CC BY
9
Front Pharmacol 2019; 10: 28 [PMID: 30828298 D01:10.3389/fphar.2019.00028]
70.Rudland PS, Barraclough R, Fernig DG, Smith JA. Growth and differentiation of the normal mammary gland and its tumours. Biochem Soc Symp 1998; 63: 120 [PMID: 9513707]
71.Ryan CJ, Tindall DJ. Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. J Clin Oncol 2011; 29: 3651-3658 [PMID: 21859989 DOI:
72.Schabath H, Runz S, Joumaa S, Altevogt P. CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci 2006; 119: 314325 [PMID: 16390867 DOI: 10.1242/jcs.02741]
73.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66: 7-30 [PMID: 26742998 DOI: 10.3322/caac.21332]
74.Simöes BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, SantiagoGómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB. Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity. Cell Rep 2015; 12: 1968-1977 [PMID: 26387946 DOI: 10.1016/j.celrep.2015.08.050]
75.Singer CF, Kronsteiner N, Marton E, Kubista M, Cullen KJ, Hirtenlehner K, Seifert M, Kubista E. MMP2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromalepithelial interactions. Breast Cancer Res Treat 2002; 72: 69-77 [PMID: 12000221 DOI:10.1023/A:1014918512569]
76.Tillyashaikhov M.N., Kamishov S.V. Features of the cellular status of immunity in patients with
cervical cancer European science, 2018 No. 5 (37) -P.75-79.
77.Tillyashaikhov M.N., Kamishov S.V. Features of the humoral status of immunity in patients with cervical cancer // Materials of the conference International scientific review of the problems and prospects of modern science and education 2018 -p. 8487
78.Truong TH, Dwyer AR, Diep CH, Hu H, Hagen KM, Lange CA. Phosphorylated Progesterone Receptor Isoforms Mediate Opposing Stem Cell and Proliferative Breast Cancer Cell Fates. Endocrinology 2019; 160: 430-446 [PMID: 30597041 DOI: 10.1210/en.2018-00990]
79.Vera-Badillo FE, Templeton AJ, de Gouveia P, Diaz-Padilla I, Bedard PL, Al-Mubarak M, Seruga B, Tannock IF, Ocana A, Amir E. Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst 2014; 106: djt319 [PMID: 24273215 D0I:10.1093/jnci/djt319]
80.Vicent GP, Ballare C, Nacht AS, Clausell J, Subtil-Rodriguez A, Quiles I, Jordan A, Beato M. Convergence on chromatin of non-genomic and genomic pathways of hormone signaling. J Steroid Biochem Mol Biol 2008; 109: 344-349 [PMID: 18417338 DOI: 10.1016/j.jsbmb.2008.03.015]
81.Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF. A variant of estrogen receptor-{alpha}, hER{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling.
82.Warner M, Huang B, Gustafsson JA. Estrogen Receptor ß as a Pharmaceutical Target. Trends Pharmacol Sci 2017; 38: 92-99 [PMID: 27979317 DOI: 10.1016/j.tips.2016.10.006]
PROSPECTS FOR USE OF TARGET DRUGS IN NEOADJUVANT CHEMOTHERAPY OF COLORECTAL CANCER METASTASIS IN THE LIVER (REVIEW)_
Niyozova Sh.Kh.
Republican Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan
SUMMARY
To increase the effectiveness of chemotherapy (CT) of metastases of colorectal cancer (CRC) in the liver therapy, targeted drugs are used, usually in combination with standard CT. However, at present, there is not enough clinical research data confirming the effectiveness of a combination of various chemotherapy regimens with drugs-inhibitors of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in conditions of neoadjuvant chemotherapy in this category of patients, which indicates the need for similar studies.
Key words: colorectal cancer, liver metastases, preoperative chemotherapy, targeted drugs.
Colon cancer is one of the most common malignant tumors, annually in the world from 800 thousand to 1.2 million patients with colorectal cancer and about 600 thousand deaths from these diseases are registered (approximately 56% of all cases). In 20% of patients with colorectal cancer (CRC) at the time of diagnosis, distant metastases are detected, primarily in the liver, and in 50% of patients metastases develop during the course of the disease, which becomes the cause of their death [1,3,11-15].
To date, surgery has been the only treatment to achieve long-term survival in patients with liver metastases of CRC. However, only a small group of patients (15-20%) can count on a potentially radical treatment, including removal of the primary tumor of the colon and liver resection. At the same time, traditional liver resection in operable patients allows achieving a 5-year survival rate of 21-37%. Recent advances in chemotherapy (CT) for metastatic colorectal cancer have significantly expanded the indications for treatment of patients at all stages of the
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disease, while the prevalence of the disease determines the difference in treatment tactics. Modern combined regimens of systemic chemotherapy have achieved 60% of the local tumor response and up to 20% of initially inoperable patients can be transferred to the surgical group after neoadjuvant treatment [2,4,6, 17].
Neoadjuvant chemotherapy can affect detectable and latent metastases, reducing the volume of the tumor mass, reducing the risk of dissemination during surgery and making possible surgery more radical. In addition, preoperative chemotherapy determines the sensitivity of the tumor to specific drugs, which is taken into account in the appointment of adjuvant treatment. Based on current evidence, the guidelines of the European Society for Medical Oncology (ESMO) suggest that the need for perioperative systemic therapy is determined by "technical criteria for resection and prognostic considerations." Preoperative surgery is warranted in patients with clearly resectable disease and a favorable prognosis; while perioperative FOLFOX or XELOX should be considered when resectability or prognostic criteria are unclear or "not excellent" [4,11,16,18,20].
Despite the fact that the use of cytotoxic drugs significantly improved the relapse-free survival rate of patients with metastatic colorectal cancer, targeted drugs are currently used to increase the effectiveness of therapy, usually in combination with standard chemotherapy. Their action is aimed at inhibiting the cell cycle and DNA repair pathways, induction of apoptosis of tumor cells. Thus, the targeted anti-VEGF drug bevacizumab, which is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits its activity, inhibits angiogenesis and thus tumor growth and metastatic progression, is currently used to treat metastatic colorectal cancer. In addition, recent studies indicate its pro-apoptotic activity, also based on blocking VEGF, which inhibits intracellular signaling pathways that trigger apoptosis. There are also high hopes for blockers of epidermal growth factor receptors (EGFR). When using monoclonal antibodies against epidermal growth factor receptors C225 (cetuximab) in combination with irinotecan after progression with 5-fluorouracil and then irinotecan, in patients with high EGFR levels, the overall effect was 22.5%. Similar studies are carried out in combination with oxaliplatin [7,8,10,12, 15,19].
Current guidelines suggest oxaliplatin-based doublet chemotherapy (FOLFOX / XELOX) as a neoadjuvant therapy for the selection of resectable CRLM, while FOLFIRI or FOLFOXIRI are alternatives. A meta-analysis showed that the addition of molecular targeted therapy had a higher overall response than CT (68% versus 43%), but did not improve survival. Similar results were also observed in the new EPOC study, which examined the effect of combining cetuximab with perioperative systemic chemotherapy: patients who received cetuximab actually had worse disease-free survival (14.1 versus 20.5 months in controls). Given these results, the authors do not recommend adding cetuximab to standard perioperative chemotherapy regimens. Bevacizumab, as well as FOLFIRI in neoadjuvant
mode, show a response of 66.7% for resectable liver metastases in patients with CRC, however, whether this leads to an increase in disease-free survival remains to be determined [5,10, 7, 21].
The optimal chemotherapy regimen for transferring patients with metastatic colorectal cancer to an operable state is still unclear. The standard doublet scheme of XT FOLFOX or FOLFIRI had a degree of such transition from 9% to 33%. Compared with FOLFIRI, FOLFOXIRI boosted triplet CT improves the rate of secondary R0 resection from 12% to 36% and median progression-free survival from 6.9 to 9.8 months. and average overall survival from 16.7 to 22.6 months, although due to greater, but manageable toxicity, for example, peripheral neuropathy and neutropenia. The addition of targeted drugs is recommended in current guidelines, however, there is no specific supporting evidence. In another study, taking bevacizumab with XELOX / FOLFOX only moderately improved resectability (from 6.1% to 8.4%) and relapse-free survival (from 8 to 9.4 months), but did not prolong overall survival [6,7].
According to a recent meta-analysis, the combination of bevacizumab and FOLFOXIRI gives more promising results - the rate of transfer of patients to an operable R0 form was 28.1%, and the median overall and disease-free survival was 30.2 and 12.4 months. respectively. Numerous randomized studies have shown that the addition of cetuximab to chemotherapy for inoperable colorectal cancer with the wild-type (WT) proto-oncogene KRAS improved the R0 resection rate by 2-3 times. However, an increase in total resection from 11% to 18% did not lead to an increase in survival in the meta-analysis. Panitumumab, another anti-EGFR agent, also increased the rate of therapeutic resections when added to FOLFOX (29% versus 17%) for inoperable CRC with KRAS-WT [9,12,19, 22, 23].
Thus, at present, there are no reliable data confirming the effectiveness of a combination of various chemotherapy regimens with drugs that inhibit vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in conditions of neoadjuvant chemotherapy in patients with CRC with liver metastases. Therefore, new studies are needed regarding the use of targeted drugs to improve the immediate and long-term results of treatment in this category, as well as the advantages of their use in preoperative chemotherapy.
REFERENCES
1.Assessorova Yu.Yu., Kireev G.V., Balenkov O.Yu. The most important modern trends in cancer incidence in different countries (review) // Journal of Theoretical and Clinical Medicine. -2009. -№2. -P.77-81.
2.Balenkov O.Yu., Yuldasheva D.Yu., Kireev G.V., Kamyshov S.V. Study of oncological morbidity in the population of Tashkent // Journal of Theoretical and Clinical Medicine. -2007. -N 3. -P.90-92.
3.Bazin I.S., Mamontov K.G. Modern approaches to chemotherapy in the complex treatment of localized
colon cancer // Oncological Coloproctology. -2011. -№2. -P.27-36.
4.Chang M.H., Ahn H.K., Lee J. et al. Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors // Cancer. -2011. -V.117. -P.143-151.
5.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. -V.13. -P.1670-1676.
6.Fedyanin M.Yu., Tryakin A.A., Tyulyandin S.A. Chemotherapy of patients with metastatic colon cancer // Oncological Coloproctology. -2012. -No 2. -C.26-34.Chang M.H., Ahn H.K., Lee J. et al. Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors // Cancer. -2011. -V.117. -P.143-151.
7.Kamishov S.V. Mechanisms of immune disorders in patients with ovarian cancer receiving chemotherapy and their dynamics during immunotherapy // Eurasian Oncological Journal, -2018 -P. 563-576
8.Kamishov S.V. Modern immunopharmacotherapy in the complex treatment of cervical cancer // Bulletin of Science and Education -2018 -V.2 (6 (42)), -P. 57-61
9.Kamishov S.V., Pulatov D.A., Nishanov D.A., Yuldasheva N.Sh. Influence of the expression level of tumor markers on the results of treatment of patients with cervical cancer who received concomitant immunotherapy // Eurasian Oncological Journal 5 (1), -2017-P. 68-76
10.Kamishov S.V., Pulatov D.A., Yusupova N.B., Niezova Sh.Kh. The state of immunoreactivity of patients with cervical cancer against the background of extracorporeal immunopharmacotherapy // Bulletin of the National. medical surgeon. center them. N.I. Pirogov 13 (1), -P. 98-102
11.Kamishov S.V., Pulatov D.A.Supportive immunotherapy in complex treatment of patients with oncogynaecological diseases //The scientific heritage -2017 -V.18 (18), 23-27
12.Kamyshov S.V., Nishanov D.A., Pulatov D.A., Yuldasheva N.S. //Izuchenie markerov apoptoza, proliferacii i angiogeneza u bol'nyh rakom jaichnika, poluchivshih soprovoditel'nuju immunoterapiju [The study of markers of apoptosis, proliferation and angiogenesis in patients with ovarian cancer who received accompanying immunotherapy]. Zlokachestvennye opuholi [Malignant tumors], 1, 84-91
13.Kamyshov S.V., Pulatov D.A., Nishanov D.A., Yuldasheva N.S., Yusupova N.B. Znachimost'ocenki molekuljarno-biologicheskih onkomarkerov v soprovoditel'noj immunoterapii pri rake shejki matki [Significance of the assessment of molecular biological tumor markers in accompanying immunotherapy for cervical cancer]. Onkologija i radiologija Kazahstana
[Oncology and radiology of Kazakhstan], 2017 V.2 -P. 45-48
14.Kamyshov S.V., Pulatov D.A., Yuldasheva N.S. Ispol'zovanie metodov gravitacionnoj hirurgii krovi v kompleksnom lechenii bol'nyh rakom jaichnika [The use of gravitational blood surgery methods in the complex treatment of patients with ovarian cancer]. Vestnik Nacional'nogo mediko-hirurgicheskogo centra im. NI Pirogova BBBulletin of the National Medical and Surgical Center after Ni Pirogov], -201712 (1), -P. 52-56Nigri G., Petrucciani N., Ferla F. et al. Neoadjuvant chemotherapy for resectable colorectal liver metastases: what is the evidence? Results of a systematic review of comparative studies // Surgeon. -
2015. -V.13. -P.83-90.
15.Nasti G., Piccirillo M.C., Izzo F. et al. Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial // Br. J. Cancer. -2013. -V.108. -P.1566-1570.
16.Nordlinger B., Sorbye H., Glimelius B. et al. Perioperative chemotherapy with FOLFOX4 and surgery vs. surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup Trial 40983): a randomized controlled trial // Lancet. -2008. -V.371. -P.1007-1016.
17.Petrelli F., Barni S. Anti-EGFR agents for liver metastases. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis // Int. J. Colorectal Dis. -2012. -V.27. -P.997-1004.
18.Pulatov D.A., Ibragimov Zh.M., Kamishov S.V. Comparative assessment of the toxicity of treatment of patients with chemoresistant colorectal cancer // Oncology and Radiology of Kazakhstan -2018 V.44 (2), -P. 58-61
19.Sabanathan D., Eslick G.D., Shannon J. Use of Neoadjuvant Chemotherapy Plus Molecular Targeted Therapy in Colorectal Liver Metastases: A Systematic Review and Meta-analysis // Clin. Colorectal Cancer. -
2016. -V.15. -P.e141-e147.
20.Schmoll H.J., 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. -V.23. -N10. -P.2479-2516.
21.Tillyashaikhov M.N., Kamishov S.V. Features of the cellular status of immunity in patients with cervical cancer European science, 2018 No. 5 (37) -P.75-79.
22.Tillyashaikhov M.N., Kamishov S.V. Features of the humoral status of immunity in patients with cervical cancer // Materials of the conference International scientific review of the problems and prospects of modern science and education 2018 -p. 8487
23.Ye L.C., Liu T.S., Ren L. et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases // J. Clin. Oncol. -2013. -V.31. -P.1931-1938.
