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Бевацизумаб в лечении немелкоклеточного рака легкого
Бевацизумаб в лечении немелкоклеточного рака легкого
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Аннотация
Ангиогенез – образование новых сосудов из уже существующих – важный этап роста и метастазирования опухоли. Фактор роста эндотелия сосудов (VEGF) является ключевым медиатором ангиогенеза, запускающим процесс формирования сосудов опухоли и влияющим на их проницаемость. Чрезмерная экспрессия VEGF наблюдается при различных онкологических заболеваниях и ассоциируется с низкими показателями выживаемости без прогрессирования и общей выживаемости больных. Антиангиогенный препарат бевацизумаб – моноклональное антитело, которое селективно связывается с VEGF, нейтрализуя его, продемонстрировал клиническую эффективность при многих злокачественных новообразованиях, в том числе и при немелкоклеточном раке легкого (НМРЛ). Восточная координирующая группа по изучению рака (Eastern Cooperative Oncology Group) инициировала исследование (E4599) для определения эффективности бевацизумаба в комбинации с паклитакселом и карбоплатином у пациентов с рецидивирующим или распространенным неплоскоклеточным НМРЛ стадий IIIB или IV, предпосылками к которому послужили результаты ранее проведенного рандомизированного исследования II фазы. В исследование не включали пациентов со смешанным гистологическим типом опухоли (преобладание плоскоклеточного компонента), метастазами в головном мозге, при наличии кровохарканья, c тяжелым соматическим статусом или общим состоянием по шкале ECOG >1. Основным оцениваемым показателем была общая выживаемость. Медиана общей выживаемости в группе, где пациенты получали химиотерапию в комбинации с бевацизумабом, составила 12,3 мес по сравнению с 10,3 мес в группе, где пациентам назначалась только химиотерапия (p=0,003). Показатель выживаемости без прогрессирования также достоверно увеличился при добавлении бевацизумаба (6,2 мес против 4,5 мес). В группе пациентов, получавших бевацизумаб, чаще регистрировались случаи гипертонии, протеинурии, кровотечений (4,4% против 0,9%, p=0,003). По результатам комбинированного анализа исследований II и III фазы были определены факторы риска тяжелого легочного кровотечения на фоне терапии бевацизумабом, к ним были отнесены эпизоды кровохарканья в анамнезе, а также образование полостей в опухоли. В настоящее время изучается действие бевацизумаба при ранних стадиях НМРЛ, его активность при МРЛ, а также возможность его назначения в комбинации с другими таргетными препаратами, такими как эрлотиниб.
Полный текст
Список литературы
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2. Kim KJ, Li B, Winer J et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362: 841–4.
3. Macchiarini P, Fontanini G, Dulmet E, et al. Angiogenesis: an indicator of metastasis in non-small cell lung cancer invading the thoracic inlet. Ann Thorac Surg 1994;57:1534–9.
4. Fontanini G, Bigini D, Vignati S et al. Microvessel count predicts metastatic disease and survival in nonsmall cell lung cancer. JPathol 1995;177:57–63.
5. Seto T, Higashiyama M, Funai H et al. Prognostic value of expression of vascular endothelial growth factor and its flt-1and KDR receptors in stage I nonsmall-cell lung cancer. Lung Cancer 2006;53:91–6.
6. Lucchi M, Fontanini G, Mussi A et al. Tumor angiogenesis and biologic markers in resected stage I NSCLC. EurJ Cardiothorac Surg 1997;12:535–41.
7. Yano S, Shinohara H, Herbst RS et al. Expression of vascular endothelial growth factor is necessarybut not sufficient for production and growth of brain metastasis. Cancer Res 2000;60:4959–67.
8. Yano S, Shinohara H, Herbst RS et al. Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeabilityf actor byh uman lung cancer cells. Am J Pathol 2000;157: 1893–903.
9. Dibbens JA, Miller DL, Damert A et al. Hypoxic regulation of vascular endothelial growth factor mRNA stabilityr equires the cooperation of multiple RNA elements.Mol Biol Cell1999;10:907–19.
10.YangJC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. NEngl JMed 2003;349:427–34.
11. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl JMed 2004; 350:2335–42.
12. Kabbinavar F, Hurwitz HI, 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. JClin Oncol 2003;21:60–5.
13. Kabbinavar FF, SchulzJ, McCleodM 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.
14. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792–9.
15. Johnson BE,Ma P,WestH et al. Preliminaryp hase II safetyev aluation of ZD6474, in combination with carboplatin and paclitaxel as 1st line treatment in patients with NSCLC. Proc Am Soc Clin Oncol 2005;23:7102.
16. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previouslyu ntreated locallya dvanced or metastatic non-small-cell lung cancer. JClin Oncol 2004;22:2184–91.
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18. Sandler AB, GrayR , Perry MC et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small cell lung cancer. NEngl JMed 2006;355:2542–50.
19. Kim SJ, Uehara H, Karashima T et al. Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapyof androgen-independent human prostate cancer growing in the bone of nude mice. Clin Cancer Res 2003;9:1200–10.
20. de Jong JS, van Diest PJ, van der Valk P et al. Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. II: correlations with proliferation and angiogenesis. J Pathol 1998;184:53–7.
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22. Hirata A, Ogawa S, Kometani T et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002;62:2554–60.
23. Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a smallmolecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activityag ainst epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003;9: 1546–56.
24. Herbst RS,Mininberg E, Henderson T et al. Phase I/ II trial evaluating blockade of tumor blood supplya nd tumor cell proliferation with combined bevacizumab and erlotinib HCl as targeted cancer therapyi n patients with recurrent non-small cell lung cancer. Eur JCancer 2003;1:S293.
25. Jung YD, Mansfield PF, Akagi M et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. EurJCancer 2002;38:1133–40.
26. Ciardiello F, Bianco R, Damiano V et al. Antiangiogenic and antitumor activityof antiepidermal growth factor receptor C225 monoclonal antibodyi n combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739–47.
27. Herbst RS, Johnson DH,Mininberg E et al. Phase I/II trial evaluating the anti-vascular endothelial growth factormonoclonal antibodybev acizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:2544–55.
28. Fehrenbacher L, O’Neill V, Belani CP et al. A phase II, multicenter, randomized clinical trial to evaluate the efficacyan d safetyof bevacizumab in combination with either chemotherapy( docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapyal one for treatment of recurrent or refractoryn onsmall cell lung cancer. Proc Am Soc Clin Oncol Annu Meet 2006;24:7062.
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