izindaba

Ocwaningweni lwe-oncology, izinyathelo zemiphumela ehlanganisiwe, ezifana nokusinda-mahhala (i-PFS) kanye nokusinda ngaphandle kwezifo (DFS), ziya ngokuya zingena esikhundleni seziphetho zendabuko zokusinda sekukonke (OS) futhi seziphenduke isivivinyo esibalulekile sokugunyazwa kwezidakamizwa yi-US Food and Drug Administration (FDA) kanye ne-European Medicines Agency (EMA). Lezi zinyathelo zithuthukisa ukusebenza kahle kokuhlolwa komtholampilo futhi zehlise izindleko ngokuhlanganisa izehlakalo eziningi (isb, ukukhula kwesimila, isifo esisha, ukufa, njll.) zibe isiphetho esisodwa sesikhathi nomcimbi, kodwa futhi zidala izinkinga.

Izinguquko ekugcineni kwezivivinyo zomtholampilo ze-antitumor

Ngeminyaka yawo-1970, i-FDA yasebenzisa isilinganiso sokuphendula esihlosiwe (ORR) lapho ivuma izidakamizwa zomdlavuza. Kwaze kwaba ngawo-1980 lapho iKomidi Lokweluleka Ngezidakamizwa ze-Oncology (ODAC) kanye ne-FDA babona ukuthi ukuthuthukiswa kokusinda, izinga lempilo, ukusebenza komzimba, kanye nezimpawu ezihlobene nesimila kwakungahambisani nokuhlobana kwe-ORR. Ezivivinyweni zomtholampilo ze-oncology, i-OS iyisiphetho somtholampilo esingcono sokulinganisa inzuzo yomtholampilo eqondile. Noma kunjalo, i-ORR isalokhu iyisiphetho esivamile somtholampilo lapho kucutshungulwa ukuvunyelwa okusheshisiwe kwezidakamizwa zomdlavuza. Ezivivinyweni zengalo eyodwa ezigulini ezinamathumba aphikisayo, i-ORR iphinde ibhekwe njengesiphetho esiyinhloko somtholampilo.

Phakathi kuka-1990 no-1999, amaphesenti angu-30 okuhlolwa kwezidakamizwa zomdlavuza okugunyazwe yi-FDA asebenzisa i-OS njengesiphetho somtholampilo esiyinhloko. Njengoba izindlela zokwelapha ezihlosiwe ziye zavela, iziphetho zomtholampilo eziyinhloko ezisetshenziselwa ukuhlola izidakamizwa ezilwa nomdlavuza nazo zishintshile. Phakathi kuka-2006 no-2011, leso sibalo sehle safinyelela kumaphesenti angu-14.5. Njengoba inani lezivivinyo zemitholampilo nge-OS njengoba isiphetho esiyinhloko sehlile, ukusetshenziswa kwamaphoyinti okugcina ayinhlanganisela njenge-PFS ne-DFS sekuvame kakhulu. Uxhaso lwezimali kanye nezinkinga zesikhathi kuqhuba lolu shintsho, njengoba i-OS idinga ukuhlolwa okude kanye neziguli eziningi kune-PFS ne-DFS. Phakathi kuka-2010 no-2020, u-42% wezivivinyo ezilawulwa ngokungahleliwe (RCTS) ku-oncology zine-PFS njengesiphetho sazo esiyinhloko. Amaphesenti angu-67 emithi elwa nesimila egunyazwe yi-FDA phakathi kuka-2008 no-2012 ayesekelwe kwezinye izindawo zokugcina, ezingu-31% zazo zisekelwe ku-PFS noma i-DFS. I-FDA manje iyaziqaphela izinzuzo zomtholampilo ze-DFS ne-PFS futhi izivumela ukuthi zisetshenziswe njengeziphetho eziyinhloko ovivinyweni olufuna ukugunyazwa ngokomthetho. I-FDA iphinde yamemezela ukuthi i-PFS nezinye iziphetho zingasetshenziswa ukusheshisa ukugunyazwa kwezidakamizwa zezifo ezimbi kakhulu noma ezisongela ukuphila.

Ama-Endpoints azoguquguquka hhayi nje kuphela njengoba kuthuthukiswa izindlela zokwelapha ezintsha, kodwa futhi njengoba izindlela zokuhlola izithombe nezaselabhorethri zithuthuka. Lokhu kufakazelwa ukushintshwa kwemibandela yeNhlangano Yezempilo Yomhlaba (i-WHO) kusetshenziswa indlela ye-RECIST Yokuhlolwa Kokusebenza Kwezimila Eziqinile (RECIST). Njengoba odokotela befunda kabanzi ngamathumba, iziguli ezike zabhekwa njengezizinzile zingase zitholakale zine-micrometastase esikhathini esizayo. Ngokuzayo, ezinye iziphetho zingase zingabe zisasetshenziswa, futhi amaphuzu amasha angase avele ukuze kusheshiswe ngokuphepha ukugunyazwa kwezidakamizwa. Ukunyuka kwe-immunotherapy, ngokwesibonelo, kuholele ekwakhiweni kwemihlahlandlela emisha yokuhlola efana ne-irRECIST kanye ne-iRECIST.

Uhlolojikelele lwephoyinti lokugcina

Iziphetho ezihlanganisiwe zisetshenziswa kabanzi ezifundweni zomtholampilo, ikakhulukazi ku-oncology kanye ne-cardiology. Iziphetho eziyinhlanganisela zithuthukisa amandla ezibalo ngokwandisa inani lemicimbi, ngokunciphisa usayizi wesampula odingekayo, isikhathi sokulandelela, kanye noxhaso.
Isiphetho esiyinhlanganisela esisetshenziswa kakhulu ku-cardiology yizehlakalo ezinkulu ezimbi zenhliziyo (MACE). Ku-oncology, i-PFS ne-DFS zivame ukusetshenziswa njengama-proxies okusinda okuphelele (OS). I-PFS ichazwa njengesikhathi esisuka kokungahleliwe siye ekuqhubekeni kwesifo noma ekufeni. Ukuqhubeka kwesimila esiqinile ngokuvamile kuchazwa ngokuvumelana neziqondiso ze-RECIST 1.1, okuhlanganisa ukuba khona kwezilonda ezintsha kanye nokwandiswa kwezilonda eziqondiwe. Ukusinda okungenamicimbi (EFS), i-DFS, kanye nokusinda kokungaphindiseli (RFS) nakho kuyiziphetho ezivamile eziyinhlanganisela. I-EFS isetshenziswa ezivivinyweni zokwelashwa kwe-neoadjuvant, futhi i-DFS isetshenziswa ezifundweni zomtholampilo zokwelashwa kwe-adjuvant.

Imiphumela ehlukene ekwelashweni okuhlukene kuma-endpoints ahlanganisiwe

Ukubika kuphela imiphumela ehlanganisiwe kungaholela ekucabangeni ukuthi umphumela wokwelapha usebenza kumcimbi wengxenye ngayinye, okungelona iqiniso ngempela. Umcabango oyinhloko ekusetshenzisweni kweziphetho ezihlanganisiwe ukuthi ukwelashwa kuzoshintsha izingxenye ngendlela efanayo. Kodwa-ke, imiphumela yokwelashwa kwe-antitumor ezintweni eziguquguqukayo ezifana nokukhula kwesimila esiyinhloko, i-metastasis, nokufa ngezinye izikhathi kuya kolunye uhlangothi. Isibonelo, isidakamizwa esinobuthi obukhulu singanciphisa ukusakazeka kwesimila kodwa sandise ukufa. Lokhu kwaba njalo ocwaningweni lwe-BELLINI lweziguli ezine-myeloma ephindaphindekayo/eyeqa, lapho i-PFS yaba ngcono kodwa i-OS yayiphansi ngenxa yamazinga aphezulu okutheleleka ahlobene nokwelashwa.

Ngaphezu kwalokho, kunedatha yangaphambi komtholampilo ephakamisa ukuthi ukusebenzisa i-chemotherapy ukunciphisa isimila esiyinhloko kusheshisa ukusakazeka okude kwezinye izimo ngoba i-chemotherapy ikhetha ama-stem cells okungenzeka ukuthi abangele i-metastasis. I-hypothesis yokuqondisa cishe ayinakwenzeka uma kunenani elikhulu lezehlakalo endaweni yokugcina eyinhlanganisela, njengoba kunjalo ngezinye izincazelo ze-PFS, i-EFS, ne-DFS. Isibonelo, uhlolo lwe-allogeneic hematopoietic stem cell transplantation therapy luvamise ukusebenzisa isiphetho esiyinhlanganisela esihlanganisa ukufa, ukubuya komdlavuza, kanye nesifo se-graft-versus-host (GVHD), eyaziwa ngokuthi i-GVHD free RFS (GRFS). Imithi yokwelapha eyehlisa ukuvela kwe-GVHD ingase inyuse izinga lokubuya komdlavuza, futhi ngokuphambene nalokho. Kulesi simo, i-GVHD namazinga okuphinda abuyele emuva kufanele ahlaziywe ngokuhlukana ukuze kulinganiswe ngokunembile isilinganiso sengozi nenzuzo yokwelashwa.

Ukubika okujwayelekile kwamazinga ahlukene emicimbi yemiphumela eyinkimbinkimbi kuqinisekisa ukuthi imiphumela yokwelashwa engxenyeni ngayinye isendleleni efanayo; Noma yikuphi "ukuhlukahluka kwekhwalithi" (okungukuthi, umehluko ekuqondeni) kuholela ekusetshenzisweni ngendlela engafanele kwamaphoyinti okugcina ayinhlanganisela.

I-EMA incoma “ukuhlaziywa komuntu ngamunye kwezinhlobo zomcimbi ngamunye kusetshenziswa amathebula afingqiwe achazayo futhi, lapho kufaneleka, ukuhlaziya ubungozi obuncintisanayo ukuze kuhlolwe umthelela wokwelashwa kumcimbi ngamunye”. Kodwa-ke, ngenxa yamandla ezibalo anganele wezifundo eziningi, umehluko omkhulu ezenzakalweni zengxenye emiphumeleni eyinhlanganisela awukwazanga ukutholwa.

Ukungabi sobala ekubikweni kwezehlakalo eziyinhlanganisela yokugcina

Ezivivinyweni zenhliziyo, kuwumkhuba ojwayelekile ukunikeza izehlakalo zengxenye ngayinye (njenge-stroke, i-myocardial infarction, ukulaliswa esibhedlela, nokufa) kanye nendawo yokugcina eyinhlanganisela ye-MACE. Kodwa-ke, ku-PFS nezinye iziphetho eziyinhlanganisela ezivivinyweni zomtholampilo ze-oncology, lo mbandela awusebenzi. Ukuhlaziywa kwezifundo ze-10 zakamuva ezishicilelwe emaphephandabeni amahlanu aphezulu e-oncology asebenzisa i-PFS njengesiphetho sathola ukuthi ezintathu kuphela (6%) ezibike ukufa kanye nezenzakalo zokuqhubeka kwesifo; Ucwaningo olulodwa kuphela olwahlukanisa phakathi kokuqhubeka kwendawo kanye ne-metastasis ekude. Ngaphezu kwalokho, ucwaningo olulodwa lwahlukanisa phakathi kokuqhubekela phambili kwendawo nokude, kodwa aluzange lunikeze inani lokufa ngaphambi kokuba isifo siqhubeke.

Izizathu zomehluko kumazinga wokubika wezindawo ezihlanganisiwe ku-cardiology kanye ne-oncology azicaci. Okunye okungenzeka ukuthi izindawo zokugcina eziyinhlanganisela ezifana ne-PFS ne-DFS ziyizinkomba zokusebenza kahle. I-MACE ivela emiphumeleni yokuphepha futhi yaqala ukusetshenziswa ekutadisheni izinkinga zokungenelela kwe-coronary percutaneous. Ama-ejensi alawulayo anezindinganiso eziphakeme zokubika imiphumela yokuphepha, ngakho kunesidingo semibhalo enemininingwane yezenzakalo ezimbi ekuhlolweni komtholampilo. Ngenkathi i-MACE isetshenziswa kabanzi njengesiphetho sokusebenza ngempumelelo, kungase kube umkhuba ojwayelekile ukunikeza amanani omcimbi ngamunye. Esinye isizathu samazinga ahlukene wokubika ukuthi i-PFS ibhekwa njengeqoqo lezenzakalo ezifanayo, kuyilapho i-MACE ibhekwa njengeqoqo lezenzakalo ezihlukile (isb., i-stroke vs. infarction ye-myocardial). Kodwa-ke, ukukhula kwesimila esiyinhloko kanye nama-metastase akude kuyahluka kakhulu, ikakhulukazi ngokomthelela womtholampilo. Zonke lezi zincazelo ziyaqagela, kodwa ngokusobala akukho neyodwa yazo ethethelela umbiko ongaphelele. Ezivivinyweni ze-oncology ezisebenzisa iziphetho eziyinhlanganisela, ikakhulukazi lapho isiphetho esiyinhlanganisela siyisiphetho esiyinhloko noma sisetshenziselwa izinjongo zokulawula, futhi lapho indawo yokugcina eyinhlanganisela ikhona njengendawo yokugcina yesibili, ukubikwa kwengxenye esobala kufanele kube yinjwayelo.