Đánh giá hiệu quả điều trị ung thư phổi không tế bào nhỏ giai đoạn IV bằng phác đồ gemcitabine cisplatin tại bệnh viện phổi trung ương

B GIO DC V O TO B Y T TRNG I HC Y H NI NGUYN THANH DNG ĐáNH GIá KếT QUả ĐIềU TRị UNG THƯ PHổI KHÔNG Tế BàO NHỏ GIAI ĐOạN IV BằNG PHáC Đồ GEMCITABINE & CISPLATIN TạI BệNH VIệN PHổI TRUNG ƯƠNG Chuyờn ngnh : Ung th Mó s : 60720149 LUN VN THC S Y HC Ngi hng dn khoa hc: PGS.TS Lấ TRUNG TH H NI - 2016 LI CM N Vi tt c lũng kớnh trng v s bit n chõn thnh, nhõn dp hon thnh bn lun ny, tụi xin c by t lũng bit n sõu sc nht ti: Ban giỏm hiu, Phũng o to sau i hc, B mụn Ung th Trng i hc Y H Ni Ban giỏm c, Phũng k hoch tng hp Bnh vin PHI TRUNG NG ó giỳp v to mi iu kin thun li cho tụi quỏ trỡnh hc v hon thnh lun ny Tụi xin chõn thnh cm n PGS TS Lấ TRUNG TH, ngi thy trc tip hng dn lun vn, ó tn tỡnh giỳp , ch bo v ng viờn tụi sut quỏ trỡnh nghiờn cu v hon thnh lun Thy dy tụi khụng ch kin thc chuyờn mụn m c o c ngh nghip, phng phỏp lun khoa hc Xin cm n th cỏc Bỏc s v nhõn viờn Khoa Ung bu Bnh vin Phi trung ng ó giỳp tụi quỏ trỡnh hc Xin chõn thnh cm n cụng sinh thnh, dng dc ca cha m;cm n nhng ngi thõn gia ỡnh ó sỏt cỏnh cựng tụi, giỳp , ng viờn v to mi iu kin cho tụi nhng nm hc va qua Tụi xin cm n bn bố, ng nghip ó giỳp , ng viờn tụi cú th hon thnh lun ny H Ni, ngy 10 thỏng 10 nm 2016 NGUYN THANH DNG LI CAM OAN Tụi l NGUYN THANH DNG, hc viờn cao hc khúa 23, chuyờn ngnh Ung th, Trng i hc Y H Ni xin cam oan: õy l lun bn thõn tụi trc tip thc hin di s hng dn ca Thy PGS TS Lấ TRUNG TH Cụng trỡnh ny khụng trựng lp vi bt k nghiờn cu no khỏc ó c cụng b ti Vit Nam Cỏc s liu v thụng tin nghiờn cu l hon ton chớnh xỏc, trung thc v khỏch quan, ó c xỏc nhn v chp nhn ca c s ni nghiờn cu cho phộp ly s liu v xỏc nhn Tụi xin hon ton chu trỏch nhim v nhng cam kt ny H Ni, ngy 10 thỏng 10 nm 2016 Ngi vit cam oan NGUYN THANH DNG CC CH VIT TT ASCO : Hip hi lõm sng ung th quc gia M (American society of clinical oncology) BN : Bnh nhõn CEA : (Carcino Embryonic Antigan ).Khỏng nguyờn biu mụ phụi AJCC : (American Joint Commitee on Cancer ) Hip hi Ung th M CK : Chu k CS : Cng s : ỏp ng G : Giai on ECOG : Liờn hip hi ung th hc phớa ụng (Eastern Cooperative Oncology Group) KPS : Ch s ton trng Karnofski MBH : Mụ bnh hc UICC : U ban phũng chng ung th quc t (Union International Contre la Cancer) UT : Ung th UTBM : Ung th biu mụ UTP : Ung th phi UTPKTBN : Ung th phi khụng t bo nh UTPTBN : Ung th phi t bo nh WHO : T chc Y t th gii (World Health Orgnization) SWOG : Hi ung th hc Tõy nam (Southwest Oncology Group) MC LC T VN CHNG 1: TNG QUAN 1.1 DCH T HC V MT S YU T NGUY C CA UTP 1.1.1 Dch t hc 1.1.2 Mt s yu t nguy c 1.2 TRIU CHNG LM SNG V CN LM SNG 1.2.1 Triu chng lõm sng 1.2.2 Cn lõm sng 10 1.2.3 Chn oỏn xỏc nh 17 1.3 Chn oỏn giai on 17 1.4 CC PHNG PHP IU TR UNG TH PHI 19 1.4.1 iu tr theo giai on 21 1.4.2 iu tr húa cht giai on IIIB-IV 24 1.4.3 Chin lc mi iu tr UTPKTBN 28 1.5 MT S HểA CHT ANG S DNG 29 1.5.1 Gemcitabine 29 1.5.2 Cisplatin 30 CHNG 2: I TNG V PHNG PHP NGHIấN CU 33 2.1 I TNG NGHIấN CU 33 2.1.1 Tiờu chun la chn 33 2.1.2 Tiờu chun loi tr 33 2.2 PHNG PHP NGHIấN CU 34 2.2.1 Thit k nghiờn cu 34 2.2.2 C mu v chn mu 34 2.2.3 Cỏc bin s nghiờn cu 34 2.2.4 Mt s ch tiờu ỏnh giỏ 36 2.2.5 Quy trỡnh tin hnh nghiờn cu 39 2.5 X Lí S LIU 41 2.6 o c nghiờn cu 41 CHNG 3: KT QU NGHIấN CU 44 3.1 MT S C TRNG C NHN I TNG NGHIấN CU 44 3.1.1 Phõn b ngi bnh theo gii 44 3.1.2 Phõn b ngi bnh theo nhúm tui 44 3.1.3 Tỡnh trng hỳt thuc 45 3.2 Triu chng lõm sng 46 3.3 Triu chng cn lõm sng 47 3.4 ỏp ng iu tr 50 3.5 TC DNG KHễNG MONG MUN CA PHC 51 3.6 THI GIAN SNG THấM 52 Chng 4: BN LUN 54 4.1 V PHN B BNH NHN THEO NHểM TUI V GII 54 4.2 TèNH TRNG HT THUC 55 4.3 THI GIAN Cể TRIU CHNG U TIấN N LC NHP VIN 56 4.4 TRIU CHNG LM SNG 57 4.5 CN LM SNG 59 4.6 Mễ BNH HC 60 4.7 KT QU IU TR 60 4.7.1 T l ỏp ng 61 4.7.2 Thi gian sng thờm 61 4.8 TC DNG KHễNG MONG MUN CA HểA TR 63 KT LUN 66 KHUYN NGH 67 TI LIU THAM KHO PH LC DANH MC BNG Bng 1.1 t bin gen UTPKTBN Bng 1.2 Bng phõn loi cỏc typ mụ hc ung th biu mụ phi ca TCYTTG 2014 16 Bng 1.3: ỏnh giỏ giai on bnh 19 Bng 1.4: Mt s th nghim lõm sng so sỏnh phỏc Gemcitabine kt hp Cisplatin hoc Carboplatin vi cỏc phỏc khỏc 27 Bng 3.1 Phõn b ngi bnh theo nhúm tui 44 Bng 3.2 Tỡnh trng hỳt thuc 45 Bng 3.3 Thi gian hỳt thuc 45 Bng 3.4 Lý vo vin 46 Bng 3.5 Thi gian cú triu chng u tiờn n nhp vin 46 Bng 3.6 V trớ u trờn phim CT 48 Bng 3.7 Tỡnh trng di cn hch trung tht 48 Bng 3.8 Hỡnh nh tn thng qua ni soi ph qun 48 Bng 3.9 T l cỏc typ mụ bnh hc 49 Bng 3.10 Phõn b bnh nhõn theo s liu iu tr húa cht 49 Bng 3.11 T l ỏp ng theo typ mụ bnh hc 50 Bng 3.12 Tỏc dng khụng mong mun ca húa cht trờn h to mỏu 51 Bng 3.13 Tỏc dng khụng mong mun ca húa cht ngoi h to mỏu 51 Bng 4.1 So sỏnh vi kt qu th nghim ngu nhiờn ca cỏc tỏc gi 62 DANH MC BIU Biu 1.1 T l mc UTP trờn th gii nm 2012 Biu 1.2 T l t vong UTP trờn th gii nm 2012 Biu 3.1 Phõn b ngi bnh theo gii tớnh 44 Biu 3.3 Phõn b bnh nhõn theo triu chng ton thõn 47 Biu 3.4 T l bnh nhõn sỳt cõn 47 Biu 3.5 T l v trớ u hai phi 47 Biu 3.6 T l ỏp ng iu tr 50 Biu 3.7 Thi gian sng thờm ton b 52 Biu 3.8 Thi gian sng thờm theo tỡnh trng hỳt thuc 52 Biu 3.9 Thi gian sng thờm theo gii 53 Biu 3.10.Thi gian sng thờm theo typ mụ bnh 53 T VN Ung th phi (UTP) l loi ung th ph bin nht trờn ton cu ng thi cng l nguyờn nhõn gõy t vong hng u ung th T l mc ung th phi rt khỏc bit gia cỏc nc v ch cú 15,6% s bnh nhõn sng qua nm k t phỏt hin bnh[2] Theo Globocan 2012, ton th gii cú khong 1,8 triu ngi mi mc UTP v khong 1,6 triu ngi cht vỡ cn bnh ny Vit Nam, cng theo Globocan 2012 nc ta cú 21865 ngi mi mc UTP chim 24.4 % tng s ca mi mc ung th v 19559 ngi cht vỡ UTP chim 21,8% [3] Theo phõn loi ca T chc y t th gii, UTP c chia lm nhúm chớnh l ung th phi khụng t bo nh (UTPKTBN) v ung th phi t bo nh (UTPTBN), ú UTPKTBN chim 80 - 85% [4] [5] UTP l bnh cú ỏc tớnh cao, tin trin nhanh, di cn sm vo nhiu tng nh gan, xng, nóo bi th tiờn lng xu Triu chng lõm sng ca bnh li nghốo nn, khụng c hiu, d nhm ln vi bnh khỏc Do vy dự ó cú nhiu tin b chn oỏn nhng phn ln bnh nhõn (khong 70%) n vin giai on mun, khụng th iu tr bng phu thut Lỳc ny, vic ỏnh giỏ mc lan trn ca bnh la chn phỏc iu tr hp lý l rt quan trng Trong iu tr ung th phi, phu thut l phng phỏp hiu qu nht i vi giai on tn thng cũn khu trỳ lng ngc Húa cht v x tr l nhng phng phỏp c ỏp dng bnh giai on mun hn[2-6] Trc thp k 80, iu tr húa cht cho bnh nhõn UTPKTBN giai on mun rt kộm hiu qu v nhiu tỏc dng ph T khong hn mt thp k nay, s i ca cỏc tỏc nhõn th h th ba nh Taxane, Gemcitabine, Vinorelbine ó m nhiu hy vng kh quan hn iu tr húa cht UTPKTBN giai on IV [7] [8] Sau ú nhiu nghiờn cu phi hp cỏc thuc mi k trờn vi nhúm platin nhanh chúng c tin hnh v hu ht cỏc nghiờn cu u cho thy cỏc phỏc phi hp ny khụng nhng lm tng t l ỏp ng, kộo di thi gian sng thờm m cũn ci thin c cht lng sng v kim soỏt cỏc triu chng ca bnh [8] Gemcitabin l mt húa cht cú hiu qu rừ rt iu tr UTP khụng t bo nh giai on mun, dựng n c hay phi hp vi platin cỏc th nghim lõm sng Do nhng hiu qu v tớnh an ton ó c chng minh qua nhiu th nghim lõm sng, phỏc Gemcitabin Cisplatin ó tr thnh mt nhng phỏc c khuyn cỏo iu tr bc UTPKTBN giai on mun trờn th gii[9] ó cú nhiu nghiờn cu c nc v trờn th gii ỏnh giỏ hiu qu ca phỏc ny vi t l ỏp ng cao, thi gian sng thờm kộo di v tỏc dng ph chp nhn c [10] [11] Ti bnh vin Phi Trung ng, phỏc Gemcitabin - Cisplatin cng ó c s dng iu tr UTPKTBN t nm 2013 nhng cha cú mt nghiờn cu no ỏnh giỏ hiu qu ca phỏc ny Vỡ vy chỳng tụi tin hnh ti ỏnh giỏ hiu qu iu tr ung th phi khụng t bo nh giai on IV bng phỏc Gemcitabine & Cisplatin ti bnh vin Phi Trung ng nhm mc tiờu sau: Nhn xột mt s c im lõm sng, cn lõm sng ca bnh nhõn ung th phi khụng t bo nh giai on IV ti bnh vin Phi Trung ng t 2013 2016 ỏnh giỏ t l ỏp ng, thi gian sng thờm v mt s c tớnh ca phỏc Gemcitabine- Cisplatin 66 KT LUN Da trờn cỏc s liu thu thp c quỏ trỡnh nghiờn cu 73 bnh nhõn UTPKTBN c iu tr bng Gemcitabin phi hp Cisplatin chỳng tụi cú mt s kt lun nh sau: c im lõm sng v cn lõm sng ca UTPKTBN giai on IV - Bnh nhõn UTPKTBN hay gp tui >40, nh cao t 50 69 tui T l nam/n l 3/1 - Triu chng lõm sng thng gp l au ngc v ho kộo di - V trớ u bờn phi nhiu hn so vi bờn trỏi, typ UTBM tuyn cú t l cao nht (49,3%) Kt qu iu tr v c tớnh ca phỏc - Kt qu iu tr UTPKTBN bnh nhõn giai on IV + T l bnh giai on IV cú th trng cũn tt ỏp ng iu tr bng Gemcitabin v cisplatin l 32,9% + ỏp ng hon ton l = 0%, ỏp ng bỏn phn l: 24/73 = 32,9%, bnh n nh l: 18/73 = 24,7%, bnh tin trin l: 31/73 = 42,5% + Thi gian sng thờm trung bỡnh ca bnh nhõn l 11,5 thỏng (95% CI 10,3 12,5 thỏng) T l sng thờm trung bỡnh nm l 41,7% * ỏnh giỏ c tớnh ca phỏc gemcitabin v cisplatin + T l nụn v bun nụn nghiờn cu ch gp mc l: 63% v l: 21% Khụng cú trng hp no d ng + Gim bch cu a nhõn trung tớnh l ph bin chim 26%, ú mc v ch l 2,7% Gim lng Hb mỏu khỏ ph bin (75,4%) + Khụng cú trng hp no cú suy thn, tỡnh trng tng tng men gan mc v l 17,8% 67 KHUYN NGH - Bnh nhõn UTPKTBN giai on IV nu s dng hoỏ tr thỡ mt nhng phỏc nờn la chn l Gemcitabine - Cisplatin vỡ tớnh an ton v hiu qu - Nờn cú thờm cỏc nghiờn cu tin cu vi c mu ln hn, nhiu bin s hn ỏnh giỏ kt qu iu tr chớnh xỏc hn v thy c 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prognosis Mod Pathol, 20, 638-647 59 Lucio Crin, Cesare Calandri, Antonio Maestri et al (2001) Gemcitabine and Cisplatin Combination in Early-Stage Non-Small-Cell Lung Cancer ONCOLOGY, 15(Suppl 6), 40-42 60 Gomez Herrero, Albert Mari A, Merino Sanjuan M Toxicity profile and adherence to the pharmacotherapeutic regimen of gemcitabincarboplatin in non small cell lung cancer, , 61 He Q, Yi T, Zhang L et al Combined chemotheraphy with domestic gemcitabine plus carboplatin in the treatment of advanced non small cell lung cancer, http://www ncbi.nlm.nih.gov/pubmed/21144290/downloads BNH N NGHIấN CU I Phn hnh chớnh S h s: H v tờn: Tui Gii: Nam: N: 2 Ngh nghip: a ch: a ch liờn lc: in thoi liờn lc: Ngy vo vin: Ngy vin: II Thụng tin trc iu tr Lõm sng * Thụng tin chung - Thúi quen hỳt thuc: +Khụng: +C loi: +Thuc lỏ:1 +Tru thuc: +Thuc lo: - S bao:/ ngy S nm: - Lý vo vin: +Ho kộo di: + Khỏihuyt: +au ngc: + Khc m: +Khú th: -Thi gian xut hin triu chng u tiờn n nhp vin: < thỏng: 3-6 thỏng: > thỏng: * 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Liu iu tr >85% - Liu Gemcitabin Carboplatin Ngy bt u iu tr Kt thỳc t ngy S chu k thc hin Ngng iu trLý S ngy ngng ỏp ng iu tr ỏp ng hon ton ỏp ng mt phn Bnh n nh Tin trin