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Опыт применения мультикиназного ингибитора регорафениб при метастатическом колоректальном раке
Кит О.И., Владимирова Л.Ю., Абрамова Н.А. и др. Опыт применения мультикиназного ингибитора регорафениба при метастатическом колоректальном раке. Современная Онкология. 2017; 19 (2): 42–46.
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Kit O.I., Vladimirova L.Y., Abramova N.A. et al. Using of multi-kinase inhibitor regorafenib for metastatic colorectal cancer. Journal of Modern Oncology. 2017; 19 (2): 42–46.
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Аннотация
Проанализированы данные об эффективности и безопасности препарата регорафениб в лечении 7 пациентов с метастатическим колоректальным раком (мКРР), резистентным к лечению цитостатиками, моноклональными антителами – блокаторами EGFR и VEGF. Максимальным достигнутым противоопухолевым эффектом у 1 пациента была частичная ремиссия, у остальных 6 – стабилизация. Длительность периода без прогрессирования от начала лечения препаратом регорафениб составила от 1,5 до 6 мес. После прогрессирования 3 пациента продолжили противоопухолевую терапию, 3 – переведены на симптоматическую терапию, 1 – продолжает терапию препаратом регорафениб, стабилизация в течение 4 мес. Из токсических явлений терапии отмечены тошнота, рвота, диарея, осложнения со стороны кожи, температурная реакция, повышение артериального давления, дисфония. Наиболее клинически значимыми были изменения лабораторных показателей у 3 пациентов (повышение уровня аланиновой и аспарагиновой трансаминаз и билирубина), которые приводили к приостановке лечения и коррекции дозы препарата. Применение препарата регорафениб при мКРР может обеспечивать адекватный контроль над опухолью и характеризуется умеренными проявлениями токсичности, что является актуальным для предлеченных пациентов, резистентных к другим видам противоопухолевой терапии.
Ключевые слова: метастатический колоректальный рак, регорафениб.
Ключевые слова: метастатический колоректальный рак, регорафениб.
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The data of the efficacy and safety regorafenib in the treatment of 7 patients with metastatic colorectal cancer (mCRC) refractory to treatment with cytostatics and monoclonal antibodies – blockers EGFR and VEGF were analyzed. The maximum anti-tumor effect in 1 patient had partial remission, in 6 – stabilization. The duration of progression-free period from start of treatment regorafenib ranged from 1.5 to 6 months. 3 patients continued antitumor therapy after progression, 3 – had the symptomatic therapy after progression, 1 – had stabilization within 4 months and continued therapy of regorafenib. Toxic effects of therapy were nausea, vomiting, diarrhea, complications of the skin, temperature reaction, increased blood pressure, dysphonia. The most clinically significant adverse events were changes in laboratory parameters in 3 patients (increase of ALT, AST and bilirubin), that resulted an interruption in the treatment and correction of the dose. The use of regorafenib in mCRC ensure adequate tumor control, and is characterized by mild toxicity that is relevant for pretreated patients resistant to other forms of anticancer therapy.
Key words: metastatic colorectal cancer, mCRC, regorafenib.
Полный текст
Список литературы
1. Jemal A. Global cancer statistics. CA Cancer J Clin 2011; 2 (61): 69–90.
2. Кит О.И., Владимирова Л.Ю., Абрамова Н.А. и др. Опыт применения моноклональных антител – блокаторов EGFR в лечении метастатического колоректального рака. Фарматека. 2015; 18 (311): 24–8. / Kit O.I., Vladimirova L.Iu., Abramova N.A. i dr. Opyt primeneniia monoklonal'nykh antitel – blokatorov EGFR v lechenii metastaticheskogo kolorektal'nogo raka. Farmateka. 2015; 18 (311): 24–8. [in Russian]
3. Van Cutsem E, Humblet Y, Gruenberger T et al. Cetuximab dose-escalation study in patients with nCRC with no or slight skin reaction on cetuximab standard dose treatment (EVEREST): preliminary PK and efficacy date of a randomized study. Proc. of ASCO 2007. Abstract 237.
4. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658–64.
5. Vladimirova LY, Kit OI, Nikipelova EA, Abramova NA. Results of monoclonal antibodies against EGFR-receptors application in patients with metastic colorectal cancer. J Clin Oncol 2013; 31 (15S) part I of II: 800S.
6. Price TJ, Peeters M, Kim TW et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15 (6): 569–79.
7. Khattak MA, Martin H, Davidson A, Phillips M. Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 2015; 14 (2): 81–90.
8. 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.
9. 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.
10. Grothey A, Van Catsem 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.
11. Li J, Qin S, Xu R et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16: 619–29.
12. Артамонова Е.В. Новые возможности терапии интенсивно-предлеченных пациентов с метастатическим колоректальным раком. Мед. совет. 2016; 10: 24–32. / Artamonova E.V. Novye vozmozhnosti terapii intensivno-predlechennykh patsientov s metastaticheskim kolorektal'nym rakom. Med. sovet. 2016; 10: 24–32. [in Russian]
13. Секачева М.И., Багмет Н.Н. Применение регорафениба при метастатическом колоректальном раке в реальной клинической практике. Современная Онкология. 2016; 18 (3): 43–7. / Sekacheva M.I., Bagmet N.N. Regorafenib application in patients with metastatic colorectal cancer in actual clinical practice. Journal of Modern Oncology. 2016; 18 (3): 43–7
14. Van Cutsem E, Ciardiello F, Seitz J-F et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol 2015; 26 (Suppl. 4): Iv117–iv121.
15. Abou-Elkacem L, Arns S, Brix G et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther 2013; 12 (7): 1322–31.
2. Кит О.И., Владимирова Л.Ю., Абрамова Н.А. и др. Опыт применения моноклональных антител – блокаторов EGFR в лечении метастатического колоректального рака. Фарматека. 2015; 18 (311): 24–8. / Kit O.I., Vladimirova L.Iu., Abramova N.A. i dr. Opyt primeneniia monoklonal'nykh antitel – blokatorov EGFR v lechenii metastaticheskogo kolorektal'nogo raka. Farmateka. 2015; 18 (311): 24–8. [in Russian]
3. Van Cutsem E, Humblet Y, Gruenberger T et al. Cetuximab dose-escalation study in patients with nCRC with no or slight skin reaction on cetuximab standard dose treatment (EVEREST): preliminary PK and efficacy date of a randomized study. Proc. of ASCO 2007. Abstract 237.
4. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658–64.
5. Vladimirova LY, Kit OI, Nikipelova EA, Abramova NA. Results of monoclonal antibodies against EGFR-receptors application in patients with metastic colorectal cancer. J Clin Oncol 2013; 31 (15S) part I of II: 800S.
6. Price TJ, Peeters M, Kim TW et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15 (6): 569–79.
7. Khattak MA, Martin H, Davidson A, Phillips M. Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 2015; 14 (2): 81–90.
8. 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.
9. 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.
10. Grothey A, Van Catsem 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.
11. Li J, Qin S, Xu R et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16: 619–29.
12. Артамонова Е.В. Новые возможности терапии интенсивно-предлеченных пациентов с метастатическим колоректальным раком. Мед. совет. 2016; 10: 24–32. / Artamonova E.V. Novye vozmozhnosti terapii intensivno-predlechennykh patsientov s metastaticheskim kolorektal'nym rakom. Med. sovet. 2016; 10: 24–32. [in Russian]
13. Секачева М.И., Багмет Н.Н. Применение регорафениба при метастатическом колоректальном раке в реальной клинической практике. Современная Онкология. 2016; 18 (3): 43–7. / Sekacheva M.I., Bagmet N.N. Regorafenib application in patients with metastatic colorectal cancer in actual clinical practice. Journal of Modern Oncology. 2016; 18 (3): 43–7
14. Van Cutsem E, Ciardiello F, Seitz J-F et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol 2015; 26 (Suppl. 4): Iv117–iv121.
15. Abou-Elkacem L, Arns S, Brix G et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther 2013; 12 (7): 1322–31.
________________________________________________
1. Jemal A. Global cancer statistics. CA Cancer J Clin 2011; 2 (61): 69–90.
2. Kit O.I., Vladimirova L.Iu., Abramova N.A. i dr. Opyt primeneniia monoklonal'nykh antitel – blokatorov EGFR v lechenii metastaticheskogo kolorektal'nogo raka. Farmateka. 2015; 18 (311): 24–8. [in Russian]
3. Van Cutsem E, Humblet Y, Gruenberger T et al. Cetuximab dose-escalation study in patients with nCRC with no or slight skin reaction on cetuximab standard dose treatment (EVEREST): preliminary PK and efficacy date of a randomized study. Proc. of ASCO 2007. Abstract 237.
4. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658–64.
5. Vladimirova LY, Kit OI, Nikipelova EA, Abramova NA. Results of monoclonal antibodies against EGFR-receptors application in patients with metastic colorectal cancer. J Clin Oncol 2013; 31 (15S) part I of II: 800S.
6. Price TJ, Peeters M, Kim TW et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15 (6): 569–79.
7. Khattak MA, Martin H, Davidson A, Phillips M. Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 2015; 14 (2): 81–90.
8. 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.
9. 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.
10. Grothey A, Van Catsem 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.
11. Li J, Qin S, Xu R et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16: 619–29.
12. Artamonova E.V. Novye vozmozhnosti terapii intensivno-predlechennykh patsientov s metastaticheskim kolorektal'nym rakom. Med. sovet. 2016; 10: 24–32. [in Russian]
13. Sekacheva M.I., Bagmet N.N. Regorafenib application in patients with metastatic colorectal cancer in actual clinical practice. Journal of Modern Oncology. 2016; 18 (3): 43–7
14. Van Cutsem E, Ciardiello F, Seitz J-F et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol 2015; 26 (Suppl. 4): Iv117–iv121.
15. Abou-Elkacem L, Arns S, Brix G et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther 2013; 12 (7): 1322–31.
Авторы
О.И.Кит*, Л.Ю.Владимирова, Н.А.Абрамова, А.Э.Сторожакова, И.Л.Попова, Н.М.Тихановская, А.А.Льянова, Л.А.Рядинская
ФГБУ «Ростовский научно-исследовательский онкологический институт» Минздрава России. 344037, Россия, Ростов-на-Дону, ул. 14-я линия, д. 63
*rnioi@list.ru
ФГБУ «Ростовский научно-исследовательский онкологический институт» Минздрава России. 344037, Россия, Ростов-на-Дону, ул. 14-я линия, д. 63
*rnioi@list.ru
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O.I.Kit*, L.Y.Vladimirova, N.A.Abramova, A.E.Storozhakova, I.L.Popova, N.M.Tikhanovskaya, A.A.Lyaynova, L.A.Ryadinskaya
Rostov Research Institute of Oncology of the Ministry of Health of the Russian Federation. 344037, Russian Federation, Rostov-on-Don, ul. 14-ia Liniia, d. 63
*rnioi@list.ru
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