Isiri-diki kenza yemapapu kenza uye huro metastasis
Pakutanga, isiri-diki yekenza yemapapu (NSCLC) metastases yehuropi yaive nehurombo husina kunaka, ine nguva yepakati yekupona yemwedzi minomwe. Asi bundu-chaiyo shanduko yakakonzera mafungu ekurapa kwakanangwa kune aya metastases ehuropi uye anogona kuvandudza nguva yese yekupona. ALK rearrangement inogona kuonekwa munenge 7% -2% yeNSCLC, saka yave chinangwa chekurapa chepamusoro NSCLC. Mapurofesa Zhang Isabella naLu Bo vanobva kuUnited States nguva pfupi yadarika vakaburitsa ongororo yakabatana muThe Lancetonology, iyo zvino yaunzwa seizvi:.
Crizotinib is the first approved anti-ALK tyrosine kinase inhibitor after showing excellent comprehensive effects, but this effect has not been translated into the control of intracranial lesions. The central nervous system (CNS) is a common site of involvement in disease progression. Up to 60% of patients will experience metastasis at this site during treatment with crizotinib: this is due to poor intracranial penetration of the drug and the inherent resistance of the tumarara mechanism.
Yechipiri-chizvarwa ALK inhibitors vane zvirinani kudzora kwekusagadzikana maronda, asi iwo haapindirani, izvo zvinoda kuti isu tiongorore dzimwe nzira dzokurapa. Ichi chinyorwa ndechekuongororwa kwebasa reALK muCS metastasis, ALK yakanangwa kurapwa kwezvironda zvisingaite, uye kuramba kurapwa kwazvino.
Basa reropa-brain barriers
Ropa-uropi chipingaidzo chinodzivirira uropi kubva pakupinda kwezvinhu zvine chepfu, asi zvakare zvinoita kuti zviomere mushonga wesystem kusvika kuuropi parenchyma. Kubva pakuona kwekuvharira, iyo yeropa-yeuropi chinodzivirira ine akati wandei maitiro: semuenzaniso, kuenderera kwakasimba kubatana pakati pee endothelial maseru uye yakaoma kutsigira chimiro chinosanganisira pericytes uye astrocyte inogona kudzora reropa-uropi chipingaidzo kuburikidza neparacrine Kubvumidzwa; yakanyanya kuramba, ingangoita ka100 iya yemapiripiri emagetsi, inovhara mamorekuru epolar.
Chikamu cheiyo systemic kurapwa inoyambuka ropa-huropi chipingamupinyi inodzingwa neeflux vatakuri. Anonyanya kufambisa efflux anotakura ndeP-glycoprotein, mapuroteni ekudzivirira mapuroteni 1-6, ABCG2.
Muchiitiko che metastasis, kuvimbika kweropa-brain barriers kunokanganisa. Panguva ino, chimiro chevascular chiripo chakanyanya kufanana nevascular structure ye tumor-origining tissue, uye yakakuvadzwa tight junction inoratidzika seyakanyanya permeable vasculature. Matanho ekuwedzera kupinza kweropa-brain chipingamupinyi anosanganisira kuparadza kwemuviri chipingamupinyi chayo kuburikidza neradiotherapy, hypertonic agents, high-intensity beam ultrasound, uye bradykinin analogs.
Zvimwe zvirongwa zvakanangwa zvine chekuita neALK inhibitors zvinogona kuvharisa mushonga kubva pakupomba kunze uye nekunyatso kuutakura kuenda kuuropi parenchyma uye tumor cell.
ALK kugadzirisa zvakare
Shanduko dzine hukama negene ALK dzinogona kuwanikwa munenge 2-7% yeNSCLC, inonyanya kufambiswa EML4-ALK. Kugadziriswazve kunotungamira ku autophosphorylation uye kuenderera kumisikidza kwe ALK, nokudaro kumisikidza iyo RAS nePI3K kusaina kukasira (ona inset). RAS activation inogona kukonzeresa zvakanyanya zvechisimba bundu hunhu uye zvakanyanya kukiriniki kufungidzira.
ALK rearrangement of isina-diki kenza yemapapu kenza targeted therapy mechanism. It can directly target ALK rearrangement proteins (such as LDK378, X396, CH5424802); in addition, it can target upstream effectors (such as EGFR), or downstream pathways (such as PLC, JAK-STAT, KRAS-MEK-ERK, AKT-mTOR- Aurora A kinase) to inhibit cell cycle progression, survival, proliferation, and vascularization; it can target DNA repair; it can also target protein formation that stimulates cell growth (eg, EGFR ligands, VEGF).
Zvakafanana nevarwere vane EGFR mutations, varwere vane ALK rearrangement vanogona kunge vari vadiki, vanosvuta zvishoma kana kusaputa kupfuura varwere verudzi rwemusango, uye vanenge vese vane adenocarcinoma-rudzi rweNSCLC.
Ongororo dzinoverengeka dzakaongorora kukosha kwekufungidzira kwe ALK kugadziriswazve muNSCLC, asi mhedzisiro yacho yakavhenganiswa. Zvidzidzo zvakaratidza kuti ALK inogadzirisazve NSCLC inopeta njodzi yekuwedzera kwechirwere kana kudzokororwa pamakore mashanu, uye inosimudzira akawanda metastases. Varwere vane ALK rearrangement vane mamwe metastases pavanowanikwa, uye njodzi yemastastasis kune pericardium, pleura, uye chiropa yakakura. Kune zvekare zvidzidzo zvinoti ALK kugadziriswazve uye yemusango-mhando varwere zvakafanana maererano nekudzokazve, kupona-kusununguka kwezvirwere, uye kurarama kwese; kune zvekare zvidzidzo zvinoratidza kuti ALK kugadzirisazve kunovandudza kupona kwese muchikamu cheI-III NSCLC varwere.
Kana iri iyo ALK rearrangement NSCLC inonyanya kuendeswa kuuropi, iyo data inosiyana zvakanyanya. Zvidzidzo zvakawana kuti 3% yevarwere vane NSCLC brain metastasis vanogona kuona ALK translocation uye 11% vanogona kuona kukwidziridzwa. Ichi chidzidzo chinoratidza kuti nhamba yekopi ye ALK gene mune metastasis inowanzo wedzera, izvo zvingave zvichikonzerwa nesarudzo yakasarudzika yeALK translocation bundu masero panguva metastasis.
Basa re crizotinib muuropi metastasis
Pfizer's crizotinib idiki mamorekuru inhibitor inotenderwa neUS Chikafu neDrug Administration (FDA) ye ALK rearrangement kufambira mberi NSCLC, yakanangana ALK, MET uye ROS tyrosine kinases. Nekudzivirira ALK uye MET tyrosine kinases, crizotinib inogona kutadzisa iyo tyrosine phosphorylation yeyakaitwa ALK.
Zvidzidzo zvakati wandei zvinosanganisira kuenzanisa crizotinib neyakajairwa chemotherapy regimens kune varwere vane advanced inofambira mberi ALK yakarongwazve NSCLC yakaratidza kuti yekutanga ine nani kufambira mberi-kusina kupona, kushanda zvakanaka kwebundu, uye hupenyu hwese hwese. Zvimwe zvidzidzo zvakaratidza kuti chinangwa chese intracranial inoshanda chiyero uye chirwere chekudzivirira chirwere checrizotinib pamasvondo e12 chaiva 18% uye 56%, maererano; nguva yepakati yekufambira mberi kwemukati mushure mekushandiswa kwechirwere ichi muvarwere vakanga vasina kurapwa kare yaiva 7 Mwedzi. Kudzora kwezvironda zvemukati pamasvondo e12 kwaive pedyo neiyo systemic maronda.
Iko kushanda kwese uye nguva yekutonga kwevarwere avo vakamboita kurapwa kwekusarudzika kweradiotherapy kwave nani. Iyo yakazara isingabatsiri inoshanda mwero yaive 33%, chirwere chinodzora mwero pamasvondo gumi nemaviri yaive 12%, uye yepakati nguva yekufambira mberi yaive mwedzi 62. Izvo zvakakosha kuti varwere vanoramba vachishandisa crizotinib vafambira mberi, asi yavo yese yekupona nguva yakareba kupfuura avo vasina kuramba vachishandisa mushonga panguva yekufambira mberi.
Munguva pfupi yapfuura, crizotinib sedanho rekutanga rekurapa chikamu chechitatu kuyedzwa kwaisanganisira varwere makumi manomwe nevapfumbamwe avo vakamboita radiotherapy ye metastases yehuropi uye vakaona kuti nguva yepakati yekufambira mberi kwekuita yakanga yakaenzana nekemotherapy boka. Pfungwa yakakosha yechidzidzo ichi ndeyekuti vese varwere vakarapwa ne radiotherapy kutanga, uye yapfuura PROFILE kudzidza yakaratidza kuti radiotherapy inogona kuvandudza kushanda uye nekudaro yakanyanyisa kusimbisa kusagadzikana kunokonzerwa necrizotinib chete.
Ruzivo rwakabatana nezve ALK rearrangement brain metastasis inobva mumishumo yenyaya uye subgroup kuongororwa kwekiriniki miedzo. Paunenge uchiongorora idzi data, zvakakosha kutonga maitiro evarwere sezvinotsanangurwa munyaya yenyaya, nokuti zvidzidzo zvakawanda zvakabatanidza zviitiko zvakasiyana-siyana pasina mutsauko: zviratidzo uye asymptomatic metastases, pre-kurapwa Mishonga yakawanda yakadai seradiotherapy, mishonga yakasiyana, uye zvakasiyana-siyana zvekutevera. Muchidzidzo chechipiri chechizvarwa che ALK inhibitors, zvakakoshawo kusiyanisa kana crizotinib yakashandiswa kare.
Iyo data inoratidza kuti kushanda kusingaite kwe crizotinib kunosiyana. Varwere vazhinji vanoratidzira kusarura kupedzisa kuregererwa kwemaronda ekuwedzera, asi matomu eCSS afambira mberi, uye nekudaro vanofanirwa kurapwa chemotherapy kana kufunga nezvewe
se yechipiri-chizvarwa zvinodhaka.
Kunyangwe crizotinib inowanzo shanda, vazhinji varwere vane ALK-vakagadziriswazve NSCLC vacharamba vaine metastases kana kufambira mberi panguva yekurapa. Zvidzidzo zvepakutanga zvakaratidza kuti CNS ndiyo nzvimbo huru yekurapa kutadza panguva yekurapwa ne crizotinib munenge hafu yevarwere. Ongororo dzichangoburwa dzakaratidza kuti kutadza kurapwa kweCNS kunoonekwa mu70% yevarwere! Izvi zvinokonzerwa nehurombo hwe CNS kukwana kwe crizotinib, asiwo nekuda kwekushomeka kwekupararira uye kupomba kunoshanda kweP-glycoprotein.
Chidzidzo chakatemwa kuwanda kwechirwere ichi mucerebrospinal fluid panguva yekurapwa kwecrizotinib mune varwere vane ALK vakagadzirisazve kenza yemapapu yehuropi metastases: 0.617 ng / mL, nepo iko kusungwa kuri serum kuri 237 ng / mL. Tsananguro yekufambira mberi kweiyo CNS-yakavakirwa maronda ndeyekuti iyo metastasis maitiro inonyanya kuita hukasha kupfuura iyo yekutanga bundu, kana shanduko mune crizotinib-inosunga domain.
Basa rechipiri-chizvarwa ALK inhibitors muuropi metastasis
Novartis's ceritinib chizvarwa chechipiri ALK-chakasarudzika tyrosine kinase inhibitor inogamuchirwa neFDA, uye zvakare inonanga IGF-1R, insulin receptor uye ROS1. Kubudikidza nedzimwe nzira, ceritinib inhibits ALK autophosphorylation uye yakadzika STAT3 nzira. Muchikamu chekutanga chekudzidza, chiyero chinoshanda chevarwere vasina crizotinib chaive 1%. Nekuda kweizvi, zvikamu zviviri zvechipiri zvidzidzo zviri kuvandudzwa uye zviri kuitwa.
Roche's alectinib akatogashira FDA kubvumidzwa kwekufambira mberi kwayo pakurapa. Zvidzidzo zvakawana kuti kune varwere vane ALK vakagadzirazve NSCLC vasina kurapwa ne crizotinib, muyero unoshanda wealectinib ndeye 93.5% (43/46 kesi), uye chikamu chakakodzera chechitatu kudzidza kuri kuitika.
Preclinical pharmacology zvidzidzo zvakatoratidzira kuti alectinib ine nani CNS kudhakwa kwezvinodhaka kupfuura crizotinib, uye iyo CNS yekumanikidza kwezvinodhaka ndeye 63-94% yeiyo serum yevasungwa. Izvi zvinogona kunge zviri nekuti alectinib yakasiyana necrizotinib uye ceritinib, P glycoprotein haina zvainoita pairi, uye haigone kuburitswa nemazvo kubva munzvimbo isingakoshese.
Mune ongororo yevarwere vanoshingirira crizotinib, makumi maviri neshanu evarwere makumi mana nevasere aisanganiswamo metastases yehuropi kana varwere vane metastases yehuropi asi vasina kurapwa, 21 varwere vakawana kuregererwa kwakazara mushure mealectinib, 47 Mumwe murwere akawana kuregererwa kwakaperera uye varwere vasere vane mamota akasimba.
Muchidzidzo ichi, vashanu varwere vakawana cerebrospinal fluid chiyero uye vakaona kuti paive nehukama hwehukama pakati peSerum uye cerebrospinal fluid isina kugadzikiswa kusagadzikana kwezvinodhaka. Iyo inofungidzirwa kuti yakadzika kwazvo yevasungwa mucerebrospinal fluid iri 5 nmol / L, iyo inodarika iyo hafu inhibitory yevasungwa ye ALK inhibitors yakataurwa kare. Muchikamu chechipiri chekudzidza, varwere gumi nevasina kugamuchira crizotinib vaibatwa nealelectinib, uye varwere vapfumbamwe vakapona mukufambira mberi-kwemwedzi inopfuura gumi nemaviri.
Kumwe kurapa kwekubudirira kwakabvumidzwa neDFA, ARIAD Pharmaceuticals 'brigatinib haingotadzise ALK chete, asi zvakare inotarisa EGFR neROS1. Chidzidzo pamushonga chakawana kuti gumi nevatanhatu vevarwere vanodzivirira crizotinib vanga vatova nemastasis asingabatsiri pavakatanga mushonga, uye 16 veava varwere vashanu vakaratidza kufungidzira mushure mekutora mushonga. inoshanda.
Kune mashoma zvidzidzo pane CNS chiitiko chekutanga- uye chechipiri-chizvarwa tyrosine kinase inhibitors, asi kune akawanda-epakati akasarudzika chikamu chechitatu miedzo.
Basa reALK Inhibitors muPial Metastasis
Kune mashoma zvidzidzo pane pial meningeal metastasis mu ALK rearrangement maronda nekuda kwehurombo hwese kufungidzira uye kuoma kwehuwandu hwekurapa mhedzisiro. Vamwe vanhu vakafunda 125 kesi dzeNSCLC pial meningeal metastasis uye vakaona kuti kupona kwese mushure mehuropi hwese radiotherapy (WBRT) haina kuvandudza, asi nguva yekurarama mushure me subarachnoid chemotherapy yaive yakareba.
Mune ongororo yekudzoka kwezana nemakumi mana nematatu emakesi eNSCLC pial meningeal metastasis, kupona kwevarwere mushure me subarachnoid chemotherapy, EGFR inhibitors, uye WBRT yakagadziridzwa. Kune zvakare mashoma mashumo ezviitiko zvinoratidza kuti kune varwere vane ALK vakagadzirazve pial meningeal metastases, maronda emukati evarwere vane crizotinib pamwe nekushandisa subarachnoid kwemethotrexate yakagadziridzwa. Asi iyo data ishoma uye hapana mhedzisiro inogona kuitwa.
Basa reimwe yechipiri-chizvarwa zvinodhaka mu pial meningeal metastasis haisati yazadzikiswa, asi iyo yazvino inoshandiswa intracranial chemotherapy regimen pamwe ne alectinib kana tyrosine kinase inhibitors inoita kunge inoshanda zvakanyanya.
Kupokana ne tyrosine kinase inhibitor kuramba
Vazhinji varwere ve crizotinib vakagadzira kuramba, uye mazhinji akaitika muCNS. Kuedza kusimudzira kusagadzikana kweiyo crizotinib idosi kukura. Mune zvimwe zviitiko zvirevo, iyo imwechete dosi ye crizotinib yakawedzerwa kubva pa250 mg kusvika pa1000 mg mune yakajairwa regimen; mamwe akasanganiswa nemimwe mishonga nekuwedzera crizotinib kusvika pa600 mg.
Mukushandisa-kuwedzera kushandiswa, mhedzisiro yakagadziridzwa kune imwe nhanho; tsananguro yeizvi ndeyekuti crizotinib ine dosi yakakura, uye kusanganiswa kwemishonga kunovandudza kushanda kwe ALK rearrangement tumors yemamwe madhiragi.
Yazvino yechipiri-chizvarwa ALK inhibitors seritinib, alectinib uye brigatinib vane yakanyanya inoshanda mwero we58-70%. Zvidzidzo zvakaratidza kuti kumwe kuchinjika kunoita iyo yechipiri-chizvarwa tyrosine kinase inhibitors inodzivirira inogona kutariswa neimwe tyrosine kinase inhibitors.
Pane humbowo hwekuti kusanganiswa kweEML4-ALK kune hukama neHsp90, iyo inoita basa rakakosha mukukura kwemhando dzakawanda dzemamota. ALK rearrangement NSCLC masero, akadai seganetespib, AUY922, retispamycin, IPI-504 nemamwe madhiragi, anogona kukonzera apoptosis uye bundu regression kuburikidza nekuora kweALK fusion protein.
Iyo yekubatanidza kurapa kwe crizotinib pamwe neIPI-504 inogona kutogonesa inonakidza kwazvo bundu regression mhedzisiro. Uye zvakare, crizotinib-inodzivirira mamota maseru zvakare yakaratidza kunzwisiswa kwakasimba kune Hsp90 inhibitors. Parizvino pane zvinoenderana Phase 1 uye Phase 2 miedzo.
Kukunda kuramba kwe crizotinib, kune zvakare zvirongwa zvezasi kana imwe nzira yekumisikidza. Semuenzaniso, pane zvidzidzo zvinoenderana paMTOR, PI3K, IGF-1R, nezvimwe. Iyo inotevera-chizvarwa kuteedzana tekinoroji inotarisirwa kuvandudza mamwe maanti-drug tekinoroji uye nekuwedzera kuyedza kurwisa cyclin-inotenderera kinases, aurora kinases uye epigenetic regulators.
Chinja ALK inhibitors yekuvandudza yavo CNS kubvumidzwa kana chiitiko
Yechipiri-chizvarwa ALK inhibitors ine yakasarudzika zvivakwa inogona kuyambuka iropa-huropi chipingamupinyi, nekudaro kusarudza sarudzo dambudziko rekuwedzera dhiza mukati meCSS. Mune modhi yegunduru, kukwana kweX-396 muuropi kwakaenzana necrizotinib, X-396 inogona kungofungidzirwa kusvika kanopfuura kana hafu iyo hafu yekudzivirira kudzikiswa mu cerebrospinal fluid, uye kusangana kwe crizotinib mu cerebrospinal fluid iri Ihafu iyo hafu yekudzivirira kusangana! Kuwedzera kushanda kweX-396 kunogona kusanganiswa nehydrogen ions uye nekuwedzera kusapindirana kwehumwe panguva imwechete yekubatanidza pamwe neALK.
X-396 parizvino iri kuitiswa kiriniki kuyedzwa kuti iongorore kana iri kiriniki inoshanda. Maumbirwo emamwe echizvarwa chechipiri madhiragi akafanana neiyo X-396, uye cerebrospinal fluid-plasma yevasungwa yemishonga yakawedzerawo, iyo ichave nemhedzisiro iri nani kumatumbu asingagadzike.
Terevhizheni, kune nzira dzekuwedzera kukwana kweCNS nekudzora mamorekuru vhoriyamu, kuwedzera mafuta ayo solubility, uye kuigadzirisa kuti isasunge kusunga kune akajairwa epuroteni mapuroteni pane eropa-uropi chipingaidzo. Alectinib ine yakasimba CNS kubvumidzwa nekuda kwehurombo kusunga kuna P glycoprotein. Chimwe chechipiri-chizvarwa ALK inhibitor PF-06463922 yakagadzirirwa kudzivirira kubuda kwayo muropa-huropi chipingamupinyi uye bundu pamusoro uye zvakanyanya kuwedzera kukwana kweCNS uye bundu. Icho chirevo ndechekuti
kudzora mamorekuru uremu, kuwedzera kusimba kwemafuta, Kuchinja huwandu hwehydrogen zvisungo.
Dzorerazve chipinga cheropa-huropi kuti uwedzere kukwana
Imwe mhinduro yekuwedzera kuwanda kwemishonga inonzi cerebrospinal fluid kuwedzera kukwirisa kweropa-rehuropi chipingaidzo. Sezvambotaurwa, iro reropa-huropi chinodzivirira chine chekuita uye chinoshanda: P glycoprotein ndicho chinhu chikuru chinobvisa zvinhu. Naizvozvo, imwe yemhinduro ndeyekudzivirira kusunga kweP glycoprotein kumushonga.
Mumuenzaniso we mbeva, kuwedzerwa kwe elacridar kunogona kuita kuti kusanzwisisika kwe crizotinib inokwana kusvika makumi manomwe makumi manomwe mushure memaawa makumi maviri nemana, uye kuwanda kweplasma kwakajairika, izvo zvinogona kunge zvichikonzerwa nekuzadzwa kwekusapinza mukati. Sezvo mubatanidzwa wemishonga iri wakanaka, kuyedzwa kwevanhu kunofanirwa kutariswa, uye kucherechedzwa kunofanirwa kubhadharwa kuchidzidzo chakasanganiswa neceritinib nemimwe mishonga.
Imwe nzira yekutsvagisa inotarisa kune vasoactive kinin, senge iko kushandiswa kweinin analogue kugadzirisa iyo yeropa-yeuropi chipingaidzo kuburikidza neprostaglandins uye nitric oxide. Kuongorora kwemhuka kwakaratidza kuti iyi regimen inogona kuwedzera iyo CNS kunwa kwemushonga uye kuwedzera kupona kwese. Vasoactive kinin inosanganisirwa neALK inhibitors inogona kuwedzera muviri usingaite, uye inogona kuongororwa zvakadzama kuburikidza neserebrospinal fluid sampling kana kiriniki yekufungidzira.
Kugadziriswa kwechipfuva microenvelo
Hupupuriro hwakakura hwakaratidza kuti metastatic tumor maseru anowanzo kwira zvisina kujairika microenvironments senge mitsipa yeropa, mitumbi yeLymphatic uye matracellular matrix. Iyi microenvelo isina kujairika inowedzera kukura kwechirwere, metastasis, uye kurapwa kwekurapa, izvo zvinonyanya kukosha pakuchinja kunotungamira kune mamwe metastases.
Imwe dzidziso ndeyekuti kuomesa mamiriro ehutano hwemuviri une hutano kunogona kuvandudza kufungidzira kwemurwere. Chimwe chezvinangwa zvikuru zvekugadzirisa ndeyekutarisana neakavhiringidzika maitiro evascular. Kuwedzeredzwa kwevascular yemidzi iyi yeropa kwakaderedzwa, izvo zvinoderedza mushonga kuti usvike pakatarisana netishu uye unokonzeresa hypoxia yemuno. Hypoxia haingowedzere chete bundu kufambira mberi uye metastasis, asi zvakare chiratidzo chebundu invasiveness uye inoderedza mhedzisiro ye oxygen-inoenderana kurapwa senge radiotherapy.
VEGF inhibitors have been used to reduce disordered angiogenesis and restore the vascular microenvironment. In the mouse glioblastoma model, the VEGF inhibitor bevacizumab reduces hypoxia and enhances the effect of radiotherapy. This type of benefit can also be seen in cytotoxicity treatment when blood vessels are normalized, but no studies have been conducted on the combination of ALK and VEGF inhibitors.
ALK inogadzirisazve basa reNSCLC midbrain radiotherapy
Zera revarwere vane ALK rearrangement tumors rakadzikira, inova imwe yeakakosha nyaya dzinofanira kutariswa pakurapa maronda emukati, nekuti varwere vazhinji vachiri kushanda, vane vana vadiki, uye vanoda kutarisira mhuri dzavo. Izvi zvinoda kuchengetedzwa kwemabasa ekuziva, kunyanya akakosha ekuziva mashandiro.
Nekuwanikwa kweALK inhibitors, tarisiro yekurarama kwevarwere iyi yakaverengerwa mumakore, uye kukosha kunofanirwa kupihwa kune-refu-kutonga nekushomeka kwenguva refu-kwenguva mhedzisiro. Varwere vane ALK vakagadziriswazve NSCLC vakagara kwenguva refu kunyangwe vaine metastases yehuropi, iyo inoshandura chinangwa chekurapa kubva nyore palliative kuchengetedza hupenyu hwehupenyu nekuziva kwevarwere.
Nekuda kwekugara kwenguva refu, varwere vane metastases madiki vanokurudzirwa kuti vafunge nezve stereotactic radiosurgery, nekuti WBRT ichaparadza kuumbwa kwendangariro uye kurangarira kweruzivo. Zvakadaro, kupararira kwehuropi metastasis kuchiri kuda WBRT, inogona kunge iri mukana wekushandisa yakakuvadzwa yeropa-brain barriers uye panguva imwe cheteyo kushandisa zvinodhaka zvakanangwa kuwedzera huwandu hwecerebrospinal fluid.
Kune mashoma data pamhedzisiro mhedzisiro ye crizotinib inosanganiswa ne radiotherapy. Naizvozvo, varwere vanogamuchira crizotinib yezvironda zvisingaite vanofanirwa kumisa mushonga kweinenge 1 zuva pamberi peiyo radiotherapy. Mune vamwe varwere, crizotinib yakashandiswa zvakare mushure me radiotherapy muuropi, uye zvakawanikwa kuti crizotinib ichiri kushanda kune maronda ekuwedzera kunze kweiyo radiotherapy, inoenderanawo neyepasi CNS kukwana kwemishonga pamberi pe radiotherapy.
Zvidzidzo zvataura kuti varwere vane ALK rearrangement yehuropi metastases vane nguva yakareba yekupona mushure me radiotherapy pane varwere vane ALK yemusango-mhando. Izvi zvinogona kunge zvichikonzerwa nekuwedzera kukwana kweropa-huropi chinodzivirira uye kuderera P-glycoprotein kutaura mukati memavhiki e radiotherapy. Kunyangwe paine njodzi yakawedzera yemhedzisiro kubva mukubatanidza kurapa, zviri nyore kuitisa zvidzidzo zvekurapa pamwe chete nemhedzisiro mhedzisiro yeALK inhibitors, uye kuwedzera kwekuwedzera mushure me radiotherapy kunogona kutariswa zvakare.
Iyo poindi yekusimbiswa ndeyekuteedzana kweakanangwa kurapwa uye radiotherapy. Zvidzidzo zvakasiyana zvakabatana zvakaratidza kuti ALK inhibitors inogona kubatsirwa kubva mukuenderera mberi kwekushandisa, asi hapana kuenzanisa kweakasiyana maALK inhibitors. Zvidzidzo zvakaratidza kuti kushandiswa kwe crizotinib mushure meWBRT kunogona zvakare kugadzirisa kudzora kwezvipenga zvisingaite. Mukupedzisa, iyo data inoratidza kuti ALK inhibitors inogona kukurudzirwa mushure me radiotherapy, uye inogona kuvandudza kushanda kwemishonga.
Mirayiridzo uye ramangwana rairo
Muzviitiko zvekufambira mberi kana metastasis yehuropi, nhaurirano dzakasiyana siyana dzinosanganisira oncology, radiotherapy, neurosurgery, nezvimwe zvinoda kutariswa. Sangano reNational Comprehensive Cancer Treatment Network rinokurudzira kuti varwere vane asymptomatic brain metastases vanofanira kushandisa crizotinib chete. Nokuda kwekufambira mberi kwezvipembenene zvemukati, SRS kana WBRT inofanira kuonekwa kana pane zviratidzo, inoteverwa nekushandiswa kweALK inhibitors. Kana ronda racho richikwanisa kurapwa neSRS, kufunga kunofanirwa kupihwa kudzivirira huropi hwese radiotherapy kuitira kuti isakanganise basa rekuziva.
Iyo mirayiridzo inokurudzira kuti crizotinib kana ceritinib inogona kushandiswa mune varwere vane asymptomatic kufambira mberi. Nyaya dzenyaya dzinoratidza kuti iyo nguva yekufambira mberi- yemahara kupona inosiyana pakati pe crizotinib ne radiotherapy mushure me radiotherapy. Kubudirira kwechipiri-chizvarwa ALK inhibitors kunofanira kukurudzira varapi kuti vashandise iyi mishonga sezvo chirwere ichi chichienderera mberi kuwedzera kusagadzikana kurapwa.
Nekuda kwemukana wepamusoro wekudzokazve mukati memusoro paunenge uchishandisa ALK inhibitors, kuongororwa kweMRI nguva nenguva kunodiwa mushure meradiotherapy kuongorora mafambiro emetastases. Kune metastases inorapwa neWBRT, zvinokurudzirwa kuita MRI mwedzi yese ye3. Ehe, ALK rearrangements ichabatsirwa nayo.
Kana iyo metastasis ichiwedzera kuwedzera, chiremba anofanirwa kushandura iyo ALK inhibitor yakashandiswa, uye kana zviratidzo zvikaonekwa, zvinofanirwa kuvezve nemwenje; kubva pakuona kwengozi-kubatsirwa reshiyo, ivo vachiri vanosarudza kuitwazve kurapwa. Kune ALK yakagadziriswazve maronda emukati, kana radiotherapy pamwe neALK inhibitors inofambira mberi, kusanganiswa kwepemetrexed kunoita senge kwakanyanya kunaka sarudzo.
Iko kushandurwa kwe ALK yakanangwa inhibitors kukurira yakajairika kusagadzikana kwezvinodhaka, kusimudzira kukwana kwayo kuCNS, uye nekuvandudza simba rayo rinosunga uye mhedzisiro mushure mekusvika pachinangwa, nekuwedzera kutsvagisa mune izvi. Munguva pfupi iri kutevera, kumisikidzwa kwemishonga iyi muCNS kuchave kwakakwirira uye kunogona kuiswa zvakateedzana kana kusagadzikana kwemishonga kusagadzikana kuchioneka.
Nekuwedzera kwemaitiro ekuongorora DNA anowanikwa, varwere vanogona kurayirwa kudzokorora biopsies kuti vaongorore nzira yekudzivirira zvinodhaka sezvavanofambira mberi, izvo zvichatungamirira kuchipatara kushandiswa kwetyrosine kinase inhibitors iyo inoshanda zvakanyanya.
mhedziso
Uropi metastasis chiyero checancer dzese chiri kuwedzera. Imwe yemapurogiramu ekuwedzera kushanda ndeyekugadzira chinyorwa pamusoro pehunhu husina kujairika hwecancer chaiyo, senge ALK rearrangement. Mune varwere w
iyo ALK yakagadziriswa kenza yemapapu, crizotinib yakaratidza kunge iri pamusoro peyakajairwa chemotherapy, asi kudzora kwayo kwezvipenga zvisingaenzaniswi hakusi kwakanaka. Iri dambudziko, uye kumuka kwekuchinja kunoenderana nemhedzisiro ye crizotinib, kwakonzera kubuda kwevakawanda vechipiri-chizvarwa anti-ALK vamiririri vanoita munzira dzakasiyana kana kuwedzera kupera kweropa-rehuropi chipingaidzo.
Mune yechipiri-chizvarwa anti-ALK gadziriro, senge ceritinib, kunyangwe iyo P glycoprotein ichiri kupomba kunze kwayo, yakaratidza kudzora kwakakura kwezvironda zvisingaite. Iko kusabatika kunoenderana nekubudirira kwechirwere uye neropa reuropi Chipingamupinyi chinogoneka chingave nezvimwe zvisina kutsanangurwa zvinhu.
Nekuti ALK-yakanangwa mishonga ingori nyowani, kuchine kutsvagurudza kushoma kwekusanganiswa kwechirwere ichi uye radiotherapy mune kesi yemasastastase ehuropi, asi ichi zvakare chimwe chezvirongwa zvakakosha uye zvinogona kuve zvinobudirira mune yekubatanidza kurapa. Mukupedzisa, zvave kujekeswa kuti varwere vane ALK rearrangement NSCLC vanogona kushingaira kurarama kwenguva yakareba mushure mekubatsirwa nemishonga mitsva yakanangwa.
Nezve iko kucherechedzwa uye mashandiro eCNS metastatic maronda ane hanya, kumwe kutsvagurudza pamusoro pesarudzo nyowani dzekurapa dzinodiwa kugadzirisa matambudziko ehupenyu hwehupenyu uye hunoshanda kufungidzira. Iko kune zvakare kudikanwa kwekukurumidza kudzidza nzira dzekurwisa zvinodhaka. Ehezve, chinhu chekutanga chakakosha ndechekuti varapi vanofanirwa kusimbisa kudzidza kwevarwere vane metastasis yehuropi kujekesa nguva yakanakisa yekushandisa yekutanga- uye yechipiri-chizvarwa tyrosine kinase inhibitors muNSCLC varwere, pamwe nenguva yakakwana yeuropi radiotherapy.
