Современные возможности таргетной терапии метастатического колоректального рака

Горбунова В.А. Современные возможности таргетной терапии метастатического колоректального рака. Современная Онкология. 2015; 17 (4): 15–21.

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Gorbunova V.A. Modern possibilities of targeted therapy in metastatic colorectal cancer. Journal of Modern Oncology. 2015; 17 (4): 15–21.

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Аннотация

Колоректальный рак (КРР) занимает третье место в мире среди злокачественных опухолей по заболеваемости – более 1,3 млн (1 360 000 в 2012 г.) новых случаев в год и четвертое место по причинам смерти от рака – 694 тыс. смертей в 2012 г. Лекарственные методы лечения КРР имеют большое значение при этом заболевании и, применяясь как в адъювантных схемах, так и для лечения метастатической стадии болезни, позволили за последние десятилетия значительно улучшить показатели продолжительности жизни больных.
Одним из последних достижений современной лекарственной терапии метастатического КРР (мКРР) стало появление нового препарата регорафениба. Регорафениб представляет собой мультикиназный ингибитор, блокирующий протеинкиназы VEGFR 1-3 и TIE-2, участвующие в ангиогенезе опухоли и подавляющие рост новых кровеносных сосудов. Препарат также угнетает онкогенные протеинкиназы KIT, RET и RAF-1, BRAF и мутантную BRAFV600E, которые участвуют в пролиферации и выживании клеток злокачественных новообразований и воздействуют на рецепторы факторов роста тромбоцитов (PDGFR) и фибробластов (FGFR), влияющих на микроокружение опухоли.
Результаты исследования III фазы регорафениба CORRECT подтверждают целесообразность использования регорафениба как новой лечебной опции для больных мКРР, многократно предварительно леченных и исчерпавших все возможности лекарственной терапии.

Ключевые слова: колоректальный рак, химиотерапия, таргетная терапия, цетуксимаб, панитумумаб, бевацизумаб, регорафениб.

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Colorectal cancer (CRC) is ranked third in the world among malignant tumors in morbidity – more than 1.3 million (1 360 000 in 2012) new cases per year, and fourth in mortality – 694 000 deaths in 2012. CRC medicamentary is very important in case of this disease, and have been applying as in case of adjuvant treatment schemas and in case of metastatic disease treatment. All this allowed us significantly improve the life expectancy of the patients last decade. One of the last achievements in modern drug therapy of metastatic CRC (mCRC) is the existence of new drug – regorafenib. Regorafenib is a multi-kinase inhibitor, blocking VEGFR 1-3 and TIE-2 protein kinases, involving in tumor angiogenesis and inhibiting the growth of new blood vessels. The drug also inhibits oncogenic protein kinases: KIT, RET and RAF-1, BRAF and mutated BRAFV600E which are involved in cell proliferation and survival of cancer cells and effects on platelet-derived growth factor receptors (PDGF-R) and fibroblast growth factor receptor (FGFR) affecting the microenvironment tumor. The results of Phase III CORRECT study concerning regorafenib show the desirability of using the regorafenib as a new therapeutic option for patients with mCRC, previously have been treated for many times and have exhausted all the possibilities of drug therapy.

Key words: colorectal cancer, chemotherapy, targeted therapy, cetuksimab, panitumumab, bevacizumab, regorafenib.

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Список литературы

1. GLOBOCAN 2012 (IARC), Section of Cancer Surveillance (10/11/2014) http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
2. Злокачественные новообразования в России в 2013 году. Под ред. А.Д.Каприна, В.В.Старинского, Г.В.Петровой. М., 2015. / Zlokachestvennye novoobrazovaniia v Rossii v 2013 godu. Pod red. A.D.Kaprina, V.V.Starinskogo, G.V.Petrovoi. M., 2015. [in Russian]
3. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343 (13): 905–14.
4. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355 (9209): 1041–7.
5. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22 (1): 23–30.
6. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.
7. Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25 (13): 1670–6.
8. Saltz LB, Clarke S, Díaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26 (12): 2013–9.
9. Bokemeyer C, Bondarenko I, Hartmann JT et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011; 22 (7): 1535–46.
10. Van Cutsem Сetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29 (15): 2011–9.
11. Douillard JY. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28 (31): 4697–705.
12. Douillard JY. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25 (7): 1346–55.
13. Passardi Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial. J Clin Oncol 2013 (Suppl.; abstr. 3517).
14. Heinemann V, von Weikersthal LF, Decker T et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15: 1065–75.
15. Stintzing S, Jung A, Rossius L et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013.
16. Schwartzberg LS, Rivera F, Karthaus M et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32: 2240–7.
17. Peeters M et al. Analysis of KRAS/NRAS mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC). J Clin Oncol 2014; 32 (Suppl. 3; abstr. LBA387).
18. Peeters M et al. Impact of post-progression anti-vascular endothelial growth factor-containing therapy on survival in patients with metastatic colorectal cancer: data from the PRIME study. Eur J Cancer 2013; 49 (Suppl. 4): abstract MC13-0024 (and poster).
19. Lenz H, Niedzwiecki D, Innocenti F et al. CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded ras analyses untreated metastatic adenocarcinoma of the colon or rectum. ESMO 2014: abstr 5010.
20. Loupakis F et al. Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer. N Engl J Med 2014; 371: 1609–18.
21. Van Cutsem E, Tabernero J, Lakomy R et al. 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 2012; 30 (28): 3499–506.
22. Giantonio BJ, Catalano PJ, Meropol NJ et al; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25 (12): 1539–44.
23. Arnold D. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol 2012; 30. Abstract CRA3503
24. Van Cutsem E, Dicato M, Geva R et al. The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010. Ann Oncol 2011; 22 (Suppl. 5): v1–9.
25. Sobrero AF, Maurel J, Fehrenbacher L 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): 2311–9.
26. Andre T et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol 2013; 24 (2): 412–9.
27. Wilhelm SM, Dumas J, Adnane L et al. 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 (1): 245–55.
28. Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Invest Drugs 2012; 21: 879–89.
29. Grothey A, van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303–12.
30. Schmoll HJ, van Cutsem E, Stein A et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 2012; 23 (10): 2479–516.
31. Cassidy J, Clarke S, Díaz-Rubio E et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105 (1): 58–64.
32. Loupakis F, Cremonlini C, Masi G et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the phase III randomized TRIBE trial. 2013 Gastrointestinal Cancers Symposium. Abstract 336. Presented January 26, 2013.
33. Koeberle D, Betticher DC, Von Moos R et al. Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). 2013 ASCO Annual Meeting. Abstract 3503. Presented June 1, 2013.
34. Koopman M, Simkens LH, Ten Tije AJ et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer Group. 2013 ASCO Annual Meeting. Abstract 3502. Presented June 1, 2013.
35. Tabernero J, Aranda E, Gomez A et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). J Clin Oncol 2010; 28 (Suppl.; abstr. 3501): 15s.
36. Yalcin S, Uslu R, Dane F et al. Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study J Clin Oncol 2010; 30 (Suppl.; abstr. 3565).
37. Van Cutsem E, Rivera F, Berry S et al. First BEAT investigators. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009; 20 (11): 1842–7.
38. Kozloff M, Yood MU, Berlin J et al. Investigators of the BRiTE study. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009; 14 (9): 862–70.
39. Sobrero A, Ackland S, Clarke S et al. AVIRI Trial investigators. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology 2009; 77 (2): 113–9.
40. Kopetz S, Hoff PM, Morris JS et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28 (3): 453–9.
41. Fuchs CS, Marshall J, Mitchell E et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25 (30): 4779–86.
42. Hecht JR, Mitchell E, Chidiac T et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009; 27 (5): 672–80.
43. Masi G, Salvatore L, Boni L et al. BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol 2015; 26 (4): 724–30.
44. Cunningham D, Lang I, Marcuello E et al. AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013; 14 (11): 1077–85.
45. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23 (16): 3697–705.

________________________________________________

1. GLOBOCAN 2012 (IARC), Section of Cancer Surveillance (10/11/2014) http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
2. Zlokachestvennye novoobrazovaniia v Rossii v 2013 godu. Pod red. A.D.Kaprina, V.V.Starinskogo, G.V.Petrovoi. M., 2015. [in Russian]
3. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343 (13): 905–14.
4. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355 (9209): 1041–7.
5. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22 (1): 23–30.
6. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.
7. Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25 (13): 1670–6.
8. Saltz LB, Clarke S, Díaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26 (12): 2013–9.
9. Bokemeyer C, Bondarenko I, Hartmann JT et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011; 22 (7): 1535–46.
10. Van Cutsem Сetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29 (15): 2011–9.
11. Douillard JY. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28 (31): 4697–705.
12. Douillard JY. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25 (7): 1346–55.
13. Passardi Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial. J Clin Oncol 2013 (Suppl.; abstr. 3517).
14. Heinemann V, von Weikersthal LF, Decker T et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15: 1065–75.
15. Stintzing S, Jung A, Rossius L et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013.
16. Schwartzberg LS, Rivera F, Karthaus M et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32: 2240–7.
17. Peeters M et al. Analysis of KRAS/NRAS mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC). J Clin Oncol 2014; 32 (Suppl. 3; abstr. LBA387).
18. Peeters M et al. Impact of post-progression anti-vascular endothelial growth factor-containing therapy on survival in patients with metastatic colorectal cancer: data from the PRIME study. Eur J Cancer 2013; 49 (Suppl. 4): abstract MC13-0024 (and poster).
19. Lenz H, Niedzwiecki D, Innocenti F et al. CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded ras analyses untreated metastatic adenocarcinoma of the colon or rectum. ESMO 2014: abstr 5010.
20. Loupakis F et al. Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer. N Engl J Med 2014; 371: 1609–18.
21. Van Cutsem E, Tabernero J, Lakomy R et al. 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 2012; 30 (28): 3499–506.
22. Giantonio BJ, Catalano PJ, Meropol NJ et al; Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25 (12): 1539–44.
23. Arnold D. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol 2012; 30. Abstract CRA3503
24. Van Cutsem E, Dicato M, Geva R et al. The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010. Ann Oncol 2011; 22 (Suppl. 5): v1–9.
25. Sobrero AF, Maurel J, Fehrenbacher L 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): 2311–9.
26. Andre T et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol 2013; 24 (2): 412–9.
27. Wilhelm SM, Dumas J, Adnane L et al. 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 (1): 245–55.
28. Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Invest Drugs 2012; 21: 879–89.
29. Grothey A, van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303–12.
30. Schmoll HJ, van Cutsem E, Stein A et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 2012; 23 (10): 2479–516.
31. Cassidy J, Clarke S, Díaz-Rubio E et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105 (1): 58–64.
32. Loupakis F, Cremonlini C, Masi G et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the phase III randomized TRIBE trial. 2013 Gastrointestinal Cancers Symposium. Abstract 336. Presented January 26, 2013.
33. Koeberle D, Betticher DC, Von Moos R et al. Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). 2013 ASCO Annual Meeting. Abstract 3503. Presented June 1, 2013.
34. Koopman M, Simkens LH, Ten Tije AJ et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer Group. 2013 ASCO Annual Meeting. Abstract 3502. Presented June 1, 2013.
35. Tabernero J, Aranda E, Gomez A et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). J Clin Oncol 2010; 28 (Suppl.; abstr. 3501): 15s.
36. Yalcin S, Uslu R, Dane F et al. Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study J Clin Oncol 2010; 30 (Suppl.; abstr. 3565).
37. Van Cutsem E, Rivera F, Berry S et al. First BEAT investigators. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009; 20 (11): 1842–7.
38. Kozloff M, Yood MU, Berlin J et al. Investigators of the BRiTE study. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009; 14 (9): 862–70.
39. Sobrero A, Ackland S, Clarke S et al. AVIRI Trial investigators. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology 2009; 77 (2): 113–9.
40. Kopetz S, Hoff PM, Morris JS et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28 (3): 453–9.
41. Fuchs CS, Marshall J, Mitchell E et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25 (30): 4779–86.
42. Hecht JR, Mitchell E, Chidiac T et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009; 27 (5): 672–80.
43. Masi G, Salvatore L, Boni L et al. BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol 2015; 26 (4): 724–30.
44. Cunningham D, Lang I, Marcuello E et al. AVEX study investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013; 14 (11): 1077–85.
45. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23 (16): 3697–705.

Авторы

В.А.Горбунова*

ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*veragorbounova@mail.ru

________________________________________________

V.A.Gorbunova*

N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*veragorbounova@mail.ru

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