iindaba

Kuphando lwe-oncology, imilinganiselo yeziphumo ezihlanganisiweyo, ezinje nge-progression-free survival (PFS) kunye nokusinda ngaphandle kwezifo (DFS), ziya zithatha indawo yesiphelo semveli sokusinda ngokubanzi (OS) kwaye ziye zaba sisiseko sovavanyo oluphambili lokuvunywa kweziyobisi yi-US Food and Drug Administration (FDA) kunye ne-European Medicines Agency (EMA). La manyathelo aphucula ukusebenza kovavanyo lweklinikhi kunye nokunciphisa iindleko ngokudibanisa iziganeko ezininzi (umzekelo, ukukhula kwe-tumor, isifo esitsha, ukufa, njl.) kwisiphelo sexesha elinye lokuya kwisiganeko, kodwa zenza iingxaki.

Utshintsho kwiziphumo zovavanyo lweklinikhi ye-antitumor

Ngeminyaka yoo-1970, i-FDA yasebenzisa ireyithi yokuphendula injongo (ORR) xa ivuma amachiza omhlaza. Kwada kwada kwaba yi-1980 ukuba i-Oncology Drug Advisory Committee (ODAC) kunye ne-FDA yaqaphela ukuba ukuphuculwa kokusinda, umgangatho wobomi, umsebenzi womzimba, kunye neempawu ezinxulumene ne-tumor azihambelani nokulungelelaniswa kwe-ORR. Kulingo lwezonyango lwe-oncology, i-OS sisiphelo sekliniki esingcono sokulinganisa inzuzo yeklinikhi ethe ngqo. Nangona kunjalo, i-ORR ihlala iyindawo eqhelekileyo yokuphela kweklinikhi xa kuqwalaselwa ukuvunywa okukhawulezileyo kwamachiza omhlaza. Kulingo lwengalo enye kwizigulana ezinamathumba aphikisayo, i-ORR ikwajongwa ngokukodwa njengeyona ndawo iphambili yokuphela kweklinikhi.

Phakathi kuka-1990 no-1999, ama-30 epesenti yolingo lwechiza lomhlaza olwamkelwe yi-FDA lwasebenzisa i-OS njengeyona ndawo iphambili yonyango. Njengoko unyango olujoliswe kuyo luye lwavela, iziphelo eziphambili zeklinikhi ezisetyenziselwa ukuvavanya amachiza okulwa nomhlaza nazo zitshintshile. Phakathi kowama-2006 no-2011, elo nani lehla laya kutsho kwi-14.5 ekhulwini. Njengoko inani lezilingo zeklinikhi kunye ne-OS njengoko isiphelo esiphambili siye sancipha, ukusetyenziswa kwee-endpoints ezihlanganisiweyo ezifana ne-PFS kunye ne-DFS kuye kwaba rhoqo. Inkxaso-mali kunye nokunyanzeliswa kwexesha kuqhuba olu tshintsho, njengoko i-OS idinga izilingo ezide kunye nezigulane ezininzi kune-PFS kunye ne-DFS. Phakathi kwe-2010 kunye ne-2020, i-42% yezilingo ezilawulwa ngokungahleliwe (RCTS) kwi-oncology zine-PFS njengesiphelo sabo esiphambili. I-67% yamachiza e-anti-tumor evunyiweyo yi-FDA phakathi kwe-2008 kunye ne-2012 yayisekelwe kwezinye iindawo zokugqibela, i-31% yazo isekelwe kwi-PFS okanye i-DFS. I-FDA ngoku iyazazi iinzuzo zeklinikhi ze-DFS kunye ne-PFS kwaye ivumela ukuba zisetyenziswe njengezona ziphumo eziphambili kwizilingo ezifuna imvume yokulawula. I-FDA iphinde yabhengeza ukuba i-PFS kunye nezinye iziphelo ezizezinye zingasetyenziselwa ukukhawulezisa ukuvunywa kwamachiza kwizifo ezinzulu okanye ezisongela ubomi.

Ii-Endpoints aziyi kuguquka kuphela njengoko unyango olutsha luphuhliswa, kodwa nanjengoko ukucinga kunye neendlela zokuvavanya iilebhu ziphucula. Oku kungqinwa kukutshintshwa kwenqobo yekhrayitheriya yoMbutho wezeMpilo weHlabathi (i-WHO) ngekhrayitheriya ye-RECIST yoVavanyo lokuSebenza kwiiNtsholongwane eziZiqina (RECIST). Njengoko oogqirha befunda ngakumbi malunga namathumba, izigulana ezikhe zathathwa njengezizinzile zinokufunyanwa zine-micrometastases kwixesha elizayo. Kwixesha elizayo, ezinye iziphelo azinakuphinda zisetyenziswe, kwaye iziphelo ezintsha zinokuvela ukukhawulezisa ngokukhuselekileyo ukuvunywa kweziyobisi. Ukunyuka kwe-immunotherapy, umzekelo, kukhokelele ekuphuhlisweni kwezikhokelo zovavanyo ezitsha ezifana ne-IRRECIST kunye ne-IRECIST.

Isishwankathelo senqaku lesiphelo

Iziphelo ezihlanganisiweyo zisetyenziswa ngokubanzi kwizifundo zeklinikhi, ngakumbi kwi-oncology kunye ne-cardiology. Isiphelo esihlanganisiweyo siphucula amandla ezibalo ngokunyusa inani leziganeko, ukunciphisa ubungakanani besampulu efunekayo, ixesha lokulandelelana, kunye nenkxaso-mali.
Eyona nto isetyenziswa kakhulu kwi-composite endpoint kwi-cardiology ziziganeko ezinkulu ezimbi ze-cardiovascular (MACE). Kwi-oncology, i-PFS kunye ne-DFS zihlala zisetyenziswa njenge-proxies yokusinda ngokubanzi (OS). I-PFS ichazwa njengexesha ukusuka kwi-randomization ukuya kwinkqubela phambili yesifo okanye ukufa. Ukuqhubela phambili kwe-tumor eqinile ngokuqhelekileyo kuchazwa ngokwemigaqo ye-RECIST 1.1, kubandakanywa ubukho bezilonda ezintsha kunye nokwandiswa kwezilonda ezijoliswe kuyo. Ukusinda okungekho siganeko (EFS), i-DFS, kunye ne-relapse-free survival (RFS) nazo ziyi-endpoints eziqhelekileyo ezihlanganisiweyo. I-EFS isetyenziswa kwizilingo zonyango lwe-neoadjuvant, kwaye i-DFS isetyenziswa kwizifundo zeklinikhi zonyango lwe-adjuvant.

Iziphumo ezahlukeneyo kwiindlela zonyango ezahlukeneyo kwii-endpoints ezidibeneyo

Ukunika ingxelo kuphela ngeziphumo ezixandileyo kunokukhokelela ekucingeni ukuba isiphumo sonyango sisebenza kwisiganeko ngasinye secandelo, okungeyonyani. Ingcinga ephambili ekusetyenzisweni kwee-endpoints ezidibeneyo kukuba unyango luya kuguqula amacandelo ngendlela efanayo. Nangona kunjalo, iziphumo zonyango lwe-antitumor kwizinto eziguquguqukayo ezifana nokukhula kwethumba, i-metastasis, kunye nokufa ngamanye amaxesha kuya kwelinye icala. Umzekelo, iyeza eliyingozi kakhulu linokunciphisa ukusasazeka kwethumba kodwa landise ukufa. Le nto yayiyimeko yovavanyo lwe-BELLINI lwezigulane ezine-myeloma ephindaphindiweyo / e-refractory, apho i-PFS iphuculwe kodwa i-OS yayiphantsi ngenxa yezinga eliphezulu losulelo olunxulumene nonyango.

Ukongeza, kukho idatha yangaphambi kwekliniki ecebisa ukuba ukusebenzisa ichemotherapy ukuthoba ithumba eliphambili kukhawulezisa ukusasazeka okude kwezinye iimeko kuba ichemotherapy ikhetha iiseli ezinokuthi zibangele imetastasis. I-hypothesis yolwalathiso ayinakwenzeka ukuba ibambe xa kukho inani elikhulu leziganeko kwi-endpoint composite, njengoko kunjalo ngezinye iinkcazo ze-PFS, i-EFS, kunye ne-DFS. Ngokomzekelo, izilingo zonyango lwe-allogeneic hematopoietic stem cell transplantation zihlala zisebenzisa i-endpoint edibeneyo equka ukufa, ukuphindaphinda komhlaza, kunye nesifo se-graft-versus-host (GVHD), eyaziwa ngokuba yi-GVHD free RFS (GRFS). Unyango olunciphisa ukwenzeka kwe-GVHD lunokunyusa izinga lokuphindaphinda komhlaza, kwaye ngokuphambeneyo. Kule meko, i-GVHD kunye namazinga okubuyisela kwakhona kufuneka ahlalutywe ngokwahlukileyo ukulinganisa ngokuchanekileyo umlinganiselo wengozi-yenzuzo yonyango.

Ingxelo yesiqhelo yamazinga ahlukeneyo esiganeko kwiziphumo ezinzima ziqinisekisa ukuba iziphumo zonyango kwicandelo ngalinye zihamba ngendlela efanayo; Nayiphi na “i-heterogeneity esemgangathweni” (oko kukuthi, iyantlukwano kwicala) ikhokelela ekusetyenzisweni ngendlela engasebenziyo kweendawo zokuphela ezidibeneyo.

I-EMA incoma "uhlalutyo lomntu ngamnye lweentlobo zeziganeko zomntu ngamnye usebenzisa iitheyibhile zesishwankathelo esichazayo kwaye, apho kufanelekileyo, uhlalutyo lomngcipheko olukhuphisanayo ukuhlola impembelelo yonyango kwisiganeko ngasinye". Nangona kunjalo, ngenxa yokungonelanga kwamandla ezibalo kwizifundo ezininzi, ukungafani okuphawulekayo kwiziganeko zecandelo kwiziphumo ezidibeneyo azikwazanga ukufunyanwa.

Ukunqongophala kokungafihli ekuchazeni iziganeko ezihlanganisiweyo zesiphelo

Kwiimvavanyo ze-cardiology, kuqhelekile ukubonelela ngesiganeko secandelo ngalinye (njenge-stroke, i-myocardial infarction, isibhedlele, kunye nokufa) kunye ne-MACE composite endpoint. Nangona kunjalo, kwi-PFS kunye nezinye iziphelo ezidibeneyo kwizilingo zeklinikhi ye-oncology, lo mqathango awusebenzi. Uhlalutyo lwezifundo ze-10 zakutshanje ezipapashwe kwiijenali ezintlanu eziphezulu ze-oncology ezazisebenzisa i-PFS njengesiphelo safumanisa ukuba ezintathu kuphela (6%) ezichaza ukufa kunye neziganeko zokuqhubela phambili kwesifo; Uphononongo olunye kuphela olwahlula phakathi kokuqhubela phambili kwendawo kunye ne-metastasis ekude. Ukongeza, olunye uphononongo lwahlula phakathi kokuqhubela phambili kwendawo kunye nokude, kodwa aluzange lubonelele ngenani lokufa ngaphambi kokuba isifo siqhubele phambili.

Izizathu zokumahluko kwimigangatho yokunika ingxelo kwiiphelo ezidibeneyo kwi-cardiology kunye ne-oncology ayicacanga. Enye into enokwenzeka kukuba iziphelo ezihlanganisiweyo ezifana ne-PFS kunye ne-DFS zizibonakaliso zokusebenza. I-MACE ivela kwiziphumo zokhuseleko kwaye yaqala ukusetyenziswa kwisifundo seengxaki zokungenelela kwe-coronary percutaneous. Ii-arhente ezilawulayo zinemigangatho ephezulu yokunika ingxelo ngeziphumo zokhuseleko, ngoko ke kukho imfuneko yamaxwebhu aneenkcukacha zeziganeko ezimbi kwiimvavanyo zeklinikhi. Xa i-MACE yayisetyenziswa ngokubanzi njengesiphelo sokusebenza ngempumelelo, isenokuba yinto eqhelekileyo ukubonelela ngezixa zesiganeko ngasinye. Esinye isizathu semigangatho yokunika ingxelo eyahlukileyo kukuba i-PFS ithathwa njengengqokelela yeziganeko ezifanayo, ngelixa i-MACE ithathwa njengengqokelela yeziganeko ezihlukeneyo (umzekelo, i-stroke vs. infarction ye-myocardial). Nangona kunjalo, ukukhula kwe-tumor ephambili kunye ne-metastases ekude kuyahluka kakhulu, ngakumbi ngokwempembelelo yeklinikhi. Zonke ezi ngcaciso ziyaqikelelwa, kodwa ngokucacileyo akukho nanye kuzo ethethelela ingxelo engaphelelanga. Kwizilingo ze-oncology ezisebenzisa i-endpoints ezihlanganisiweyo, ngakumbi xa isiphelo esihlanganisiweyo sisona siphelo siphambili okanye sisetyenziselwa iinjongo zokulawula, kwaye xa isiphelo esihlanganisiweyo sikhoyo njengesiphelo sesibini, ingxelo yesiganeko esicacileyo kufuneka ibe yinto eqhelekileyo.