medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2016-10-24-32medsovet-1401Research ArticleОнкологияOncologyНовые возможности терапии интенсивно-предлеченных пациентов с метастатическим колоректальным ракомNEW POSSIBILITIES OF THERAPY OF INTENSIVELY PRETREATED METASTATIC COLORECTAL CANCER PATIENTSАРТАМОНОВАЕ. В.ARTAMONOVAE. V.

д.м.н.

Москва

MD

Российский онкологический научный центр им. Н.Н. Блохина Минздрава РоссииРоссияFSBI Blokhin Russian Oncologic Scientific Center of the Ministry of Health of RussiaRussian Federation2016301220160102432Copyright © АРТАМОНОВА Е.В., 20162016АРТАМОНОВА Е.В.ARTAMONOVA E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/1401

Статья посвящена результатам изучения нового мультикиназного ингибитора регорафениба у больных рефрактерным метастатическим раком толстой кишки. По данным двух рандомизированных исследований III фазы, препарат достоверно увеличивает общую выживаемость, выживаемость без прогрессирования и контроль заболевания больных мКРР с прогрессированием после предшествующей стандартной химио- и таргетной терапии. Эффективность регорафениба не зависела от статуса KRAS опухоли, других биомаркеров, а также режимов предшествующей терапии и проведенных ранее линий лечения: выигрыш в выживаемости регистрировался во всех подгруппах пациентов. Основными нежелательными явлениями в группе регорафениба были ладонно-подошвенный синдром, слабость, диарея, анорексия, изменения голоса, повышение артериального давления, мукозит и сыпь/шелушение. Большинство нежелательных явлений регистрировались в начале курса лечения и хорошо контролировались за счет снижения дозы или временного прекращения приема препарата, кумулятивной токсичности не отмечено. Две широкомасштабные наблюдательные программы подтвердили эффективность регорафениба в реальной клинической практике. 

The review deals with research of new multikinase inhibitor regorafenib used for treatment of chemorefractory metastatic colorectal cancer. Regorafenib inhibits various protein kinases implicated in oncogenesis, angiogenesis, and the tumour microenvironment. In two placebo- controlled, randomized, phase III trials (CORRECT and CONCUR) treatment with regorafenib has demonstrated statistically significant improvements in terms of overall survival, progression-free urvival and disease control rates when compared with placebo in pretreated patients. Correlative analyses suggest a clinical benefit favouring regorafenib across various patient subgroups including subgroups defined by KRAS mutational status and other biomarkers. The most common grade ≥3 adverse events were hand-foot syndrome, fatigue, diarrhea, hypertension and rash/desquamation. The benefit provided by regorafenib was observed in two open-label, single-arm studies (REBECCA and CONSIGN) performed in the real-world setting.

рефрактерный метастатический колоректальный ракпоздние линии терапиирегорафенибchemorefractory metastatic colorectal cancerlate treatment linesregorafenibReferenceshttp://globocan.iarc.fr/Pages/fact_sheets_population. aspx.http://globocan.iarc.fr/Pages/fact_sheets_population. aspx.Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg, 2009, 22: 191-7.Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg, 2009, 22: 191-7.Myers MH, Gloeckler LA. Cancer patients survival rates. CA, 1989, 39: 21.Myers MH, Gloeckler LA. Cancer patients survival rates. CA, 1989, 39: 21.Wingo PA, Tong T, Bolden S. Cancer statistics. CA, 1995, 45: 8-30.Wingo PA, Tong T, Bolden S. Cancer statistics. CA, 1995, 45: 8-30.Weber SM, Jarnagin WR, DeMatteo RP et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol, 2000, 7: 643-650.Weber SM, Jarnagin WR, DeMatteo RP et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol, 2000, 7: 643-650.Choti MA, Sitzmann JV, Tiburi MF et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg, 2002, 235: 759-766.Choti MA, Sitzmann JV, Tiburi MF et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg, 2002, 235: 759-766.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: 4575-4580.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: 4575-4580.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.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.Grothey А, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol, 2004, 22: 1209-1214.Grothey А, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol, 2004, 22: 1209-1214.Van Cutsem E, Cervantes A, Nordlinger B and Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 2014, 25(suppl 3): iii1-iii9.Van Cutsem E, Cervantes A, Nordlinger B and Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 2014, 25(suppl 3): iii1-iii9.Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colon Cancer, Version 2.2016. http://www.nccn.org/professionals/physician_ gls/pdf/colon.pdf.Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colon Cancer, Version 2.2016. http://www.nccn.org/professionals/physician_ gls/pdf/colon.pdf.Van Cutsem E, Cervantes A, Adam R et al. ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer. Annals of Oncology, 2016, 0: 1- 38, Advance Access published July 7, 2016.Van Cutsem E, Cervantes A, Adam R et al. ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer. Annals of Oncology, 2016, 0: 1- 38, Advance Access published July 7, 2016.Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum– applying current evidence to clinical practice. Cancer Treat Rev, 2012, 38: 397- 406.Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum– applying current evidence to clinical practice. Cancer Treat Rev, 2012, 38: 397- 406.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: 5326-5334.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: 5326-5334.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.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.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 S): abstr. CRA 3503.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 S): abstr. CRA 3503.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: 320-331.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: 320-331.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 oxaliplatinbased therapy. Targ. Oncol., published online 26 dec 2015: doi:10.1007/s11523-015-0402-9.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 oxaliplatinbased therapy. Targ. Oncol., published online 26 dec 2015: doi:10.1007/s11523-015-0402-9.Chau I1, 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 Aug 20, 14: 605. doi: 10.1186/1471- 2407-14-605.Chau I1, 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 Aug 20, 14: 605. doi: 10.1186/1471- 2407-14-605.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.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.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: 245-55.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: 245-55.Mross K, Frost A, Steinbild S et al. A phase I dose-escalation study of regorafenib )BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin. Cancer Res, 2012, 18(9): 2658-67.Mross K, Frost A, Steinbild S et al. A phase I dose-escalation study of regorafenib )BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin. Cancer Res, 2012, 18(9): 2658-67.Strumberg D, Scheulen ME, Schultheis B et al. Regorafenib (BAY 73-4506) in advansed colorectal cancer: a phase I study. Br. J. Cancer, 2012, 22, 106(11): 1722-1727.Strumberg D, Scheulen ME, Schultheis B et al. Regorafenib (BAY 73-4506) in advansed colorectal cancer: a phase I study. Br. J. Cancer, 2012, 22, 106(11): 1722-1727.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.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.Van Cutsem E. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). JCO, 2012, 30(15 S): p 203s; ASCO 2012. Abstract 3502.Van Cutsem E. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). JCO, 2012, 30(15 S): p 203s; ASCO 2012. Abstract 3502.Grothey A, Van Cutsem E, Siena S et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. ASCO GI January 14-16, 2013, San Francisco, CA. Poster 467.Grothey A, Van Cutsem E, Siena S et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. ASCO GI January 14-16, 2013, San Francisco, CA. Poster 467.Khan G, Moss RA, Braiteh F, Saltzman M. Proactive strategies for regorafenib in metastatic colorecnal cancer: implication for oprimal patients management. Cancer Manage Res, 2014, 6: 93-103.Khan G, Moss RA, Braiteh F, Saltzman M. Proactive strategies for regorafenib in metastatic colorecnal cancer: implication for oprimal patients management. Cancer Manage Res, 2014, 6: 93-103.Siena S, Grothey A, Sobrero A, Falcone A, Ychou M, Lenz HJ, et al. Effects of regorafenib therapy on health-related quality of life in patients with metastatic colorectal cancer in the phase III CORRECT study. Eur J Cancer, 2013, 49(2): Abstract 2156.Siena S, Grothey A, Sobrero A, Falcone A, Ychou M, Lenz HJ, et al. Effects of regorafenib therapy on health-related quality of life in patients with metastatic colorectal cancer in the phase III CORRECT study. Eur J Cancer, 2013, 49(2): Abstract 2156.Li J, Qin S, Xu R, Yau TC, Ma B, Pan H 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, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2015, 16(6): 619-29. doi:10. 1016/ S1470-2045(15)70156-7.Li J, Qin S, Xu R, Yau TC, Ma B, Pan H 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, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2015, 16(6): 619-29. doi:10. 1016/ S1470-2045(15)70156-7.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. Annals of Oncology, 2015, 26(suppl. 4): iv117- iv121, abstr. LBA-05.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. Annals of Oncology, 2015, 26(suppl. 4): iv117- iv121, abstr. LBA-05.Van Cutsem E, Ciardiello F, Yshour M et al. Regorafenib in previously treated metastatic colorectal cancer (mCRR): analysis of age subgroups in open-label phase 3b CONSIGN trial. ASCO, 2016, abstr. 3524.Van Cutsem E, Ciardiello F, Yshour M et al. Regorafenib in previously treated metastatic colorectal cancer (mCRR): analysis of age subgroups in open-label phase 3b CONSIGN trial. ASCO, 2016, abstr. 3524.Tougeron D, Desseigne F, Etienne PL, Dourthe LM, Mineur L, Paule B, et al. REBECCA: a large cohort study of regorafenib (REG) in the reallife setting in patients (pts) previously treated for metastatic colorectal cancer (mCRC). Ann Oncol., 2014, 25(4): iv167-209. doi:10.1093/ annonc/mdu333.Tougeron D, Desseigne F, Etienne PL, Dourthe LM, Mineur L, Paule B, et al. REBECCA: a large cohort study of regorafenib (REG) in the reallife setting in patients (pts) previously treated for metastatic colorectal cancer (mCRC). Ann Oncol., 2014, 25(4): iv167-209. doi:10.1093/ annonc/mdu333.Grothey A, George S, Van Cutsem E et al. Optimizing treatmant outcomes with regorafenib: personalized dosing and other strategies to support patients care. Oncologist, 2014, 19(6): 669-80.Grothey A, George S, Van Cutsem E et al. Optimizing treatmant outcomes with regorafenib: personalized dosing and other strategies to support patients care. Oncologist, 2014, 19(6): 669-80.De Wit M, Boers-Doets CB, Saettini A et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer, 2014, 22(3): 837-846.De Wit M, Boers-Doets CB, Saettini A et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer, 2014, 22(3): 837-846.Belum VR, Wu S, Lacouture ME et al. Risk of hand-foot skin reaction with the novel multikinese inhibitor regorafenib: a meta-analysis. Invest. New Drugs, 2013, 31(4): 1078-86.Belum VR, Wu S, Lacouture ME et al. Risk of hand-foot skin reaction with the novel multikinese inhibitor regorafenib: a meta-analysis. Invest. New Drugs, 2013, 31(4): 1078-86.Wang Z, Xu J, Nie W et al. Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur. J Clin. Pharmacol., 2014, 70(2): 225-31.Wang Z, Xu J, Nie W et al. Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur. J Clin. Pharmacol., 2014, 70(2): 225-31.Tabernero J, Siena S, Sobrero A et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol, 2015, 16: 937-48.Tabernero J, Siena S, Sobrero A et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol, 2015, 16: 937-48.Ellis LM, Bernstein DS, Voest EE et al. American Society of Clinical Oncology perspective : raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Onc, 2014, 32(12): 1277-80.Ellis LM, Bernstein DS, Voest EE et al. American Society of Clinical Oncology perspective : raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Onc, 2014, 32(12): 1277-80.Nielsen DL, Palshof JA, Larsen FOl et al. A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy. Cancer treatment reviews, 2014, 40: 701-715.Nielsen DL, Palshof JA, Larsen FOl et al. A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy. Cancer treatment reviews, 2014, 40: 701-715.Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double- blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol, 2012,13: 993-1001.Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double- blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol, 2012,13: 993-1001.Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med, 2007, 357: 2040-8.Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med, 2007, 357: 2040-8.

The authors declare that there are no conflicts of interest present.