Оптимизация второй линии лечения метастатического колоректального рака: новые возможности таргетной терапии
Оптимизация второй линии лечения метастатического колоректального рака: новые возможности таргетной терапии
Артамонова Е.В., Манзюк Л.В. Оптимизация второй линии лечения метастатического колоректального рака: новые возможности таргетной терапии. Современная Онкология. 2016; 18 (1): 25–31.
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Artamonova E.V., Manzyuk L.V. The optimization of second-line therapy for metastatic colorectal cancer: new targeted therapy options. Journal of Modern Oncology. 2016; 18 (1): 25–31.
Оптимизация второй линии лечения метастатического колоректального рака: новые возможности таргетной терапии
Артамонова Е.В., Манзюк Л.В. Оптимизация второй линии лечения метастатического колоректального рака: новые возможности таргетной терапии. Современная Онкология. 2016; 18 (1): 25–31.
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Artamonova E.V., Manzyuk L.V. The optimization of second-line therapy for metastatic colorectal cancer: new targeted therapy options. Journal of Modern Oncology. 2016; 18 (1): 25–31.
Успехи в лечении метастатического колоректального рака (мКРР), достигнутые за последние годы, во многом связаны с широким применением таргетных препаратов и высокоэффективных химиотерапевтических режимов в повседневной клинической практике, а также с внедрением концепции длительного лечения – «continuum of care». Данная концепция предполагает четкое планирование последовательности назначения различных режимов и выбора оптимальной комбинации режима химиотерапии (ХТ) и таргетного препарата на каждом этапе лечения. При таком подходе возрастает роль 2-й линии терапии, и в настоящем обзоре затронуты основные вопросы, касающиеся выбора наилучшей комбинации для лечения больных мКРР на данном этапе. Оптимальным вариантом последовательной терапии для большинства больных с нерезектабельными метастазами является применение оксалиплатинсодержащего режима в 1-й линии и переход на схему FOLFIRI (инфузионный дуплет иринотекана и 5-фторурацила) во 2-й линии. Поэтому выбор наиболее эффективного таргетного препарата для назначения вместе с комбинацией FOLFIRI представляется сегодня чрезвычайно актуальной задачей. Таргетные биологические препараты, такие как анти-EGFR антитела и ингибиторы ангиогенеза бевацизумаб и афлиберцепт, были изучены в различных комбинациях во 2-й линии терапии мКРР. Применение анти-EGFR антител во 2-й линии терапии обеспечило увеличение выживаемости без прогрессирования (ВБП) заболевания, но не привело к достоверному увеличению продолжительности жизни, в то время как блокада ангиогенеза оказалась эффективной не только в отношении ВБП, но и продолжительности жизни, как у бевацизумаб-наивных пациентов, так и у пациентов, получавших бевацизумаб в 1-й линии терапии. Афлиберцепт стал первым таргетным препаратом, который при использовании во 2-й линии терапии в комбинации с режимом FOLFIRI достоверно увеличил все показатели эффективности, включая продолжительность жизни, ВБП и частоту объективного ответа, в широкой популяции больных мКРР.
Ключевые слова: метастатический колоректальный рак, афлиберцепт, терапия второй линии.
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Advances in the treatment of metastatic colorectal cancer (mCRC) during the past years, largely associated with the wide use of targeted agents and effective chemotherapy regimens in routine clinical practice, as well as with the introduction of the "continuum of care" concept. This concept means a clear planning of the treatment sequence and identifying the optimal combination of the chemotherapy regimen and targeted agent at each setting. Following this approach the role of the 2-nd line setting is dramatically icreasing, and this review aimed to identify the best treatment combination for the mCRC patients at this setting. The optimal treatment sequence for most patients with unresectable metastases is the use of oxaliplatin containing regimen the in 1-st line and switch to FOLFIRI (duplet containing irinotecan and infusion of 5-fluorouracil) in the 2-nd line treatment for metastatic colorectal cancer. Therefore, the choice of the most effective targeted agent in combination with FOLFIRI seems extremely actual. Various targeted biological agents including as anti-EGFR antibodies as well as antiangiogenic agents such as bevacizumab and aflibercept have been studied in various combinations in the 2-nd line setting for mCRC treatment. Anti-EGFR antibodies in 2-nd line treatment increased progression-free survival, but didn’t result in the overall survival increase, while angiogenesis inhibitors were effective in terms of PFS and OS in bevacizumab-naive patients as well as in bevacizumab pretreated patients. Aflibercept was the first targeted agent showed the increase of overall survival as well as progression-free survival and objective response rate in 2-line setting when combined with FOLFIRI in a broad population of mCRC patients.
1. Adams RA, Meade AM, Seymour MT et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011; 12 (7): 642–53.
2. 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): 2103–14.
3. 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): abstract 365.
4. Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). 2007 GI Cancers Symposium, abstr. 238.
5. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22 (2): 229–37.
6. Saltz LB, Clarke S, Diaz-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: 2012–9.
7. 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.
8. Grothey A. A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer. Nat Clin Pract Oncol 2009; 6 (1): 10–1.
9. De Gramont A, Chibaudel B, Bourges O et al. Definition of oxaliplatin sensitivity in patients with advanced colorectal cancer previously treated with oxaliplatin-based therapy. J Clin Oncol 2009; 27 (15 Suppl.): 4024.
10. De Gramont A, Buyse M, Abrahantes JC et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J Clin Oncol 2007; 25: 3224–9.
11. Jordan K, Kellner O, Kegel T et al. Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Clin Colorectal Cancer 2004; 4 (1): 46–50.
12. Kohne CH, De Greve J, Hartmann JT et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the firstline treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008; 19: 920–6.
13. 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: 4779–86.
14. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370: 143–52.
15. Gill S, Dowden S, Colwell B et al. Navigating later lines of treatment for advanced colorectal cancer – optimizing targeted biological therapies to improve outcomes. Cancer Treat Rev 2014; 40: 1171–81.
16. Giantonio BJ, Catalano PJ, Meropol NJ et al. 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.
17. Grothey A, Sugrue MM, Purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol 2008; 26: 5326–34.
18. Cohn AL, Bekaii-Saab T, Bendell JC et al. Clinical outcomes in bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): Results from ARIES observational cohort study (OCS) and confirmation of BRiTE data on BV beyond progression (BBP). J Clin Oncol 2010; 28 (15 Suppl.): 3596.
19. Arnold D, Andre T, Bennouna J et al. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: results of randomized phase III intergroup study. J Clin Oncol 2012; 30 (15 Suppl.): abstr. CRA 3503.
20. Masi G et al. Ann Oncol 2012; 23 (Suppl. 9): abstr. LBA17.
21. 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.
22. Loupakis F, Cremolini C, Fioravanti A et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer 2011; 104 (8): 1262–9.
23. Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002; 99 (17): 11393–8.
24. Kim ES, Serur A, Huang J et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A. 2002; 99: 11399–404.
25. Limentani S, Just R, Purdham A et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: Preliminary results. J Clin Oncol 2008; 26 (Suppl.; abstr. 3556): 167s.
26. Rixe O, Verslype C, Khayat D et al. A phase I dose escalation (DE) and pharmacokinetics (PK) study of intravenous aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in patients with advanced solid tumors (STs). J Clin Oncol 2008; 26 (Suppl.; abstr. 3557): 167s.
27. Verslype C, Spano C, van Cutsem E et al. Validation of the selected dose of aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a phase I clinical trial of patients (pts) with advanced solid tumors (STs): Preliminary results. J Clin Oncol 2008; 26 (Suppl.; abstr. 14540): 631s.
28. Van Cutsem E, Tabernero J, Lakomy R et al. Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational phase III trial (EFC10262–VELOUR). Ann Oncol 2011; 22 (Suppl. 5): v10–v18.
29. 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: 3499–506.
30. Tabernero J, van Cutsem E, Lakomy R et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin, and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50: 320–31.
31. Van Cutsem E, Joulain F, Hoff PM et al. Aflibercept plus FOLFIRI versus placebo plus FOLFIRI in second-line metastatic colorectal cancer: a post Hoc analysis of survival from the phase III VELOUR study subsequent to exclusion of patients who had recurrence during or within 6 months of completing adjuvant oxaliplatin-based therapy. Targ. Oncol. Published online 26 dec 2015: doi:10.1007/s11523-015-0402-9.
32. Chau I, Joulain F, Iqbal SU, Bridgewater J. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. BMC Cancer 2014; 14: 605. doi: 10.1186/1471-2407-14-605.
________________________________________________
1. Adams RA, Meade AM, Seymour MT et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011; 12 (7): 642–53.
2. 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): 2103–14.
3. 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): abstract 365.
4. Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). 2007 GI Cancers Symposium, abstr. 238.
5. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22 (2): 229–37.
6. Saltz LB, Clarke S, Diaz-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: 2012–9.
7. 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.
8. Grothey A. A comparison of XELOX with FOLFOX-4 as first-line treatment for metastatic colorectal cancer. Nat Clin Pract Oncol 2009; 6 (1): 10–1.
9. De Gramont A, Chibaudel B, Bourges O et al. Definition of oxaliplatin sensitivity in patients with advanced colorectal cancer previously treated with oxaliplatin-based therapy. J Clin Oncol 2009; 27 (15 Suppl.): 4024.
10. De Gramont A, Buyse M, Abrahantes JC et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J Clin Oncol 2007; 25: 3224–9.
11. Jordan K, Kellner O, Kegel T et al. Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. Clin Colorectal Cancer 2004; 4 (1): 46–50.
12. Kohne CH, De Greve J, Hartmann JT et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the firstline treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008; 19: 920–6.
13. 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: 4779–86.
14. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370: 143–52.
15. Gill S, Dowden S, Colwell B et al. Navigating later lines of treatment for advanced colorectal cancer – optimizing targeted biological therapies to improve outcomes. Cancer Treat Rev 2014; 40: 1171–81.
16. Giantonio BJ, Catalano PJ, Meropol NJ et al. 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.
17. Grothey A, Sugrue MM, Purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol 2008; 26: 5326–34.
18. Cohn AL, Bekaii-Saab T, Bendell JC et al. Clinical outcomes in bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): Results from ARIES observational cohort study (OCS) and confirmation of BRiTE data on BV beyond progression (BBP). J Clin Oncol 2010; 28 (15 Suppl.): 3596.
19. Arnold D, Andre T, Bennouna J et al. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: results of randomized phase III intergroup study. J Clin Oncol 2012; 30 (15 Suppl.): abstr. CRA 3503.
20. Masi G et al. Ann Oncol 2012; 23 (Suppl. 9): abstr. LBA17.
21. 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.
22. Loupakis F, Cremolini C, Fioravanti A et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer 2011; 104 (8): 1262–9.
23. Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002; 99 (17): 11393–8.
24. Kim ES, Serur A, Huang J et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A. 2002; 99: 11399–404.
25. Limentani S, Just R, Purdham A et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: Preliminary results. J Clin Oncol 2008; 26 (Suppl.; abstr. 3556): 167s.
26. Rixe O, Verslype C, Khayat D et al. A phase I dose escalation (DE) and pharmacokinetics (PK) study of intravenous aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in patients with advanced solid tumors (STs). J Clin Oncol 2008; 26 (Suppl.; abstr. 3557): 167s.
27. Verslype C, Spano C, van Cutsem E et al. Validation of the selected dose of aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a phase I clinical trial of patients (pts) with advanced solid tumors (STs): Preliminary results. J Clin Oncol 2008; 26 (Suppl.; abstr. 14540): 631s.
28. Van Cutsem E, Tabernero J, Lakomy R et al. Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational phase III trial (EFC10262–VELOUR). Ann Oncol 2011; 22 (Suppl. 5): v10–v18.
29. 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: 3499–506.
30. Tabernero J, van Cutsem E, Lakomy R et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin, and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50: 320–31.
31. Van Cutsem E, Joulain F, Hoff PM et al. Aflibercept plus FOLFIRI versus placebo plus FOLFIRI in second-line metastatic colorectal cancer: a post Hoc analysis of survival from the phase III VELOUR study subsequent to exclusion of patients who had recurrence during or within 6 months of completing adjuvant oxaliplatin-based therapy. Targ. Oncol. Published online 26 dec 2015: doi:10.1007/s11523-015-0402-9.
32. Chau I, Joulain F, Iqbal SU, Bridgewater J. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. BMC Cancer 2014; 14: 605. doi: 10.1186/1471-2407-14-605.
Авторы
Е.В.Артамонова*, Л.В.Манзюк
ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*artamonovae@mail.ru
________________________________________________
E.V.Artamonova*, L.V.Manzyuk
N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*artamonovae@mail.ru