. . . . . . . . . . . . . . "5.1 \tFarmakodynamick\u00E9 vlastnosti"@cs . . . . . . "005.001" . . "Farmakoterapeutick\u00E1 skupina: jin\u00E1 cytostatika, slou\u010Deniny platiny\nATC k\u00F3d: L01XA03\nOxaliplatina je antineoplastick\u00E1 l\u00E9\u010Div\u00E1 l\u00E1tka z nov\u00E9 skupiny platinov\u00FDch deriv\u00E1t\u016F, kde je atom platiny v\u00E1z\u00E1n v komplexu s 1,2-diaminocyklohexanem (\u201EDACH\u201C) a oxal\u00E1tovou skupinou. Oxaliplatina tvo\u0159\u00ED jedin\u00FD enantiomer, (SP-4-2)-[(1R,2R)-cyklohexan-1,2-diamin-kN,kN\u00B4] [ethanedioato(2-)-kO1,kO2] platinu.\uF020\nOxaliplatina vykazuje \u0161irok\u00E9 spektrum jak in vitro cytotoxicity, tak in vivo protin\u00E1dorov\u00E9 aktivity na r\u016Fzn\u00FDch n\u00E1dorov\u00FDch modelov\u00FDch syst\u00E9mech, v\u010Detn\u011B model\u016F kolorekt\u00E1ln\u00EDho karcinomu u lid\u00ED. Oxaliplatina rovn\u011B\u017E p\u016Fsob\u00ED in vitro a in vivo v\u00A0r\u016Fzn\u00FDch modelov\u00FDch syst\u00E9mech rezistentn\u00EDch na cisplatinu.\nV kombinaci s\u00A05-fluorouracilem (5-FU) bylo pozorov\u00E1no synergick\u00E9 cytotoxick\u00E9 p\u016Fsoben\u00ED jak in vitro , tak in vivo .\nStudie mechanismu p\u016Fsoben\u00ED oxaliplatiny, kter\u00FD nen\u00ED je\u0161t\u011B zcela objasn\u011Bn, podporuj\u00ED hypot\u00E9zu, \u017Ee hydratovan\u00FD metabolit oxaliplatiny vstupuje do interakce s DNA a doch\u00E1z\u00ED tak k tvorb\u011B intra- a inter- m\u016Fstk\u016F mezi vl\u00E1kny DNA, co\u017E vede k\u00A0ukon\u010Den\u00ED synt\u00E9zy DNA. V\u00FDsledkem je cytotoxick\u00FD a protin\u00E1dorov\u00FD efekt.\nU pacient\u016F s\u00A0metastazuj\u00EDc\u00EDm karcinomem tlust\u00E9ho st\u0159eva je \u00FA\u010Dinnost oxaliplatiny (85 mg/m2 opakovan\u011B ka\u017Ed\u00E9 dva t\u00FDdny) v\u00A0kombinaci s\u00A05-fluorouracilem (5-FU)/kyselinou folinovou (FA) prok\u00E1z\u00E1na ve t\u0159ech klinick\u00FDch studi\u00EDch:\nV prvn\u00ED linii l\u00E9\u010Dby dvouramenn\u00E1 srovn\u00E1vac\u00ED studie f\u00E1ze III EFC2962 randomizovala 420 pacient\u016F do skupiny l\u00E9\u010Den\u00E9: 5-fluorouracilem (5-FU)/kyselinou folinovou (FA) samostatn\u011B (LV5FU2, N=210) nebo kombinac\u00ED oxaliplatina +5-fluorouracil (5-FU)/kyselina folinov\u00E1 (FA) (FOLFOX4, N=210).\nU p\u0159edl\u00E9\u010Den\u00FDch pacient\u016F srovn\u00E1vac\u00ED t\u0159\u00EDramenn\u00E1 studie f\u00E1ze III EFC4584 randomizovala 821 pacient\u016F refraktern\u00EDch k irinotekanu (CPT-11) + 5-fluorouracil (5-FU)/kyselina folinov\u00E1 (FA) do kombinac\u00ED bu\u010F 5-fluorouracil (5-FU)/kyselina folinov\u00E1 (FA) samostatn\u011B (LV5FU2, N=275), oxaliplatina v\u00A0monoterapii (N=275) nebo kombinace oxaliplatiny s 5-fluorouracilem (5-FU)/kyselinou folinovou (FA) (FOLFOX4, N=271).\nZ\u00E1v\u011Brem, nekontrolovan\u00E1 studie f\u00E1ze II EFC2964 zahrnula pacienty refraktern\u00ED k 5-fluorouracilu (5-FU)/kyselin\u011B folinov\u00E9 (FA) samostatn\u011B. Pacienti byli l\u00E9\u010Deni oxaliplatinou s 5-fluorouracilem (5-FU)/kyselinou folinovou (FA) (FOLFOX4, N=57).\nUveden\u00E9 dv\u011B randomizovan\u00E9 klinick\u00E9 studie, EFC2962 v\u00A0l\u00E9\u010Db\u011B prvn\u00ED linie a EFC4584 u ji\u017E l\u00E9\u010Den\u00FDch pacient\u016F, demonstrovaly v\u00FDznamn\u011B vy\u0161\u0161\u00ED l\u00E9\u010Debnou odpov\u011B\u010F a prodlou\u017Een\u00ED doby p\u0159e\u017E\u00EDv\u00E1n\u00ED bez progrese (PFS)/doby do progrese (TTP) ve srovn\u00E1n\u00ED s\u00A0l\u00E9\u010Dbou samotn\u00FDm 5-fluorouracilem (5-FU)/kyselinou folinovou (FA).\nVe studii EFC4584 proveden\u00E9 u p\u0159edl\u00E9\u010Den\u00FDch refraktern\u00EDch pacient\u016F rozd\u00EDl v\u00A0medi\u00E1nu celkov\u00E9ho p\u0159e\u017Eit\u00ED (OS) mezi kombinac\u00ED oxaliplatiny a 5-fluorouracil (5-FU)/kyselina folinov\u00E1 (FA) nedos\u00E1hl statistick\u00E9 v\u00FDznamnosti.\nOdpov\u011B\u010F na l\u00E9\u010Dbu u FOLFOX4 versus LV5FU2\n\tOdpov\u011B\u010F na l\u00E9\u010Dbu, % \uFFFD(95% CI)\nnez\u00E1visl\u00E9 radiologick\u00E9 p\u0159ezkoum\u00E1n\u00ED \nanal\u00FDza ITT \n\tLV5FU2\n\tFOLFOX4\n\tOxaliplatina samostatn\u011B\n\tPrvn\u00ED linie\nEFC2962\nP\u0159ezkoum\u00E1n\u00ED odpov\u011Bdi na l\u00E9\u010Dbu ka\u017Ed\u00FDch 8 t\u00FDdn\u016F\n\t22\n(16-27)\n\t49\n(42-56)\n\tNA*\n\t\n\thodnota p=0,0001\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC4584\n(refraktern\u00ED k CPT-11 + 5-FU/FA)\nP\u0159ezkoum\u00E1n\u00ED odpov\u011Bdi na l\u00E9\u010Dbu ka\u017Ed\u00FDch 6 t\u00FDdn\u016F\n\t0,7\n(0,0-2,7)\n\t11,1\n(7,6-15,5)\n\t1,1\n(0,2-3,2)\n\t\n\thodnota p\uF020< 0,0001\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC2964\n(refraktern\u00ED \nk 5-FU/FA)\nP\u0159ezkoum\u00E1n\u00ED odpov\u011Bdi na l\u00E9\u010Dbu ka\u017Ed\u00FDch 12 t\u00FDdn\u016F\n\t\nNA*\n\t\n23\n(13-36)\n\t\nNA*\nNA = neaplikovateln\u00E9\nMedi\u00E1n obdob\u00ED p\u0159e\u017Eit\u00ED bez progrese (PFS)/Medi\u00E1n doby do progrese (TTP)\nFOLFOX4 versus LV5FU2\n\tMedi\u00E1n PFS/TTP, m\u011Bs\u00EDce \uFFFD(95% CI)\nnez\u00E1visl\u00E9 radiologick\u00E9 p\u0159ezkoum\u00E1n\u00ED anal\u00FDzou ITT\n\tLV5FU2\n\tFOLFOX4\n\tOxaliplatina samostatn\u011B\n\tPrvn\u00ED linie\nEFC2962 (PFS)\n\t6,0\n(5,5-6,5)\n\t8,2\n(7,2-8,8)\n\tNA*\n\t\n\tLog-rank hodnota p=0,0003\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC4584 (TTP)\n(refraktern\u00ED k CPT-11 + 5-FU/FA)\n\t2,6\n(1,8-2,9)\n\t5,3\n(4,7-6,1)\n\t2,1\n(1,6-2,7)\n\t\n\tLog-rank hodnota p=0,0001\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC2964\n(refraktern\u00ED \nk 5-FU/FA)\n\t\nNA*\n\t\n5,1\n(3,1-5,7)\n\t\nNA*\n*NA = neaplikovateln\u00E9\nMedi\u00E1n celkov\u00E9 doby p\u0159e\u017Eit\u00ED (OS) u FOLFOX4 versus LV5FU2\n\tMedi\u00E1n OS, m\u011Bs\u00EDce \uFFFD(95% CI)\nITT anal\u00FDza\n\tLV5FU2\n\tFOLFOX4\n\tOxaliplatina samostatn\u011B\n\tPrvn\u00ED linie\nEFC2962\n\t14,7\n(13-18,2)\n\t16,2\n(14,7-18,2)\n\tNA*\n\t\n\tLog-rank hodnota p=0,12\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC4584*\n(refraktern\u00ED k CPT-11 + 5-FU/FA)\n\t8,8\n(7,3-9,3)\n\t9,9\n(9,1-10,5)\n\t8.1\n(7.2-8.7)\n\t\n\tLog-rank hodnota p=0,09\n\t\n\tP\u0159edl\u00E9\u010Den\u00ED pacienti\nEFC2964\n(refraktern\u00ED \nk 5-FU/FA)\n\t\nNA*\n\t\n10,8\n(9,3-12,8)\n\t\nNA*\n*NA = neaplikovateln\u00E9\nU p\u0159edl\u00E9\u010Den\u00FDch pacient\u016F (EFC4584), kte\u0159\u00ED byli na po\u010D\u00E1tku studie symptomati\u010Dt\u00ED, vykazovala v\u00FDznamn\u00E9 zlep\u0161en\u00ED symptom\u016F v\u011Bt\u0161\u00ED \u010D\u00E1st l\u00E9\u010Den\u00E1 oxaliplatinou/5-fluorouracilem (5-FU)/kyselinou folinovou (FA), ve srovn\u00E1n\u00ED s\u00A0pacienty l\u00E9\u010Den\u00FDmi 5-fluorouracilem (5-FU)/kyselinou folinovou (FA) samostatn\u011B (27,7% vs. 14,6%, p<0,0033). U dosud nel\u00E9\u010Den\u00FDch pacient\u016F (EFC2962) nebyl nalezen \u017E\u00E1dn\u00FD statistick\u00FD rozd\u00EDl mezi dv\u011Bma l\u00E9\u010Den\u00FDmi skupinami v\u00A0hodnocen\u00ED v\u0161ech aspekt\u016F kvality \u017Eivota. Nicm\u00E9n\u011B sk\u00F3re kvality \u017Eivota bylo obecn\u011B lep\u0161\u00ED v\u00A0kontroln\u00EDm rameni v\u00A0hodnocen\u00ED celkov\u00E9ho pocitu zdrav\u00ED a bolesti a hor\u0161\u00ED pro nauzeu a zvracen\u00ED v\u00A0rameni oxaliplatiny. \nV\u00A0adjuvantn\u00ED l\u00E9\u010Db\u011B bylo ve srovn\u00E1vac\u00ED studii MOSAIC f\u00E1ze III (EFC3313) randomizov\u00E1no 2246 pacient\u016F (899 stadium II Duke B2 a 1347 stadium III Duke C) po kompletn\u00ED resekci prim\u00E1rn\u00EDho n\u00E1doru tlust\u00E9ho st\u0159eva do skupiny l\u00E9\u010Den\u00E9 bu\u010F 5 FU/FA samostatn\u011B (LV5FU2 N=1123, B2/C=448/675) nebo kombinac\u00ED oxaliplatiny a 5 FU/FA (FOLFOX 4 N=1123, B2/C=451/672).\nEFC 3313, 3-let\u00E9 bezp\u0159\u00EDznakov\u00E9 p\u0159e\u017Eit\u00ED (ITT anal\u00FDza)* \uFFFDpro celkovou populaci\n\tL\u00E9\u010Debn\u00E9 rameno\n\tLV5FU2\n\tFOLFOX4\n\tProcento 3-let\u00E9ho bezp\u0159\u00EDznakov\u00E9ho p\u0159e\u017Eit\u00ED (95% CI)\n\t73,3\n(70,6 \u2013 75,9)\n\t78,7\n(76,2 \u2013 81,1)\n\tPom\u011Br rizika (95% CI)\n\t0,76\n(0,64 \u2013 0,89)\n\tStratifikovan\u00FD log-rang test\n\tP = 0,0008\n* medi\u00E1n sledov\u00E1n\u00ED 44,2 m\u011Bs\u00EDc\u016F (v\u0161ichni pacienti sledov\u00E1ni minim\u00E1ln\u011B 3 roky)\nStudie demonstrovala celkov\u011B v\u00FDznamnou v\u00FDhodu v\u00A0p\u0159e\u017Eit\u00ED po 3 letech onemocn\u011Bn\u00ED pro kombinaci oxaliplatiny a 5 FU/FA (FOLFOX 4) oproti 5 FU/FA samostatn\u011B (LV5FU2).\nEFC 3313 3-let\u00E9 bezp\u0159\u00EDznakov\u00E9 p\u0159e\u017Eit\u00ED (ITT anal\u00FDza)* \uFFFDpodle st\u00E1dia onemocn\u011Bn\u00ED\n\tSt\u00E1dium onemocn\u011Bn\u00ED\n\tSt\u00E1dium II\n(Duke B2)\n\tSt\u00E1dium III\n(Duke C)\n\tL\u00E9\u010Debn\u00E9 rameno\n\tLV5FU2\n\tFOLFOX4\n\tLV5FU2\n\tFOLFOX4\n\tProcento 3-let\u00E9ho bezp\u0159\u00EDznakov\u00E9ho p\u0159e\u017Eit\u00ED (95% CI)\n\t84,3\n(80,9 \u2013 87,7)\n\t87,4\n(84,3 \u2013 90,5)\n\t65,8\n(62,2 \u2013 69,5)\n\t72,8\n(69,4 \u2013 76,2)\n\tPom\u011Br rizika (95% CI)\n\t0,79\n(0,57 \u2013 1,09)\n\t0,75\n(0,62 \u2013 0,90)\n\tLog-rank test\n\tP = 0,151\n\tP = 0,002\n* medi\u00E1n sledov\u00E1n\u00ED 44,2 m\u011Bs\u00EDce (v\u0161ichni pacienti sledov\u00E1ni minim\u00E1ln\u011B 3 roky)\nCelkov\u00E1 doba p\u0159e\u017Eit\u00ED (ITT anal\u00FDza)\nV\u00A0\u010Dase anal\u00FDzy 3-let\u00E9ho bezp\u0159\u00EDznakov\u00E9ho p\u0159e\u017Eit\u00ED, co\u017E bylo prim\u00E1rn\u00EDm c\u00EDlem studie MOSAIC, bylo v\u00A0rameni FOLFOX 4 85,1% pacient\u016F na\u017Eivu, versus 83,8% v\u00A0rameni LV5FU2. To je hodnoceno jako celkov\u00E9 sn\u00ED\u017Een\u00ED rizika mortality o 10% ve prosp\u011Bch re\u017Eimu FOLFOX 4, nedosahuj\u00EDc\u00ED statistickou v\u00FDznamnost (pom\u011Br rizika = 0,90).\nU podskupiny nemocn\u00FDch ve stadiu II (Duke B) byly v\u00FDsledky 92,2% proti 92,4 % (pom\u011Br rizika = 1,01) a u podskupiny ve stadiu III (Duke C) 80,4% proti 78,1% (pom\u011Br rizika = 0,87), pro FOLFOX4 a LV5FU2.\nOxaliplatina pod\u00E1van\u00E1 v monoterapii byla hodnocena u pediatrick\u00E9 populace ve dvou studi\u00EDch f\u00E1ze I (69 pacient\u016F) a ve dvou studi\u00EDch f\u00E1ze II (166 pacient\u016F). Celkem bylo l\u00E9\u010Deno 235 d\u011Btsk\u00FDch pacient\u016F (ve v\u011Bku 7 m\u011Bs\u00EDc\u016F a\u017E 22 let) se solidn\u00EDmi n\u00E1dory. \u00DA\u010Dinnost oxaliplatiny v monoterapii v\u00A0l\u00E9\u010Den\u00E9 pediatrick\u00E9 populaci nebyla prok\u00E1z\u00E1na. N\u00E1bor v\u00A0obou studi\u00EDch f\u00E1ze II byl zastaven z\u00A0d\u016Fvodu nedostate\u010Dn\u00E9 l\u00E9\u010Debn\u00E9 odpov\u011Bdi. \n"@cs . . . . . . . . . . . .