Новые аспекты первой линии химиотерапии метастатического колоректального рака

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Аннотация

Колоректальный рак (КРР) устойчиво занимает 3-е место в мире в структуре заболеваемости и смертности. В последнее время благодаря прогрессу в химиотерапии и хирургическом лечении метастатического колоректального рака (мКРР) и использованию мультидисциплинарного подхода алгоритмы лечения больных изменились. В зависимости от клинической ситуации выделяют 4 группы больных мКРР: с исходно резектабельными метастазами, с потенциально операбельными метастазами, с неоперабельными метастазами с симптомным течением болезни или быстрым прогрессированием, которые могут перенести интенсивное лечение, а также группу больных с неоперабельными метастазами и выраженной сопутствующей патологией. Оказалось, что помимо мутаций в экзоне 2 гена KRAS есть еще целый ряд более редких мутаций (в экзонах 3 и 4 гена KRAS, а также мутации в гене NRAS), также определяющих резистентность к анти-EGFR-терапии. В исследовании PRIME 17% больных, отнесенных в соответствии со старым тестом в группу без мутации (KRAS wt), имеют эти редкие мутации. Выбор таргетного препарата в 1-й линии лечения больных мКРР с мутацией RAS ограничен только бевацизумабом, а у пациентов без мутации можно использовать как анти-EGFR моноклональные антитела, так и бевацизумаб. Наличие мутации BRAF является фактором негативного прогноза больных мКРР и коррелируется с уменьшением продолжительности жизни. Дальнейшие исследования в этой области помогут разрешить оставшиеся вопросы и оптимизировать лечебные подходы в отношении разных групп пациентов.

Ключевые слова: метастатический колоректальный рак, терапия 1-й линии, таргетная терапия, мутации RAS.

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Colorectal cancer (CRC) steadily occupies the third position in the morbidity and mortality in the world. Due to advance in chemotherapy, surgery and the use of multidisciplinary approach in patients with metastatic colorectal cancer (mCRC) the CRC treatment algorithms have changed recently. Depending on the clinical situation there are 4 groups of patients with CRC: resectable group, potentially resectable group, unresectable group of patients who could undergo the intensive treatment, unresectable group of patients with concomitant diseases. It was found, that besides mutations in 2 exone KRAS there is a scope of rare mutations (exons 3 and 4 in KRAS gene and mutation in NRAS gene) which determines the resistance to EGFR inhibitors as well. The PRIME study found that 17% of patients, who were included in to the group without mutations (KRAS WT), according to the old type of test, could have these rare mutations. The target choice in first line therapy in mCRC patients RAS mutant is only bevacizumab. In RAS WT patients as EGFR inhibitors, so bevacizumab can be used. The presence of BRAF mutation is a factor of the negative prognosis in patients with mCRC and is correlated with a reduction in life expectancy. Further research in the field of molecular genetic characteristics of the tumor will help to solve the remaining points and to optimize treatment in different patients` groups.

Key words: metastatic colorectal cancer, first-line therapy, targeted therapy, RAS mutations.

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Список литературы

1. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
2. Weber SM, Jarnagin WR, DeMatteo RP et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 2000; 7: 643–50.
3. Choti MA, Sitzmann JV, Tiburi MF et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235: 759–66.
4. Tomlinson JS, Jarnagin WR, DeMatteo RP et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25: 4575–80.
5. Adam R, Barroso C. Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases. J Clin Oncol 2011; 29. Abstr. 3519.
6. 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: 2479–516.
7. Nordlinger B, Sorbye H, Glimelius B et al. Perioperative chemotherapy with FOLFOX-4 and surgery vs. surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371: 1007–16.
8. Nordlinger B, Sorbye H, Glimelius B et al. Perioperative FOLFOX-4 chemotherapy and surgery vs. surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet 2013; http://dx.doi.org/10.1016/S1470-2045(13)70447-9
9. Primrose JN, Falk S, Finch-Jones M et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. Proc ASCO 2013. Abstr. 3504.
10. 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. JCO 2008; 26: 2012–9.
11. 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.
12. 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.
13. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX-6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22 (2): 229–37.
14. 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.
15. Kohne CH, Greve De J, Hartmann JT et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008; 19: 920–6.
16. Fuchs CS, Marshall J, Mitchell E et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluorpyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25: 4779–86.
17. 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: 23–30.
18. 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.
19. Saltz LB, Clarke S, Diaz-Rubio E at al. Bevacizumab (Bev) in combination with XELOX or FOLFOX-4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). GI Cancers Sympos 2007. Abstr. 238.
20. Kabbinavar F, Hurwitz HL, Fehrenbacher L et al. Phase II randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21: 60.
21. 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: 3697–705.
22. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–42.
23. Falcone A, Cremolini C, Masi G et al. FOLFOXIRI/bevacizumab (bev) vs. FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol 2013; 31. Abstr. 3505.
24. Loupakis F, Schirripa M, Caparello C et al. Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab. Brit J Cancer 2013; 108: 2549–56.
25. Cunningham D, Lang I, Marcuello E et al. Bevacizumab plus capecitabin vs. capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label randomized phase III trial. Lancet Oncol 2013; 14: 1077–85.
26. Saunders MP, Lang I, Marcuello E et al. Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer. J Clin Oncol 2013; 31. Abstr. 3521.
27. 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): 642–53.
28. 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.
29. 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.
30. Zhou SW, Huang YY, Wei Y et al. No survival benefit from adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in KRAS wild type patients: a meta-analysis. Ed.: A.Goel. Baylor University Medical Center, USA. PLoS ONE 2012; 7 (11): e50925.
31. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
32. Jen J, Powell SM, Papadopoulos N et al. Molecular determinants of dysplasia in colorectal lesions. Cancer Res 1994; 54: 5523–6.
33. Engeland van M, Roemen GM, Brink M et al. K-ras mutations and RASSF1 a promoter methylation in colorectal cancer. Oncogene 2002; 21 (23): 3792–5.
34. 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.
35. 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: 1166–9.
36. 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: 374–9.
37. Douillard JY, Siena S, Cassidy J. Randomized, phase III study of panitumumab (pmab) with FOLFOX-4 compared to FOLFOX-4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial. Eur J Cancer 2009; 7 (Suppl. 3): 10LBA.
38. Douillard JY, Oliner KS, Siena S et al. Panitumumab FOLFOX-4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369: 1023–34.
39. Rosen O, Yi J, Hurwitz HI et al. Clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Ann Oncol 2008; 19 (Suppl. 6): 19. Abstr. 0-035.
40. Hurwitz HI, Yi J, Ince W et al. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncol 2009; 14 (1): 22–8.
41. Heinemann V, von Weikersthal LF, Deker T et al. Randomized comparison of FOLFIRI plus cetuximab vs. FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol 2013; 31 (Suppl.). Abstr. LBA3506.
42. Heinemann V, Stintzing S, Jung A, Rossius L. 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. Eur J Cancer 2013; 49 (Suppl. 3). Abstr. LBA17.
43. Schwartzberg LS, Rivera F, Karthaus M et al. Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX-6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). J Clin Oncol 2013; 31 (Suppl.). Abstr. 3631.
44. Oliner KS, Douillard J-Y, Siena S et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX vs. FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol 2013; 31 (Suppl.). Abstr. 3511.
45. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med 2009; 361 (1): 98–9.
46. Souglakos J, Philips J, Wang R et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 2009; 101 (3): 465–72.
47. van Cutsem E, KoЁhne CH, Laґng I et al. Cetuximab 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.
48. 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.
49. Ince WL, Jubb AM, Holden SN et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 2005; 97 (13): 981–9.
50. Richman SD, Seymour MT, Chambers P et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009; 27 (35): 5931–7.

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Е.В.Артамонова

ФГБУ Российский онкологический научный центр им. Н.Н.Блохина РАМН

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E.V.Artamonova

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