Umdlavuza wamaphaphu ongewona omncane kanye ne-brain metastasis
Phambilini, ama-metastases obuchopho obungewona amangqamuzana amaphaphu (NSCLC) ayenokubikezelwa okubi, nesikhathi sokusinda esiyizinyanga eziyi-7. Kodwa ukuguqulwa okuqondene nesimila kubangele igagasi lokwelapha okuhlosiwe kulawa ma-metastases obuchopho futhi kungathuthukisa isikhathi sokusinda sisonke. Ukuhlelwa kabusha kwe-ALK kungabonwa cishe ku-2%–7% we-NSCLC, ngakho-ke sekuyimpokophelo yokwelapha ye-NSCLC ethuthukisiwe. Osolwazi uZhang Isabella kanye noLu Bo base-United States basanda kushicilela isibuyekezo esihlobene ku-The Lancetonology, manje esethulwa kanje:.
I-Crizotinib ingeyokuqala evunyelwe i-anti-ALK tyrosine kinase inhibitor ngemva kokubonisa imiphumela emihle kakhulu ebanzi, kodwa lo mphumela awuzange uhunyushwe ekulawuleni izilonda ze-intracranial. I-central nervous system (CNS) iyindawo evamile yokubandakanyeka ekuqhubekeleni phambili kwesifo. Iziguli ezifika ku-60% zizobhekana ne-metastasis kule sayithi ngesikhathi sokwelashwa nge-crizotinib: lokhu kungenxa yokungenwa kahle kwe-intracranial yomuthi kanye nokumelana ngokwemvelo kwendlela yesimila.
I-ALK inhibitors yesizukulwane sesibili inokulawula okungcono kwezilonda ze-intracranial, kodwa azihambisani, okudinga ukuthi sihlole ezinye izindlela zokwelapha. Lesi sihloko siwukubuyekezwa kwendima ye-ALK ku-CNS metastasis, ukwelashwa okuhlosiwe kwe-ALK yezilonda ze-intracranial, nokumelana nokwelashwa kwamanje.
Indima yesithiyo segazi-ubuchopho
Umgoqo wegazi nobuchopho uvikela ubuchopho ekungeneni kwezinto ezinobuthi, kodwa futhi wenza kube nzima ukuthi imithi yesistimu ifinyelele ku-parenchyma yobuchopho. Ngokombono wokuvimbela, umgoqo wegazi-ubuchopho unezici eziningana: isibonelo, uxhumano oluqinile oluqhubekayo phakathi kwamangqamuzana e-endothelial kanye nesakhiwo esisekela esiyinkimbinkimbi esihlanganisa ama-pericytes nama-astrocyte angalawula umgoqo wegazi-ubuchopho ngokusebenzisa i-paracrine Permeability; ukumelana okuphezulu, izikhathi ezingaba ngu-100 kunama-capillaries e-peripheral, ngokukhetha ukuvimbela ama-molecule e-polar.
Ingxenye yokwelashwa okuhlelekile okweqa umgoqo wegazi nobuchopho ixoshwa abathuthi be-efflux. Izithuthi ezivame kakhulu ze-efflux yi-P-glycoprotein, i-multidrug resistance protein 1-6, i-ABCG2.
Endabeni ye-metastasis, ubuqotho bomgoqo wegazi-ubuchopho buyaphazamiseka. Ngalesi sikhathi, ukwakheka kwemithambo ekhona kufana nesakhiwo semithambo yezicubu eziphuma isimila, kanti ukuhlangana okuqinile okulimele kubonakala kuwumthambo okwazi ukungena kalula. Amasu okukhulisa ukungeneka komgoqo wegazi nobuchopho ahlanganisa ukucekela phansi umgoqo wawo kusetshenziswa i-radiotherapy, ama-hypertonic agents, i-high-intensity beam ultrasound, nama-bradykinin analogs.
Izinhlelo eziqondiswe kakhulu ezihlobene nama-ALK inhibitors zinganqanda umuthi ukuthi ungaphumi futhi uwuthuthele ngokuphumelelayo ku-parenchyma yobuchopho namaseli wesimila.
Ukuhlelwa kabusha kwe-ALK
Ukudluliselwa okuhlobene nofuzo kwe-ALK kungatholakala cishe ku-2-7% we-NSCLC, okuvamile ukudluliselwa kwe-EML4-ALK. Ukuhlelwa kabusha kuholela ku-autophosphorylation kanye nokusebenza okuqhubekayo kwe-ALK, ngaleyo ndlela kusebenze i-RAS kanye ne-PI3K yokusayina i-cascade (bona inset). Ukwenza kusebenze i-RAS kungase kubangele izici zesimila ezinolaka kakhulu kanye nokubikezelwa komtholampilo okubi kakhulu.
Ukuhlelwa kabusha kwe-ALK kwendlela yokwelapha ehloselwe umdlavuza wamaphaphu ongewona omncane. Ingaqondisa ngokuqondile amaprotheni okuhlelwa kabusha kwe-ALK (afana ne-LDK378, X396, CH5424802); ngaphezu kwalokho, ingabhekisa ama-effectors akhuphukayo (afana ne-EGFR), noma izindlela eziya phansi (njenge-PLC, JAK-STAT, KRAS-MEK-ERK, AKT-mTOR- Aurora A kinase) ukuvimbela ukuqhubeka komjikelezo wamaseli, ukusinda, ukwanda, kanye ne-vascularization; ingakhomba ukulungiswa kwe-DNA; ingase futhi iqondise ukwakheka kwamaprotheni akhuthaza ukukhula kwamangqamuzana (isb, EGFR ligands, VEGF).
Ngokufanayo neziguli ezinokuguqulwa kwe-EGFR, iziguli ezinokuhlelwa kabusha kwe-ALK zingase zibe zincane, zibheme kancane noma zingabhemi kuneziguli zohlobo lwasendle, futhi cishe zonke ziyi-adenocarcinoma-type NSCLC.
Ucwaningo oluningana luhlole ukubaluleka kokubikezelwa kokuhlelwa kabusha kwe-ALK ku-NSCLC, kodwa imiphumela ixubile. Ucwaningo luye lwabonisa ukuthi i-ALK ehlelwe kabusha i-NSCLC iphinda kabili ingozi yokuqhubeka kwesifo noma ukuphindaphinda eminyakeni engu-5, futhi ikhuthaza ama-metastases amaningi. Iziguli ezinokuhlelwa kabusha kwe-ALK ziba nama-metastase amaningi lapho zitholwa, futhi ingozi yokumetastasis ku-pericardium, pleura, nesibindi inkulu. Kukhona futhi izifundo ezithi ukuhlelwa kabusha kwe-ALK kanye neziguli zohlobo lwasendle ziyefana ngokubuyela emuva, ukusinda okungenazifo, nokusinda sekukonke; kukhona futhi izifundo ezibonisa ukuthi ukuhlelwa kabusha kwe-ALK kuthuthukisa ukusinda okuphelele ezigulini ze-NSCLC zesigaba I-III.
Ngokuqondene nokuthi ukuhlela kabusha kwe-ALK i-NSCLC kungenzeka yini ukuthi idluliselwe ebuchosheni, idatha iyahlukahluka kakhulu. Ucwaningo luthole ukuthi u-3% weziguli ezine-metastasis yobuchopho ye-NSCLC zingabona ukudluliselwa kwe-ALK futhi u-11% ungabona ukukhuliswa. Lolu cwaningo lubonisa ukuthi inombolo yekhophi ye-ALK yofuzo ku-metastasis ivame ukwanda, okungenzeka kube ngenxa yenzuzo ekhethiwe yamaseli we-ALK translocation tumor ngesikhathi se-metastasis.
Indima ye-crizotinib ku-metastasis yobuchopho
I-Pfizer's crizotinib inhibitor encane ye-molecule egunyazwe i-US Food and Drug Administration (FDA) ye-ALK yokuhlela kabusha i-NSCLC, eqondise ku-ALK, MET kanye ne-ROS tyrosine kinases. Ngokuvimbela i-ALK ne-MET tyrosine kinases, i-crizotinib ingavimbela i-tyrosine phosphorylation ye-ALK ecushiwe.
Ucwaningo oluningi oluhlanganisa ukuqhathanisa i-crizotinib nemithi ejwayelekile yokwelapha ngamakhemikhali ezigulini ezine-ALK ehlelwe kabusha ye-NSCLC ethuthukile ibonise ukuthi eyokuqala inokusinda okungcono ngaphandle kokuqhubekela phambili, ukusebenza kahle kwesimila, kanye nezinga lempilo lilonke. Olunye ucwaningo luye lwabonisa ukuthi inani eliphelele lenhloso elisebenzayo le-intracranial kanye nezinga lokulawula izifo ze-crizotinib emasontweni angu-12 lalingu-18% no-56%, ngokulandelana; isikhathi esimaphakathi sokuqhubekela phambili kwe-intracranial ngemva kokusetshenziswa kwalesi sidakamizwa ezigulini ezingalashwa ngaphambilini kwakuyizinyanga eziyi-7. Ukulawulwa kwezilonda ze-intracranial emasontweni angu-12 kwakuseduze nalokho kwezilonda zesistimu.
Ukusebenza kahle kanye nobude besikhathi sokulawula iziguli ezake zenziwa i-intracranial radiotherapy kuye kwaba ngcono. Isilinganiso esisebenzayo sokungena ngaphakathi kwengqondo sasingu-33%, izinga lokulawula isifo emasontweni ayi-12 lalingu-62%, kanti isikhathi esimaphakathi sokuqhubekela phambili kwakuyizinyanga eziyi-13.2. Kubalulekile ukuthi iziguli eziqhubeka nokusebenzisa i-crizotinib ziye zathuthuka, kodwa isikhathi sabo sokuphila sonke side kunalabo abangazange baqhubeke nokusebenzisa umuthi ngesikhathi sokuqhubeka.
Muva nje, i-crizotinib njengesivivinyo sokuqala sesigaba sesi-3 sokwelashwa sasihlanganisa iziguli ze-79 ezazike zathola ukwelashwa nge-radiotherapy ngenxa ye-metastases yobuchopho futhi zathola ukuthi isikhathi esimaphakathi sokuqhubekela phambili kwe-intracranial sasilingana neqembu le-chemotherapy. Iphuzu elibalulekile lalolu cwaningo ukuthi zonke iziguli zelashwa nge-radiotherapy kuqala, futhi ucwaningo lwangaphambilini lwe-PROFILE lubonise ukuthi i-radiotherapy ingathuthukisa ukusebenza kahle futhi ngakho-ke igcizelele ngokweqile umphumela we-intracranial obangelwa i-crizotinib yodwa.
Ulwazi oluhlobene mayelana ne-ALK yokuhlela kabusha imetastase yobuchopho ivela emibikweni yamacala kanye nokuhlaziywa kweqembu elingaphansi kokuhlolwa komtholampilo. Lapho uhlaziya le datha, kubalulekile ukwahlulela izici zeziguli njengoba kuchazwe embikweni wecala, ngoba izifundo eziningi ziye zafaka amacala ahlukahlukene ngaphandle kokuhlukaniswa: ama-metastases anezimpawu kanye ne-asymptomatic, ukwelashwa kwangaphambili Ukwelashwa Okuningi okufana ne-radiotherapy, imithi ehlukene, kanye ukulandelwa okuhlukile. Ocwaningweni lwe-ALK inhibitors yesizukulwane sesibili, kuyadingeka futhi ukuhlukanisa ukuthi i-crizotinib ike yasetshenziswa yini ngaphambili.
Idatha ibonisa ukuthi ukusebenza kwe-intracranial kwe-crizotinib kuyehluka. Iziguli eziningi zibonisa ukuxolelwa okuphelele kwezilonda ze-extracranial, kodwa izimila ze-CNS ziye zathuthuka, ngakho-ke zidinga ukwelashwa ngamakhemikhali noma zicabangele ukwelashwa.
se yezidakamizwa zesizukulwane sesibili.
Nakuba i-crizotinib ngokuvamile isebenza kahle, iziguli eziningi ezine-NSCLC ehlelwe kabusha yi-ALK zisazoba nama-metastases noma ukuqhubeka phakathi nokwelashwa. Ucwaningo lwangaphambili lubonise ukuthi i-CNS iyindawo eyinhloko yokwehluleka ukwelashwa ngesikhathi sokwelashwa nge-crizotinib cishe engxenyeni yeziguli. Ucwaningo lwakamuva lubonise ukuthi ukwehluleka kokwelashwa kwe-CNS kubonakala ku-70% yeziguli! Lokhu kungenxa yokungafinyeleleki kahle kwe-CNS ye-CNS ye-crizotinib, kodwa futhi ngenxa yokusabalaliswa okulinganiselwe kwe-passive kanye nokumpompa okusebenzayo kwe-P-glycoprotein.
Ucwaningo lunqume ukugcwala komuthi ku-cerebrospinal fluid ngesikhathi sokwelashwa kwe-crizotinib ezigulini ezinomdlavuza wamaphaphu ohlelwe kabusha we-ALK: 0.617 ng/mL, kuyilapho ukugxila ku-serum kungu-237 ng/mL. Incazelo yokuqhubeka kwezilonda ezisekelwe ku-CNS ukuthi inqubo ye-metastasis inolaka kune-tumor eyinhloko, noma ukuguqulwa kwesizinda se-crizotinib-binding.
Indima yesizukulwane sesibili se-ALK inhibitors ku-metastasis yobuchopho
I-Novartis's ceritinib iyisizukulwane sesibili se-ALK-specific tyrosine kinase inhibitor egunyazwe yi-FDA, futhi ihlose futhi i-IGF-1R, i-insulin receptor kanye ne-ROS1. Ngezinye izindlela, i-ceritinib ivimbela i-ALK autophosphorylation kanye nendlela engezansi ye-STAT3. Ocwaningweni lwesigaba 1, izinga elisebenzayo leziguli ezingenayo i-crizotinib lalingama-62%. Ngokubheka lokhu, izifundo ezimbili zesigaba sesi-2 ziyathuthukiswa futhi ziyaqaliswa.
I-alectinib kaRoche isivele ikutholile imvume ye-FDA ngenqubekelaphambili yayo ekwelashweni. Ucwaningo luye lwathola ukuthi ezigulini ezine-ALK ehlelwe kabusha i-NSCLC engazange yelashwe nge-crizotinib, izinga elisebenzayo le-alectinib lingama-93.5% (amacala angu-43/46), kanti ucwaningo olufanele lwesigaba sesi-3 luyaqhubeka.
Ucwaningo lwe-preclinical pharmacology seluvele lukhombisile ukuthi i-alectinib inokungeneka okungcono kwezidakamizwa ze-CNS kune-crizotinib, futhi ukugcwala kwezidakamizwa ze-CNS zomuthi kungu-63-94% we-serum concentration. Lokhu kungase kube ngenxa yokuthi i-alectinib ihlukile ku-crizotinib ne-ceritinib, i-P glycoprotein ayinawo umthelela kuyo, futhi ayikwazi ukukhishwa ngenkuthalo endaweni ye-intracranial.
Ocwaningweni lweziguli ezimelana ne-crizotinib, iziguli ezingama-21 kwezingu-47 ezifakiwe zazingama-metastase obuchopho asymptomatic noma iziguli ezine-metastase yobuchopho kodwa akukho ukwelashwa, iziguli eziyi-6 zithole ukuxolelwa okuphelele ngemuva kwe-alectinib, i-5 Isiguli esisodwa sathola ukuxolelwa okuyingxenye kanti iziguli eziyisishiyagalombili zinezimila ezizinzile.
Kulolu cwaningo, iziguli ezi-5 zenze ukukalwa koketshezi lwe-cerebrospinal futhi zathola ukuthi kunokuhlobana okuqondile phakathi kwe-serum ne-cerebrospinal fluid ukugxila kwezidakamizwa okungahlanganisiwe. Kucatshangwa ukuthi ukugxila okuphansi kakhulu ku-cerebrospinal fluid kungu-2.69 nmol / L, okudlula ukuhlushwa okuyingxenye ye-ALK inhibitors okubikwe ngaphambilini. Esigabeni sesibili socwaningo, iziguli eziyi-14 ezingazange zithole i-crizotinib zelashwe nge-alectinib, kanti iziguli eziyi-9 zasinda ngaphandle kokuqhubekela phambili isikhathi esingaphezu kwezinyanga eziyi-12.
Okunye ukwelashwa okuyimpumelelo okugunyazwe i-FDA, i-ARIAD Pharmaceuticals' brigatinib ayivimbi i-ALK kuphela, kodwa futhi iqondise i-EGFR ne-ROS1. Ucwaningo ngomuthi lwathola ukuthi iziguli ezingu-16 ezimelana ne-crizotinib zase zine-metastasis ye-intracranial lapho ziqala umuthi, futhi ezi-4 kulezi ziguli ezi-5 zabonisa ukuthwebula izithombe ngemva kokuthatha umuthi. ngempumelelo.
Kunezifundo ezimbalwa ngomsebenzi we-CNS wesizukulwane sokuqala nesesibili se-tyrosine kinase inhibitors, kodwa kunezilingo zesigaba sesi-3 ezimaphakathi eziningi.
Indima ye-ALK Inhibitors ku-Pial Metastasis
Kunezifundo ezimbalwa ze-pial meningeal metastasis ezilonda zokuhlelwa kabusha kwe-ALK ngenxa yokungabi bikho kwesibikezelo esiphelele kanye nobunzima bokulinganisa umphumela wokwelapha. Abanye abantu bafunde izehlakalo eziyi-125 ze-NSCLC pial meningeal metastasis futhi bathola ukuthi ukusinda sekukonke ngemuva kokwelashwa nge-radiotherapy yobuchopho (WBRT) akuzange kube ngcono, kodwa isikhathi sokusinda ngemva kokwelashwa ngamakhemikhali kwe-subarachnoid sasinde.
Ekuhlaziyweni okubuyela emuva kwamacala angu-149 we-NSCLC pial meningeal metastasis, ukusinda okuphelele kweziguli ngemva kwe-subarachnoid chemotherapy, i-EGFR inhibitors, ne-WBRT kwathuthukiswa. Kukhona futhi imibiko embalwa yamacala abonisa ukuthi ezigulini ezine-ALK ehlelwe kabusha i-metastase ye-meningeal metastases, izilonda ezisekhanda ezigulini ezine-crizotinib kanye nokusetshenziswa kwe-subarachnoid ye-methotrexate kuye kwaba ngcono. Kodwa idatha iyindlala futhi akukho siphetho esingenziwa.
Iqhaza lezinye izidakamizwa zesizukulwane sesibili ku-pial meningeal metastasis ayikafinyeleli, kodwa uhlobo lwemithi yokwelapha ngamakhemikhali e-intracranial esetshenziswa njengamanje kanye ne-alectinib noma i-tyrosine kinase inhibitors ibonakala iphumelela kakhulu.
Ukumelana nokumelana ne-tyrosine kinase inhibitor
Iziguli eziningi ze-crizotinib zithole ukumelana, futhi eziningi zenzeka ku-CNS. Umzamo wokuthuthukisa umphumela we-crizotinib we-intracranib ukukhuphuka komthamo. Kwezinye imibiko yesimo, umthamo owodwa we-crizotinib unyusiwe kusuka ku-250 mg kuya ku-1000 mg ohlelweni olujwayelekile; ezinye ziye zahlanganiswa nezinye izidakamizwa ngenkathi kwandisa i-crizotinib ku-600 mg.
Ekusetshenzisweni kokwenyusa umthamo, umphumela uthuthukisiwe ngokwezinga elithile; incazelo yalokhu ukuthi i-crizotinib inomthamo omkhulu, futhi inhlanganisela yezidakamizwa ithuthukisa ukusebenza kwe-ALK rearrangement tumors kwezinye izidakamizwa.
I-ALK inhibitors yesizukulwane sesibili samanje se-seritinib, i-alectinib ne-brigatinib inezinga eliphezulu elisebenzayo lama-58-70%. Ucwaningo luye lwabonisa ukuthi ukuguqulwa okuthile okwenza isizukulwane sesibili se-tyrosine kinase inhibitors ukumelana kungaqondiswa amanye ama-tyrosine kinase inhibitors.
Kunobufakazi bokuthi ukuhlanganiswa kwe-EML4-ALK kuhlobene ne-Hsp90, edlala indima ebalulekile ekukhuleni kwezinhlobo eziningi zamathumba. Ukuhlelwa kabusha kwe-ALK amaseli e-NSCLC, afana ne-ganetespib, i-AUY922, i-retispamycin, i-IPI-504 nezinye izidakamizwa, angabangela i-apoptosis kanye nokuhlehla kwesimila ngokonakala kwe-ALK fusion protein.
Ukwelashwa okuhlangene kwe-crizotinib kanye ne-IPI-504 kungavele kuzuze umphumela ojabulisa kakhulu wokuhlehla kwesimila. Ngaphezu kwalokho, amaseli wesimila amelana ne-crizotinib nawo abonise ukuzwela okuqhubekayo kuma-Hsp90 inhibitors. Njengamanje kunezinhlolo zeSigaba 1 neSigaba sesi-2 ezihlobene.
Ukuze unqobe ukumelana kwe-crizotinib, kukhona futhi nezinhlelo zezindlela ezingezansi zomfula noma ezinye zokuvula. Isibonelo, kukhona izifundo ezihlobene ku-mTOR, PI3K, IGF-1R, njll. Ubuchwepheshe bokulandelana kwesizukulwane esilandelayo kulindeleke ukuthi buthuthukise obunye ubuchwepheshe bokulwa nezidakamizwa kanye nokuhlola okwengeziwe ngokumelene ne-cyclin-dependent kinases, i-aurora kinases nezilawuli ze-epigenetic.
Lungisa ama-ALK inhibitors ukuze uthuthukise ukungeneka kwawo kwe-CNS noma umsebenzi
I-ALK inhibitors yesizukulwane sesibili enezici eziyingqayizivele ingawela umgoqo wegazi-ubuchopho, ngaleyo ndlela ixazulule ngokukhetha inkinga yokwandisa umthamo ngaphakathi kwe-CNS. Kumodeli yegundane, ukufinyeleleka kwe-X-396 ebuchosheni kulingana ne-crizotinib, i-X-396 ngokwethiyori ingase ifinyelele ngaphezu kokuphindwe kane kokugxiliswa kwengxenye ye-inhibitory ku-cerebrospinal fluid, kanye nokugxila kwe-crizotinib ku-cerebrospinal fluid isigamu ukuhlushwa okuyingxenye yokuvimbela! Ukusebenza okukhuphukile kwe-X-396 kungase kuhlanganiswe nama-ion e-hydrogen kanye nomphumela okhuphukile we-intracranial ekugxilweni okufanayo lapho kuhlanganiswa ne-ALK.
I-X-396 okwamanje yenza izivivinyo zomtholampilo ukuze ihlole ukuthi ingabe iyasebenza yini ngokomtholampilo. Isakhiwo sezinye izidakamizwa zesizukulwane sesibili sifana ne-X-396, futhi isilinganiso sokuhlushwa kwe-cerebrospinal fluid-plasma yezidakamizwa sikhuphuke, okuzoba nomthelela ongcono kuma-intracranial tumors.
Ngokwethiyori, kunezindlela zokwandisa ukungena kwe-CNS ngokunciphisa ivolumu yamangqamuzana, ukwandisa ukuncibilika kwamafutha, nokuwalungisa ukuze kugwenywe ukubopha amaprotheni avamile e-efflux kumgoqo wegazi nobuchopho. I-Alectinib inokungeneka okuqinile kwe-CNS ngenxa yokungabopheli kahle ku-P glycoprotein. Esinye isizukulwane sesibili i-ALK inhibitor PF-06463922 yakhelwe ukugwema ukuphuma kwayo esivimbeni segazi nobuchopho kanye nendawo yesimila futhi yandise ngokukhethekile ukungenwa ku-CNS nesimila. Umgomo uthi
ukunciphisa isisindo samangqamuzana, ukwandisa ukuncibilika kwamafutha, Kushintshwe inani lamabhondi e-hydrogen.
Lawula umgoqo wegazi nobuchopho ukuze ukhuphule ukungena
Esinye isixazululo sokwandisa ukugcwala koketshezi lwe-cerebrospinal yesidakamizwa ukukhulisa ukungeneka komgoqo wegazi nobuchopho. Njengoba kushiwo ngaphambili, umgoqo wegazi nobuchopho unendima engenzi lutho futhi esebenzayo: I-P glycoprotein iyisici esiyinhloko esisusa izinto ngenkuthalo. Ngakho-ke, esinye sezixazululo ukuvimbela ukuboshwa kwe-P glycoprotein emthini.
Kumodeli yegundane, ukungezwa kwe-elacridar kungenza ukuhlushwa kwe-crizotinib kwe-intracranial kufike izikhathi ezingu-70 ngemva kwamahora angu-24, futhi ukugxila kwe-plasma kuyinto evamile, okungenzeka kube ngenxa yokugcwala kokumuncwa kwe-intracranial. Njengoba umphumela ohlangene wezidakamizwa muhle, ukuhlolwa kwabantu kufanele kucatshangelwe, futhi kufanele kuqashelwe ocwaningweni kuhlanganiswe ne-ceritinib nezinye izidakamizwa.
Esinye isiqondiso socwaningo sigxile ku-kinin ye-vasoactive, njengokusetshenziswa kwama-kinin analogue ukuze kulawuleke umgoqo wegazi nobuchopho nge-prostaglandin ne-nitric oxide. Ukuhlolwa kwezilwane kubonise ukuthi lolu hlobo lwemithi lungakhuphula ukuthathwa kwe-CNS yomuthi futhi kwandise ukusinda sekukonke. I-kinin ye-Vasoactive ehlanganiswe ne-ALK inhibitors ingakhuphula umzimba we-intracranial, futhi ingacwaningwa ngokwenani ngesampula yoketshezi lwe-cerebrospinal noma ukubikezelwa komtholampilo.
Ukulungiswa kwe-tumor microenvironment
Ubufakazi obunamandla bubonise ukuthi amangqamuzana e-metastatic tumor maningi amathuba okuthi ahlasele imvelo engavamile njengemithambo yegazi, imithambo ye-lymphatic kanye ne-extracellular matrix. Le mvelo encane engajwayelekile ikhulisa ukukhula kwesimila, ukumetastasis, nokumelana nokwelashwa, okubaluleke kakhulu ekuguqukeni kofuzo okuholela kumametastase engeziwe.
Omunye umbono uwukuthi ukujwayela isimo sokuphila kwezicubu ezinempilo kungathuthukisa ukubikezela kwesiguli. Enye yezinhloso eziyinhloko zokujwayelekile ukubhekana nesakhiwo se-vascular disorder. I-vascular perfusion yale mithambo yegazi iyancishiswa, okunciphisa umuthi ukuthi ufinyelele izicubu ezihlosiwe futhi kubangele i-hypoxia yendawo. I-Hypoxia ayikhulisi nje kuphela ukukhula kwesimila kanye nokumetastasis, kodwa futhi kuwuphawu lokuhlasela kwesimila futhi yehlisa imiphumela yokwelashwa okuncike kumoya-mpilo njenge-radiotherapy.
I-VEGF inhibitors isetshenziselwe ukunciphisa i-angiogenesis ephazamisekile futhi ibuyisele i-vascular microenvironment. Kumodeli yegundane ye-glioblastoma, i-VEGF inhibitor bevacizumab yehlisa i-hypoxia futhi ithuthukisa umphumela we-radiotherapy. Lolu hlobo lwenzuzo lungabuye lubonakale ekwelashweni kwe-cytotoxicity lapho imithambo yegazi ijwayelekile, kodwa azikho izifundo ezenziwe ngenhlanganisela ye-ALK ne-VEGF inhibitors.
I-ALK ihlela kabusha indima ye-NSCLC midbrain radiotherapy
Iminyaka yobudala yeziguli ezine-ALK rearrangement tumors iphansi kakhulu, okungenye yezindaba ezibalulekile okufanele zicatshangelwe lapho kwelashwa izilonda ze-intracranial, ngoba iziguli eziningi zisasebenza, zinezingane ezincane, futhi zidinga ukunakekela imindeni yazo. Lokhu kudinga ukuvikelwa kwemisebenzi yengqondo, ikakhulukazi imisebenzi ebalulekile yengqondo.
Ngokutholakala kwe-ALK inhibitors, isikhathi sokusinda salezi ziguli sibalwa eminyakeni, futhi kufanele kubekwe kuqala ekulawuleni isikhathi eside ngemiphumela engemihle yesikhathi eside encane. Iziguli ezine-ALK ehlelwe kabusha i-NSCLC ziye zaphila isikhathi eside ngisho noma zinama-metastases ebuchosheni, okushintsha inhloso yokwelashwa isuke ekudambiseni elula iye ekugcineni izinga lempilo nokusebenza kwengqondo kweziguli.
Ngenxa yesikhathi eside sokusinda, iziguli ezinama-metastase amancane zinconywa ngokuqinile ukuthi zicabangele ukuhlinzwa kwe-stereotactic radiosurgery, ngoba i-WBRT izobhubhisa ukwakheka kwenkumbulo nokukhunjulwa kolwazi. Noma kunjalo, i-metastasis yobuchopho esabalalisiwe isadinga i-WBRT, okungenzeka kube yithuba lokusebenzisa umgoqo owonakele wegazi nobuchopho futhi kanyekanye usebenzise izidakamizwa eziqondiwe ukuze kwandiswe ukugcwala koketshezi lwe-cerebrospinal.
Kukhona idatha embalwa ngemiphumela emibi ye-crizotinib ehlanganiswe ne-radiotherapy. Ngakho-ke, iziguli ezithola i-crizotinib yezilonda ze-intracranial kufanele ziyeke umuthi okungenani usuku olu-1 ngaphambi kwe-radiotherapy. Kwezinye iziguli, i-crizotinib iphinde yasetshenziswa ngemva kokwelashwa nge-radiotherapy ebuchosheni, futhi kwatholakala ukuthi i-crizotinib isasebenza kahle ezilonda ze-extracranial ngemva kwe-radiotherapy, ebuye ihambisane nokungena okuphansi kwe-CNS kwezidakamizwa ngaphambi kwe-radiotherapy.
Ucwaningo luye lwabika ukuthi iziguli ezine-ALK rearrangement metastases yobuchopho zinesikhathi eside kakhulu sokusinda ngemva kwe-radiotherapy kuneziguli ezinohlobo lwasendle lwe-ALK. Lokhu kungase kube ngenxa yokwanda kokungeneka komgoqo wegazi nobuchopho kanye nokuncipha kokubonakaliswa kwe-P-glycoprotein phakathi namasonto okwelashwa nge-radiotherapy. Naphezu kokwanda kwengozi yemiphumela engemihle evela ekwelashweni okuhlangene, kulula ukwenza izifundo zokwelapha ezihlanganisiwe ezinemiphumela engemihle embalwa ye-ALK inhibitors, kanye nokungeneka okuthuthukisiwe ngemva kokwelashwa nge-radiotherapy kungaphinde kuqondiswe futhi.
Iphuzu okufanele ligcizelelwe ukulandelana kokwelashwa okuhlosiwe kanye ne-radiotherapy. Ucwaningo oluhlukahlukene oluhlobene lubonise ukuthi ama-ALK inhibitors angazuza ekusetshenzisweni okuqhubekayo, kodwa akukho ukuqhathaniswa kwama-ALK inhibitors ahlukene. Ucwaningo selukhombisile ukuthi ukusetshenziswa kwe-crizotinib ngemuva kwe-WBRT nakho kungathuthukisa ukulawulwa kwezilonda ezifakwa ngaphakathi. Ekuphetheni, idatha ibonisa ukuthi i-ALK inhibitors inganconywa ngemva kwe-radiotherapy, futhi ingase ithuthukise ukusebenza kwezidakamizwa.
Izinkombandlela nezikhombisi-ndlela zesikhathi esizayo
Ezimeni zokuthuthuka noma i-metastasis yobuchopho, izingxoxo zemikhakha eminingi ezibandakanya i-oncology, i-radiotherapy, i-neurosurgery, njll. zidinga ukucatshangelwa. I-National Comprehensive Cancer Treatment Network incoma ukuthi iziguli ezine-asymptomatic metastases yobuchopho zidinga ukusebenzisa i-crizotinib iyodwa. Ukuze kuqhutshekwe nezilonda ze-intracranial, i-SRS noma i-WBRT kufanele icatshangelwe uma kunezimpawu, kulandele ukusetshenziswa kwe-ALK inhibitors. Uma isilonda singelashwa nge-SRS, kufanele kucatshangelwe ukugwema i-radiotherapy yobuchopho yonke ukuze kungathinti ukusebenza kwengqondo.
Imihlahlandlela incoma ukuthi i-crizotinib noma i-ceritinib isengasetshenziswa ezigulini ezinokuthuthuka okungabonakali. Imibiko yamacala ikhombisa ukuthi ubude besikhathi sokusinda ngaphandle kokuqhubekela phambili siyahluka phakathi kwe-crizotinib ne-radiotherapy ngemuva kokwelashwa nge-radiotherapy. Ukusebenza kwe-ALK inhibitors yesizukulwane sesibili kufanele kukhuthaze odokotela ukuthi basebenzise le mithi njengoba lesi sifo siqhubeka ukuze kuthuthukiswe ukwelashwa kwe-intracranial.
Ngenxa yamathuba aphezulu okuphinda abuyele emkhathini lapho kusetshenziswa ama-ALK inhibitors, ukuhlolwa kwe-MRI kaningi kuyadingeka ngemva kokwelashwa nge-radiotherapy ukuze kuhlolwe ukuqhubeka kwe-metastase. Kuma-metastase alashwe yi-WBRT, kunconywa ukwenza i-MRI njalo ezinyangeni ezi-3. Vele, ukuhlelwa kabusha kwe-ALK kuzozuza kukho.
Uma i-metastasis iqhuma nakakhulu, udokotela kufanele aguqule i-ALK inhibitor esetshenzisiwe, futhi uma izimpawu zivela, kufanele ziphinde zikhishwe; ngokombono wesilinganiso sengozi nenzuzo, basancamela ukuphinda belashwe. Ngezilonda ze-ALK ezihlelwe kabusha ze-intracranial, uma i-radiotherapy kanye ne-ALK inhibitors kuqhubeka, inhlanganisela ye-pemetrexed ibonakala iyinketho engcono kakhulu.
Ukuguqulwa kwama-ALK ama-inhibitors ahlosiwe ukuze kunqobe ukumelana nezidakamizwa okuvamile, kuthuthukise ukungeneka kwayo ku-CNS, futhi kuthuthukise amandla ayo okubopha kanye nomthelela ngemva kokufinyelela okuhlosiwe, ucwaningo olwengeziwe mayelana nalokhu. Esikhathini esizayo esiseduze, ukugcwala kwale mithi ku-CNS kuzoba phezulu futhi kungasetshenziswa ngokulandelana lapho kuvela ukumelana nemithi ngaphakathi kwe-cranial.
Ngokukhula kwamasu atholakalayo okuhlola i-DNA, iziguli zingase zelulekwe ukuba ziphinde ama-biopsies ukuze zihlole indlela yokumelana nomuthi njengoba ziqhubeka, okuzoqondisa ukusetshenziswa komtholampilo kwe-tyrosine kinase inhibitors esebenza kangcono.
Isiphetho
Izinga le-metastasis ebuchosheni layo yonke imidlavuza liyakhula. Enye yezinhlelo zokwandisa ukusebenza kahle ukwenza i-athikili mayelana nokungajwayelekile kofuzo komdlavuza othize, njengokuhlelwa kabusha kwe-ALK. Ezigulini w
I-ALK iphinde yahlelwa umdlavuza wamaphaphu, i-crizotinib ibonise ukuthi iphakeme kunokwelashwa ngamakhemikhali okujwayelekile, kodwa ukulawula kwayo izilonda ezisezinhliziyweni akukalungi. Le nkinga, kanye nokuvela kwezinguquko ezihlobene nemiphumela ye-crizotinib, kuye kwabangela ukuvela kwama-anti-ALK amaningi esizukulwane sesibili asebenza ezindleleni ezihlukene noma ukwandisa ukuvuthwa kwesithiyo segazi-ubuchopho.
Kumalungiselelo esizukulwane sesibili sokulwa ne-ALK, njenge-ceritinib, nakuba i-P glycoprotein isayimpompa ngokwengxenye, ibonise ukulawula okukhulu kwezilonda ze-intracranial. Umphumela we-intracranial uncike ekusebenzeni kahle komuthi kanye ne-blood brain Barrier permeability kungase kube nezinye izici ezingachazwanga.
Ngenxa yokuthi izidakamizwa eziqondiswe ku-ALK zisemisha, luseluncane ucwaningo mayelana nenhlanganisela yalesi sidakamizwa kanye ne-radiotherapy uma kwenzeka ama-metastases ebuchosheni, kodwa lokhu kuphinde kube ngolunye lwezinhlelo ezibalulekile nezinamandla okusebenza ekwelashweni okuhlangene. Sengiphetha, kuye kwacaciswa ukuthi iziguli ezine-ALK yokuhlela kabusha i-NSCLC zingaphila ngokukhuthele isikhathi eside ngemva kokuzuza emithini emisha ehlosiwe.
Ngokuphathelene nokuqonda nokusebenza kwezilonda ze-CNS metastatic, ucwaningo olwengeziwe mayelana nezinketho zokwelashwa ezintsha luyadingeka ukuze kuxazululwe izinkinga zekhwalithi yokuphila kanye nokuqagela kokusebenza. Kunesidingo esiphuthumayo futhi sokucwaninga izindlela zokumelana nemithi. Yiqiniso, into yokuqala ebalulekile ukuthi odokotela kufanele baqinise ucwaningo lweziguli ezine-metastasis yobuchopho ukuze kucaciswe isikhathi esifanele sokusetshenziswa kwe-tyrosine kinase inhibitors yesizukulwane sokuqala nesesibili ezigulini ze-NSCLC, kanye nesikhathi esifanele sobuchopho. i-radiotherapy.
