Опухоли головы и шеи. 2016; 6: 30-34
ВЕМУРАФЕНИБ В ЛЕЧЕНИИ БОЛЬНЫХ МЕЛАНОМОЙ С МЕТАСТАЗАМИ В ГОЛОВНОЙ МОЗГ
https://doi.org/10.17650/2222-1468-2016-6-4-30-34Аннотация
Эффективность традиционной химиотерапии (темозоломид, фотемустин, ломустин) в монорежиме и ее комбинаций с лучевой терапией на весь головной мозг у больных меланомой с церебральными метастазами не превышает 7–10 %, без существенного влияния на общую выживаемость, которая составляет 2–4 мес. Таргетная терапия улучшила выживаемость больных диссеминированной меланомой с мутациями BRAFV600. У пациентов с метастазами в головной мозг таргетные препараты позволяют не только контролировать системный опухолевый процесс, но и достичь эффекта в лечении церебральных метастазов. Так, эффективность таргетной терапии препаратом вемурафениб у больных меланомой с мутациями BRAFV600 при метастатическом поражении головного мозга, по данным литературы, а также по результатам собственных исследований, достигает 18,0–44,5 % с медианой выживаемости больных от 5,3 до 8,0 мес. Представлены данные, свидетельствующие о том, что назначение вемурафениба больным меланомой с метастатическим поражением головного мозга обеспечивает контроль над болезнью у большинства пациентов и обладает существенным преимуществом по сравнению со стандартной химиотерапией и лучевой терапией на весь головной мозг. На основании данных этих исследований можно предложить проведение таргетной терапии вемурафенибом в качестве 1-й линии противоопухолевого лекарственного лечения больных меланомой с мутацией BRAFV600 и с метастатическим поражением головного мозга. Новые таргетные препараты показали обнадеживающие результаты в лечении метастазов в головной мозг, несмотря на наличие гематоэнцефалического барьера и эффлюкс-системы. За последние годы значительно улучшилось понимание биологии и механизмов метастатического поражения головного мозга, работы гематоэнцефалического барьера, проникновения противоопухолевых препаратов в центральную нервную систему. В будущем, с появлением новых мишеней, активно развивающаяся таргетная терапия будет играть все более возрастающую роль в лечении церебральных метастазов меланомы.
Список литературы
1. Schouten L.J., Rutten J., Huveneers H.A. et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698–705.
2. Tabouret E., Chinot O., Metellus P. et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res 2012;32(11):4655–62.
3. Fife K., Colman M., Stevens G. et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004;22:1293–300.
4. Davies M., Liu P., McIntyre S. et al. Prognostic factors for survival in melanoma patients with bran metastases. Cancer 2011;117(8):1687–96. DOI: 10.1002/cncr.25634.
5. Eigentler T., Figl A., Krex D. et al. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 2011;117(8):1697–703. DOI: 10.1002/cncr.25631.
6. Bezjak A., Adam J., Barton R. et al. Symptom response after palliative radiotherapy for patients with brain metastases. Eur J Cancer 2002;38(4):487–96.
7. Khuntia D., Brown P., Li J., Mehta M.P. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 2006;24(8):1295–304.
8. Tsao M.N., Lloyd N., Wong R. et al. Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 2006;3: CD003869.
9. Agarwala S., Kirkwood J., Gore M. et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22(11):2101–7.
10. Atkins M., Sosman J., Agarwala S. et al. Temozolomide, thalidomide and whole brain radiation therapy for patients with brain metastases from metastatic melanoma: a phase II Cytokine Working Group study. Cancer 2008;113(8):2139–45. DOI: 10.1002/cncr.23805.
11. Margolin K., Atkins B., Thompson A. et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 2002;128:214–8.
12. Mornex F., Thomas L., Mohr P. et al. A prospective randomized multicenter phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melamoma Res 2003;13(1): 97–103.
13. Long G.V., Margolin K.A. Multidisciplinary approach to brain metastasis from melanoma: the emerging role of systemic therapies. Am Soc Clin Oncol Educ Book 2013;393–8. DOI: 10.1200/EdBook_AM.2013.33.393.
14. Jakob J.A., Bassett R.L. Jr, Ng C.S. et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012;118(16):4014–23. DOI: 10.1002/cncr.26724.
15. Kefford R., Malo M., Arance A. et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open label, single arm, phase 2, multicenter study. Paper presented at: 2013 Society for Melanoma Research Congress; November 17–20, 2013. Philadelphia, PA.
16. Dummer R., Goldinger S., Turtschietal C. Vemurafenib in patients with BRAF V600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study. Eur J Cancer 2014;50(3):611–21. DOI: 10.1016/j.ejca.2013.11.002.
17. Gibney G., Marynchenko M., Ayas C. et al. Treatment patterns and outcome in BRAF V600E mutant melanoma patients with brain metastases receiving vemurafenib in the real world setting. In: 2014 ASCO Annual Meeting.
18. Larkin J., DelVecchio M., Ascierto P. et al. Vemurafenib in patients with BRAF V600 mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014;15(4):436–44. DOI: 10.1016/S1470-2045(14)70051-8.
19. Berghoff A.S., Preusser M. The future of targeted therapies for brain metastases. Future Oncol 2015;11(16):2315–27. DOI: 10.2217/fon.15.127
20. Venur V.A., Ahluwalia M.S. Targeted Therapy in Brain Metastases: Ready for Primetime? ASCO EDUCATIONAL BOOK. 2016.
Head and Neck Tumors (HNT). 2016; 6: 30-34
VEMURAFENIB IN TREATMENT OF MELANOMA WITH BRAIN METASTASES
https://doi.org/10.17650/2222-1468-2016-6-4-30-34Abstract
The effectiveness of traditional chemotherapy (with temozolomide, fotemustine, lomustine) alone or in combination with whole brain radiotherapy in melanoma patients with cerebral metastases does not exceed 7–10 % with no significant impact on survival, which is around 2–4 months. Targeted therapy helped to improve survival of patients with disseminated melanoma and BRAF V600 mutations. The use of targeted drugs in patients with brain metastases allows to control the tumor process and to succeed in treatment of cerebral metastases. According to currently available research data and our own results, the effectiveness of targeted therapy with vemurafenib in melanoma patients positive for BRAF V600 mutations with brain metastases reaches 18.0–44.5 % with median survival of 5.3–8.0 months. Evidences suggest that the use of vemurafenib in melanoma patients with brain metastases ensure effective disease control in most of the cases and has a significant advantage comparing to conventional chemotherapy and whole brain radiotherapy. According to the results of these studies vemurafenib can be recommended as a 1st line targeted drug for treatment of melanoma patients with BRAF V600 mutations and brain metastases. Despite the existence of blood-brain barrier and efflux systems, new targeted drugs showed promising results in treatment of brain metastases. Over the last few years we have enhanced our understanding of brain metastasis mechanisms, principles of blood-brain barrier functioning, and ways of cancer drugs penetration into the central nervous system. Targeted therapy is constantly developing and will play an increasing role in treatment of melanoma cerebral metastases in the future with finding of new targets.
References
1. Schouten L.J., Rutten J., Huveneers H.A. et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698–705.
2. Tabouret E., Chinot O., Metellus P. et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res 2012;32(11):4655–62.
3. Fife K., Colman M., Stevens G. et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004;22:1293–300.
4. Davies M., Liu P., McIntyre S. et al. Prognostic factors for survival in melanoma patients with bran metastases. Cancer 2011;117(8):1687–96. DOI: 10.1002/cncr.25634.
5. Eigentler T., Figl A., Krex D. et al. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 2011;117(8):1697–703. DOI: 10.1002/cncr.25631.
6. Bezjak A., Adam J., Barton R. et al. Symptom response after palliative radiotherapy for patients with brain metastases. Eur J Cancer 2002;38(4):487–96.
7. Khuntia D., Brown P., Li J., Mehta M.P. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 2006;24(8):1295–304.
8. Tsao M.N., Lloyd N., Wong R. et al. Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 2006;3: CD003869.
9. Agarwala S., Kirkwood J., Gore M. et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22(11):2101–7.
10. Atkins M., Sosman J., Agarwala S. et al. Temozolomide, thalidomide and whole brain radiation therapy for patients with brain metastases from metastatic melanoma: a phase II Cytokine Working Group study. Cancer 2008;113(8):2139–45. DOI: 10.1002/cncr.23805.
11. Margolin K., Atkins B., Thompson A. et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 2002;128:214–8.
12. Mornex F., Thomas L., Mohr P. et al. A prospective randomized multicenter phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melamoma Res 2003;13(1): 97–103.
13. Long G.V., Margolin K.A. Multidisciplinary approach to brain metastasis from melanoma: the emerging role of systemic therapies. Am Soc Clin Oncol Educ Book 2013;393–8. DOI: 10.1200/EdBook_AM.2013.33.393.
14. Jakob J.A., Bassett R.L. Jr, Ng C.S. et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012;118(16):4014–23. DOI: 10.1002/cncr.26724.
15. Kefford R., Malo M., Arance A. et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open label, single arm, phase 2, multicenter study. Paper presented at: 2013 Society for Melanoma Research Congress; November 17–20, 2013. Philadelphia, PA.
16. Dummer R., Goldinger S., Turtschietal C. Vemurafenib in patients with BRAF V600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study. Eur J Cancer 2014;50(3):611–21. DOI: 10.1016/j.ejca.2013.11.002.
17. Gibney G., Marynchenko M., Ayas C. et al. Treatment patterns and outcome in BRAF V600E mutant melanoma patients with brain metastases receiving vemurafenib in the real world setting. In: 2014 ASCO Annual Meeting.
18. Larkin J., DelVecchio M., Ascierto P. et al. Vemurafenib in patients with BRAF V600 mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014;15(4):436–44. DOI: 10.1016/S1470-2045(14)70051-8.
19. Berghoff A.S., Preusser M. The future of targeted therapies for brain metastases. Future Oncol 2015;11(16):2315–27. DOI: 10.2217/fon.15.127
20. Venur V.A., Ahluwalia M.S. Targeted Therapy in Brain Metastases: Ready for Primetime? ASCO EDUCATIONAL BOOK. 2016.
