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Mukutsvagisa oncology, matanho emhedzisiro, akadai sekufambira mberi-kusina kupona (PFS) uye kupona-kusina chirwere (DFS), kuri kuwedzera kutsiva magumo echinyakare ekurarama kwese (OS) uye ave musimboti wekuyedza kubvumidzwa kwezvinodhaka neUS Food and Drug Administration (FDA) neEuropean Medicines Agency (EMA). Aya matanho anovandudza kuedza kwekiriniki uye kuderedza mari nekubatanidza zviitiko zvakawanda (semuenzaniso, kukura kwebundu, chirwere chitsva, rufu, nezvimwewo) mune imwe nguva-ku-chiitiko chekupedzisira, asi zvinogadzirawo matambudziko.

Shanduko mumagumo eAntitumor Clinical Trials

Mumakore ekuma1970, iyo FDA yakashandisa mwero wekupindura chinangwa (ORR) pakubvumidza mishonga yegomarara. Yakanga isati yasvika kuma1980 apo iyo Oncology Drugs Advisory Committee (ODAC) neFDA vakaziva kuti kuvandudzwa mukupona, kunaka kwehupenyu, kushanda kwemuviri, uye zviratidzo zvine chekuita nebundu zvaisaenderana neORR correlations. Mune oncology kiriniki miedzo, OS iri nani kiriniki yekupedzisira yekuyera yakananga kiriniki kubatsirwa. Zvakadaro, ORR inoramba iri yakajairika imwe nzira yekiriniki yekupedzisira kana uchifunga nezve kukurumidza kubvumidzwa kwemishonga yegomarara. Mumiyedzo yeruoko rumwe chete muvarwere vane refractory tumors, ORR inonyanya kutariswa seyekutanga kliniki yekupedzisira.

Pakati pa1990 na1999, 30 muzana yeFDA-yakatenderwa kenza yemushonga miedzo yakashandisa OS seyekutanga kiriniki yekupedzisira. Sezvo marapirwo anonangwa akashanduka, iwo ekutanga ekiriniki endpoints anoshandiswa kuongorora anti-cancer mishonga akachinja zvakare. Pakati pa2006 na2011, nhamba iyi yakaderera kusvika pa14,5%. Sezvo huwandu hwemakiriniki ekuyedzwa neOS seyekupedzisira kupera kwadzikira, kushandiswa kweanosanganiswa ekupedzisira sePFS neDFS kwave kuwanda. Mari uye zvimhingamipinyi zvenguva zviri kutyaira shanduko iyi, sezvo OS inoda miedzo yakareba uye varwere vakawanda kupfuura PFS neDFS. Pakati pa2010 na2020, 42% yezviyedzo zvakadzorwa zvisina kujairika (RCTS) mune oncology ine PFS seyavo yekutanga magumo. 67% yemishonga inorwisa bundu yakagamuchirwa neFDA pakati pe2008 ne2012 yakavakirwa pane mamwe mamagumo, 31% ayo akavakirwa paPFS kana DFS. Iyo FDA ikozvino inoziva mabhenefiti ekiriniki eDFS nePFS uye inoatendera kuti ashandiswe semapeji ekutanga mumiedzo yekutsvaga mvumo yekutonga. Iyo FDA yakazivisawo kuti PFS nedzimwe nzira dzekupedzisira dzinogona kushandiswa kukurumidza kubvumidzwa kwemishonga yezvirwere zvakakomba kana zvinouraya.

Endpoints inoshanduka kwete chete sekuvandudzwa kwekurapa kutsva, asiwo sekufungidzira uye nzira dzekuyedza marabhoritari dzichivandudza. Izvi zvinoratidzwa nekutsiviwa kweWorld Health Organisation (WHO) maitiro neRECIST yeAssessment of Efficacy in Solid Tumors (RECIST). Sezvo varapi vachidzidza zvakawanda nezvemamota, varwere vanomboonekwa vakagadzikana vanogona kuwanikwa vaine micrometastases mune ramangwana. Mune ramangwana, mamwe magumo anogona kunge asisashandiswe, uye mitsva mitsva inogona kubuda kuti ikurumidze kukurumidza kubvumidzwa kwezvinodhaka. Kusimuka kwe immunotherapy, semuenzaniso, kwakatungamira kukudziridzwa kwemitemo mitsva yekuongorora senge irRECIST uye iRECIST.

Composite end point overview

Composite endpoints inoshandiswa zvakanyanya muzvidzidzo zvekiriniki, kunyanya mune oncology uye cardiology. Composite endpoints inovandudza nhamba yehuwandu nekuwedzera nhamba yezviitiko, kuderedza inodiwa saizi yemuenzaniso, nguva yekutevera, uye mari.
Iyo inonyanya kushandiswa yakasanganiswa endpoint mu cardiology yakakura yakashata yemoyo zviitiko (MACE). Mune oncology, PFS neDFS zvinowanzo shandiswa semaproxies ekupona kwese (OS). PFS inotsanangurwa senguva kubva ku randomisation kusvika kukukura kwechirwere kana kufa. Kukura kwebundu rakasimba kunowanzotsanangurwa maererano neRECIST 1.1 mirayiridzo, kusanganisira kuvapo kwezvironda zvitsva uye kuwedzera kwezvironda zvinotarirwa. Chiitiko-isina kupona (EFS), DFS, uye relapse-free survival (RFS) ndiwo zvakare akajairwa anoumbwa endpoints. EFS inoshandiswa mukuedzwa kweneoadjuvant therapy, uye DFS inoshandiswa muzvidzidzo zvekliniki zveadjuvant therapy.

Kusiyana kwakasiyana mukurapa kwakasiyana pamakomponi endpoints

Kuzivisa mhinduro dzakasanganiswa chete kunogona kukonzera kufunga kuti kurapwa kunoshanda kune chimwe nechimwe chechikamu chiitiko, izvo zvisiri zvechokwadi. Chinhu chikuru chekufungidzira mukushandiswa kwezvikamu zvekupedzisira ndezvekuti kurapwa kuchashandura zvikamu nenzira yakafanana. Nekudaro, izvo zvinokonzeresa antitumor kurapa pane zvinosiyana zvakaita seyekutanga bundu kukura, metastasis, uye kufa dzimwe nguva zvinoenda zvakapesana. Semuenzaniso, mushonga une muchetura unogona kuderedza kupararira kwebundu asi kuwedzera kufa. Izvi ndizvo zvakaitika mukuedzwa kweBELLINI kwevarwere vane myeloma yakadzokororwa / refractory, apo PFS yakagadziridzwa asi OS yakanga yakaderera nekuda kwehuwandu hwehutachiwana hune chokuita nekurapa.

Pamusoro pezvo, kune preclinical data inoratidza kuti kushandisa chemotherapy kudzikisa bundu rekutanga rinomhanyisa kupararira kure mune dzimwe nguva nekuti chemotherapy inosarudza stem masero anogona kukonzera metastasis. The directionality hypothesis haigoni kubata kana pane nhamba huru yezviitiko mumagumo ekupedzisira, sezvinoitwa nedzimwe tsanangudzo dzePFS, EFS, uye DFS. Semuyenzaniso, allogeneic hematopoietic stem cell transplantation therapy miedzo inowanzoshandisa magumo akaumbwa anosanganisira kufa, kenza kudzoka, uye graft-versus-host disease (GVHD), inozivikanwa seGVHD yemahara RFS (GRFS). Mishonga inoderedza GVHD inogona kuwedzera huwandu hwegomarara rekudzoka, zvichipesana. Muchiitiko ichi, GVHD uye kudzoka zvakare kunofanirwa kuongororwa zvakasiyana kuti kuyera nemazvo chiyero chengozi-yebhenefiti yekurapa.

Kurongeka kwehuwandu hwezviitiko zvakasiyana-siyana zvemigumisiro yakaoma inovimbisa kuti migumisiro yekurapa pane imwe neimwe chikamu iri munzira imwechete; Chero "mhando yehuterogeneity" (kureva, misiyano mugwara) inotungamira mukusashanda kwekushandisa kweanoumbwa magumo.

EMA inokurudzira "kuongororwa kwega kwega kwemhando dzezviitiko zvega ega uchishandisa matafura epfupiso anotsanangura uye, pazvinenge zvakakodzera, kuongororwa kwenjodzi yemakwikwi kuongorora maitiro ekurapa pachiitiko chimwe nechimwe". Zvisinei, nekuda kwekusakwana kwehuwandu hwehuwandu hwezvidzidzo zvakawanda, kusiyana kukuru kwezviitiko zvezvikamu mumigumisiro yezvikamu hazvigone kuonekwa.

Kushaikwa kwekubuda pachena mukushuma zviitiko zvakaumbwa zvemagumo

Mune cardiology miedzo, inowanzoita tsika yekupa chiitiko chechikamu chimwe nechimwe (zvakadai sesitiroko, myocardial infarction, kuchipatara, uye kufa) pamwe chete neMACE composite endpoint. Nekudaro, kune PFS uye mamwe akaumbwa ekupedzisira mune oncology kiriniki miedzo, iyi chiyero haishande. Kuongororwa kwezvidzidzo zvekupedzisira zve10 zvakabudiswa mumabhuku mashanu epamusoro e-oncology akashandisa PFS semagumo akawana kuti zvitatu chete (6%) zvakashuma kufa uye zviitiko zvekufambira mberi kwechirwere; Chidzidzo chimwe chete chakasiyanisa kufambira mberi kwenzvimbo uye kure kure metastasis. Mukuwedzera, imwe ongororo yakasiyanisa kufambira mberi kwenzvimbo uye kure, asi haina kupa huwandu hwevakafa chirwere chisati chaenderera mberi.

Zvikonzero zvekusiyana kwezviyero zvekubika zveanosanganiswa endpoints mucardiology uye oncology hazvina kujeka. Imwe mukana ndeyekuti magumo emubatanidzwa akadai sePFS neDFS zviratidzo zvekushanda. MACE yakabva kune zvakachengeteka uye yakatanga kushandiswa mukudzidza kwezvinetso zvepercutaneous coronary intervention. Masangano anodzora ane mwero wepamusoro wekutaura mhedzisiro yekuchengetedza, saka panoda kunyorwa kwakadzama kwezviitiko zvakashata mukuedzwa kwekiriniki. Apo MACE yaishandiswa zvakanyanya semagumo ekushanda, inogona kunge yakave tsika yakajairika kupa huwandu hwechiitiko chimwe nechimwe. Chimwe chikonzero chemitemo yakasiyana-siyana yekubika ndeyekuti PFS inofungidzirwa kuva muunganidzwa wezviitiko zvakafanana, nepo MACE inofungidzirwa kuva muunganidzwa wezviitiko zvakasiyana (semuenzaniso, sitiroko vs. myocardial infarction). Nekudaro, kukura kwebundu rekutanga uye metastases kure zvinosiyana zvakanyanya, kunyanya maererano nemhedzisiro yekiriniki. Tsananguro idzi dzese ndedzekufungidzira, asi zviri pachena kuti hapana imwe yadzo inopembedza mushumo usina kukwana. Kumiyedzo yeoncology inoshandisa magumo emubatanidzwa, kunyanya kana iyo composite endpoint iriyo yekutanga magumo kana ichishandiswa pazvinangwa zvekutonga, uye kana iyo composite endpoint iripo seyechipiri endpoint, pachena chikamu chiitiko kushuma kunofanirwa kuve kwakajairwa.