6Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
METASTATIK ME'DA ADENOKARSINOMALARIDA VEGF-R2 BLOKATORINI QO'LLANILISHI
M. M. Mallaev R. A. Abdusattorov B. B. Sharobidinov
Akfa Medline tibbiyot markazi
ANNOTATSIYA
O'tkazilgan randomirlashgan tadqiqotimiz ning maqsadi birinchi qator kimyoviy davoni qabul qilgan, Her 2neu manfiy metastatik me'da adenokarsinomali bemorlarni VEGF-R2 blokatori ramisirumab bilan davolashdagi afzalliklarini baholashdan iborat.
Kalit so'zlar: Her 2neu manfiy metastatik me'da adenokarsinoma, VEGF-R2 blokatori, : ramicirumab va irinotekan
KIRISH
Oxirgi yillarda me'da saratonining uchrash darajasi kamayganligiga qaramasdan ushbu kasallik hamon o'zining yuqori ahamiyatini saqlab qolmoq da. Hozirda me'da saratoni uchrashi bo'yicha umumiy saraton kasalliklarining 8%ni, o'lim ko'rsatkichi boyicha 10%ni tashkil etadi. Kasallik ko'proq erkaklarda kuzatilib, Osiyo mintaqasida uchrash chastotasi eng yuqori ko'rsatkichga ega. MSning yosh bo'yicha uchrashi o'rtacha 69 yoshni tashkil etib, 75-84 yosh oralig'ida eng yuqori ko'rsatkichga ega bo'ladi. MS tashhisi qo'yilgan barcha bosqichdagi bemorlar uchun 5 yillik umr ko'rsatkichi 27,7%ni tashkil etadi. Shuni qayd etish kerakki, oxirgi yillar davomida MS bilan kasallanish ko'rsatkichi kamaydi. Biroq, tashxislash va davolashdagi yutuqlarga qaramasdan MSning kechki bosqichlarida 5 yillik umr ko'rsatkichi yomonligicha (3,7%) qolmoqda. Me'dada uchrovchi barcha yomon sifatli o'sma kasalliklarining asosiy ulushi me'da adenokarsinomasiga ( > 95%) to'g'ri keladi. Kam uchrovchi turlari sarasiga esa mezenhimal, limfaproliferativ va neyroendokrin neoplazmlar kiradi. Oxirgi besh dekadada kasallik uchrashi kamaygandek bo'lsada hozirda ham ko'plab dunyo mamlakatlari ushbu kasallikdan aziyat chekmoqda (1). Hozirgi kunda endoskopiya, xirurgiya va ummumiy davo usullari hamda kasallikka multiditsiplionar yondashuv imkoni bolganiga qaramasdan hamon MAKli bemorlar 5 yillik o'rtacha yashovchanligi qoniqarsizligicha ( 25-30%)
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
qolmoqda. Kasallikning erta tashhislanishi ( TNM klassifikatsiyasi bo'yicha T1 bosqichda) va to'g'ri va samarali davo taktikasini tanlanishi yuqoridagi ko'rsatgichlarni yaxshilashga olib kelishi shubhasiz.
MATERIAL VA METODLAR
Tadqiqot uchun "Akfa Medlayn" klinikasi sharoitida birinchi qator kimyoviy davoni standart bo'yicha qabul qilgan 39 nafar Her 2neu manfiy metastatik me'da adenokarsinomali bemorlar tanlab olindi. Bemorlarning 20 nafarida (51.3%) paraaortal limfa tugunlarining zararlanishi, hamda 8 nafar (20.6%) bemorda o'smaning qo'shni a'zo va qon tomirlarga o'sib o'tishi aniqlangan, shu sababli ushbu holatlar norezektabel kasallik sifatida baholangan. Bemorlarning 11 nafarida esa (28.2%) distant metastazlar aniqlangan (jigar, qorin parda va tana skelet suyaklari). Bemorlar birinchi qator standart davo sifatida 5-FU va platina unumli dori vositalarini qabul qilgan. Ularning 20 nafari ikkinchi qator kimyoviy davo sifatida ramicirumab va irinotekan hamda 19 nafari irinotekan va platsebo qabul qilgan.
Davolashning olib borilishi - bemorlar ramucirumab va irinotekan yoki platsebo va irinotekan oluvchi guruhlarda 1:1 nisbatda randomizatsiyalangan. Ramucirumab (8 mg/kg) 1 va 15-kunlarda vena ichiga infuziya ko'rinishida yoki davolanishning 1-21 kunlarida irinotekan 350 mg/m2 bilan birgalikda infuziya ko'rinishida yuboriladi. Bemorlar kasallikning progressiyasi, nojo'ya ta'sirlarining ortib ketganligida yoki bemorlarning davodan o'zlari bosh tortmagunicha davom ettirildi.
NATIJA VA UNI BAHOLASH
O'simtani baholash dastavval va har 6 haftada bir marta kasallikning rivojlanishiga qadar o'tkazildi. Kaplan-Meier usuli KHY (kasallikdan holi yashovchanlik) va UY (umumiy yashovchanlik) uchun yashovchanlik egri chizig'ini yaratishda ishlatilgan. O'rtacha KHY va UY tegishli 95% CI (ishonchlilik indeksi) Kaplan-Meier usuli yordamida baholandi. Davolanish samarasining xavf darajasi (HR) tabaqalanmagan Cox PH modeli yordamida, p-qiymati esa tabaqalanmagan log-darajali test yordamida hisoblangan. Kasallikni bosqichlashda Milliy Saraton Institutining me'da saratoni uchun umumiy terminologiya mezonlariga (NCI-CTCAE; versiya 4.02) muvofiq olingan. Atamalarning qisqartmalari matin ichida keltirilgan.
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
Ramicirumab va irinotekan qabul qilgan bemorlarning umumiy yashovchanligi (11.4 oy; 95% CI: 7.0-17.9), irinotekan va platsebo guruhidagi bemorlarnikiga nisbatan (7.0 oy; 95% CI: 3.4-14.6) yuqori ekanligi aniqlangan (HR-0.68 (0.33-1.41) p=0.30). Yuqori kasallikdan holi yashovchanlik ko'rsatgichi ham aynan ramiciruman kambinatsiyalangan guruh hisobiga to'g'ri kelgan.
Davoning nojo'ya ta'sirlari - ramucirumab va irinotekan hamda platsebo va irinotekan kombinatsiyasini qabul qilgan bemorlarda har qanday darajadagi kamida bitta nojo'ya ta'sir kuzatilgan. Ikkala guruhdagi har qanday darajadagi keng tarqalgan nojo'ya ta'sirlar sifatida quyidagilarni keltirish mumkin: burundan qon ketish, neytropeniya, alopetsiya, charchoq, ishtahaning pasayishi, leykopeniya, ko'ngil aynishi, ich qotishi, gipertenziya, periferik sensorli neyropatiya, qusish, anemiya, yo'tal, periferik neyropatiya, periferik shish va pireksiya. Ramucirumab va irinotekan guruhi irinotekan va platsebo guruhiga nisbatan (nojo'ya ta'sir darajasi >3) yuqori neytropeniya (45,0% ga nisbatan 15,8%), leykopeniya (20,0% ga qarshi 0,0%), anemiya (10,0% ga nisbatan 0,0%) va periferik sensorli neyropatiya (10,0% va 5,35%) teng bo'lgan mos ravishda.
- Ramisirumab va irinotekan (n=20) yashovchanlik medianasi 11.4 oy
- Irinotekan va platsebo (n=19) yashovchanlik medianasi 7 oy
I I I I ! I I I I I I I I I 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time (months)
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
ramisirumab 20 20 18 16 14 11 10 6 5 2 0 0 0 0 0
va
irinotekan
irinotekan 19 17 13 10 9 8 7 5 3 3 1 0 0 0 0 va platsebo
Rasm 1. Her 2neu manfiy mahalliy tarqoq me'da adenokarsinomali bemorlarning umumiy
yashovchanligi
Time (months)
ramisirumab va 20 15 12 6 4 3 3 1 0 0 0 0 0 0 irinotekan
irinotekan va 19 12 5 0 0000000 000 platsebo
Rasm 2. Her 2neu manfiy mahalliy tarqoq me'da adenokarsinomali bemorlarning
kasallikdan holi yashovchanligi.
TADQIQOT TAHLILI
Me'da saratonidagi so'nggi terapevtik yutuqlar asosan VEGFR-2 va HER-2 [8,15] ga qaratilgan. HER-2-musbat ko'krak bezi saratoniga asoslangan mavjud klinik ma'lumotlar HER-2 ning ortiqcha ishlab chiqarilishi va o'sma angiogenezining faollashishi o'rtasidagi bog'liqlikni ko'rsatadi. O'sma hujayralarida HER-2 ning haddan tashqari ko'payishi VEGF tasiri doirasi va angiogenezning faollanishiga sabab bo'ladi va ushbu hususiyat tufayli o'smaning omon qolishi mexanizmlari (surveillance) yuzaga keladi va faollashadi [13,16]. Ramucirumab monoklonal antitana - VEGFR-2 antagonisti hisoblanadi, ligandlarning bog'lanishiga va endotelial hujayralardagi retseptorlar faollashishiga to'sqinlik qiladi [17]. Trastuzumab qarshiligini VEGFR-2 ingibitorlari, masalan, ramucirumab kabi angiogenez
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
ingibitorlari orqali bartaraf etish mumkin. So'ngi nashr etilgan tadqiqot natijalariga ko'ra HER2-musbat metastatik me'da saratoni bilan og'rigan bemorlarda trastuzumabni davom ettirish klinik samaradorlikka ega [18]. Biroq, prospektiv va retrospektiv tadqiqotlar birinchi qatorli trastuzumab va kimyoterapiya kombinatsiyasida kasallik progressiyasi yuzaga kelgan bemorlarda ikkinchi qator sifatida trastuzumab kombinatsiyalaridan foydalanish UY va KHY kabi muhim prognostik omillardagi sezilarli farqni yo'q ekanligini ko'rsatadi [9,15,18]. Birinchi qator sifatida 5-FU va platina unumi olgan bemorlarning tadqiqot qilinganida, platsebo va irinotekan guruhi (7,0 oy; 95% CI: 3.4-14.6) ikkinchi qator ramusirumab va irinotekan kombinatsiyasi bilan solishtirganda yuqori o'rtacha UY (11,4 oy; 95% CI: 7,0-17,9) erishilganligini kuzatishimiz mumkin. Ramucirumab va irinotekan guruhida KHY platsebo va irinotekan guruhiga nisbatan uzun ekanligini ko'rishingiz mumkin. Hozirgi vaqtda ramucirumab uchun davo samarasini boholaydigan aniq biomarkerlar mavjud emas, shuning uchun davolanishdayuqori samaradorlikka erishadigan bemorlarni tanlash qiyin. VEGF yo'li bilan bog'liq bo'lgan asoratlar alohida qiziqish uyg'otdi: qon ketish hodisalari, gipertenziya, oshqozon-ichakdan qon ketishi va proteinuriya. Ushbu kichik guruh tahlilining cheklovlari kichik namuna hajmi va bu retrospektiv tahlil bo'lib, etarlicha quvvatga ega emas edi. Davolanish vositalarining samaradorligi va xavfsizligi bo'yicha kuzatilgan raqamli farqni statistik jihatdan ahamiyatli deb hisoblash mumkin emas va bemorlar trastuzumab bilan oldingi terapiyaning kichik guruhida randomizatsiyalanmaganligi bilan izohlashda qo'shimcha qiyinchilik tug'diradi. Bizning kichik guruh tahlilimiz, namuna hajmi bilan cheklangan bo'lsa-da, ramucirumabga asoslangan terapiyaning raqamli klinik afzalliklarini aniqladi. Oldindan trastuzumab olmagan bemorlarda ramucirumab asosidagi kombinatsiyalangan terapiyaning klinik afzalliklarini tasdiqlash uchun istiqbolli klinik tadkikotlarda qo'shimcha tadqiqotlar o'tkazish talab etiladi.
XULOSA
So'nggi sinovlar shuni ko'rsatdiki, HER+ manfiy bo'lgan metastatik me'da saratonida birinchi va ikkinchi qator davoni tanlashda yetarlicha samarali vositalar mavjud emas (trastuzumab). Ushbu kichik guruh tahlili natijalari shuni ko'rsatadiki, ramucirumab irinotekan bilan birgalikda HER+ manfiy bo'lgan metastatik me'da adenoikarsinomali bemorlarda davolashning boshqariladigan asoratlarining kamligi bilan samarali. Ramucirumabning irinotekan bilan birgalikda qo'llanilishi birinchi
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
qator terapiyadan qat'i nazar, bemorlar uchun standart tibbiy yordam bo'lib qolmoqda.
REFERENCES
1. Berse B., Brown L., Van de Water L., et al.: Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tis- sues, macrophages and tumors./ Mol. Biol. Cell, 1992; 3:211-220.
2. Blanke C, Haller D, Benson A., et al. A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adeno-carcinoma. Ann Oncol 2001; 12: 1575-1580.
3. Gallamini A., Borra A. Role of PET in gastric cancer. Curr. Treat. Options Oncol. 2014. 15: P.248-261.
4. Koss L.G., Melamed M.R. Koss Diagnostic Cytology and Its Histopathologic Basis. Philadelphia: Lippincott Williams & Wilkins, 2006.
5. Pouget J.P., Navarro-Teulon I., Bardies M., et al. Clinical radioimmunotherapy -the role of radiobiology. Nat. Rev. Clin. Oncol. 2011. 8: P.720-734.
6. Tubbs R.R., Stoler M.H. Cell and Tissue Based Molecular Pathology E-Book. Philadelphia: Elsevier Health Sciences, 2009. P. 452
7. Younes A. Beyond chemotherapy: new agents for targeted treatment of gastric cancer. Nat Rev Clin Oncol 2011; 8: P. 85-96.
8. Zeldis JB, Knight R, Hussein M, et al. A review of the history, properties, and use of the immunomodulatory compound lenalidomide. Ann N Y Acad Sci 2011; 1222:P.76-82.
9. Cunningham D, Starling N, Rao S, et al. Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer. N. Engl. J. Med., Jan 2008; 358: 36 - 46
10. Edwards P. et al. Prospective comparison of Dl vs modified D2 gastrectomy for carcinoma // Br. J. Cancer. - 2004. - Vol. 90, N 10. - P. 1888-1892.
11. Eliuahu D., Michalooilz D., Oren M., et al Overexpression p53 antigen makes established cells highly tumor nic//Ibid. - 1985. - Vol. 3. - P. 158-160.
12. Ellis L.M., Liu W., et al. Vascular endothelial growth factor (VEGF) expression and alternate splicing in non-metastatic and metastatic human colon cancer cell lines./Proc. Am. Assoc. Cancer Res., 1995; 36: 88a
13. Eroglu A., Demirci S., Ayyildiz A., et al. Serum concentrations of vascular en-dothelial growth factor and nitrite as an estimate of in vivo nitric oxide in pa-tients with gastric cancer. Br J Cancer 80:1630-1634, 1999.
Academic Research in Educational Sciences VOLUME 2 | ISSUE 12 | 2021
ISSN: 2181-1385
Scientific Journal Impact Factor (SJIF) 2021: 5.723 Directory Indexing of International Research Journals-CiteFactor 2020-21: 0.89
DOI: 10.24412/2181-1385-2021-12-1434-1440
14. Ferrara N., Alitalo K., et al. Clinical applications of angiogenic growth factors and their inhibitors./Nat. Med., 1999; 5: 1359-1364.
15. Ferrara N., et al. Vascular endothelial growth factor: molecular and biological aspects./ Curr. Top. Microbiol., Immunol., 1999; 237: 1-30.
16. Ferrara N., Henzel W., et al. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells./ Biochem. Bio-phys. Res. Comraun., 1989; 161: 851-858.
17. Findlay M, Cunningham D, Norman A et al. A phase II study in advanced gastroesophageal cancer using epirubicin and cisplatin in combination with con-tinuous infusion 5-fluorouracil (ECF). Arm Oncol 1994; 5: 609-616.
18. Folkman J., et al. Tumor angiogenesis: therapeutic implications./ N. Eng. J. Med., 1971;285:1182-1186.
19. Fukushimai M., Morita M. et al Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. International journal of molecular medicine 12: 839-844, 2003.
20. Gadgeel S., Shields A., Heilbrun L., et al. Phase II study of paclitaxel and car-boplatin in patients with advanced gastric cancer. Am J Clin Oncol 2003; 26: 37-41.
21. Grau J, Domingo-Domenech J, Morente V, et al. Low thymidylate synthase expression in the primary tumor predicts favorable clinical outcome in resected gastric cancer patients treated with adjuvant tegafur. Oncology 2004;66:226-33.
