomized trial of the German AIO CRC study group: Cetuximab plus XELIRI versus cetuximab plus XELOX as first-line treatment for patients with metastatic colorectal cancer (mCRC). ASCO Meeting. Abstracts, 2010, 28: 3540.

32. Adams RA, Meade AM, Seymour MT et al. Intermittent vs. continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet Oncol, 2011, 12(7): 642–653.

33. Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet, 2011, 377(9783): 2103–2114.

34. Maughan, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wildtype advanced colorectal cancer (ACRC): a randomised superiority trial (MRC COIN). Eur J Cancer, 2009, 7(3): 4 (abstr 6LBA).

35. Garufi C, Torsello A, Tumolo S et al. POCHER (preoperative chemotherapy for hepatic resection) with cetuximab (Cmab) plus CPT-11/5- fluorouracil (5-U)/leucovorin(FA)/oxaliplatin (L-OHP) (CPT-11-FFL) in unresectable colorectal liver metastases (CLM). J Clin Oncol, 2009, 27: suppl. abstr e15020. 2009 ASCO Annual Meeting.

36. Robert C et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol, 2005, 6: 491-500.

37. Segaert S et al. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors Ann. Oncol., 2005, 16: 1425-1433.

38. Segaert S et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J. Dtsch. Dermatol. Ges., 2005, 3: 599-606.

39. Schrag D et al. Cetuximab therapy and symptomatic hypomagnesemia. Natl. Cancer Inst., 2005, 97(16): 1221-1810.

40. Saltz LB et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc. Am. Soc. Clin. Oncol., 2001, 20(2a): Abstract 7.

41. Gullick WJ, Hughes CM, Mellon K et al. Immunohistochemical detection of the epidermal growth factor receptor in paraffin-embedded human tissues. J Pathol, 1991, 164: 285– 289.

42. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer, 2006, 6: 803–812.

43. Nicholson RI, Gee JM, Happer ME et al. EGFR and cancer prognosis. Eur J Cancer, 2001, 37(Suppl. 4): S9–15.

44. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol, 2005, 23: 5235–5246.