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A cikin binciken ilimin oncology, matakan sakamako na fili, irin su tsira ba tare da ci gaba ba (PFS) da tsira ba tare da cuta ba (DFS), suna ƙara maye gurbin abubuwan ƙarshe na al'ada na rayuwa gabaɗaya (OS) kuma sun zama babban tushen gwaji don amincewar magunguna ta Hukumar Abinci da Magunguna ta Amurka (FDA) da Hukumar Kula da Magunguna ta Turai (EMA). Wadannan matakan inganta ingantaccen gwaji na asibiti kuma suna rage farashin ta hanyar haɗa abubuwa da yawa (misali, haɓakar ƙari, sabon cuta, mutuwa, da dai sauransu) zuwa ƙarshen ƙarshen lokaci-lokaci, amma kuma suna haifar da matsaloli.

Canje-canje a cikin ƙarshen gwajin gwaji na asibiti na antitumor

A cikin 1970s, FDA ta yi amfani da ƙimar amsawar haƙiƙa (ORR) lokacin amincewa da magungunan kansa. Sai a cikin 1980s cewa Kwamitin Shawarar Magungunan Magunguna na Oncology (ODAC) da FDA sun gane cewa haɓakawa a cikin rayuwa, ingancin rayuwa, aikin jiki, da alamun da ke da alaƙa da ƙari ba su dace da alaƙar ORR ba. A cikin gwaje-gwajen asibiti na oncology, OS shine mafi kyawun ƙarshen asibiti don auna fa'idar asibiti kai tsaye. Koyaya, ORR ya kasance madadin ƙarshen ƙarshen asibiti na gama gari yayin la'akari da haɓakar amincewar magungunan kansa. A cikin gwaje-gwajen hannu ɗaya a cikin marasa lafiya tare da ciwace-ciwacen ƙwayar cuta, ana kuma la'akari da ORR musamman azaman ƙarshen ƙarshen asibiti na farko.

Tsakanin 1990 da 1999, kashi 30 cikin 100 na gwajin maganin cutar kansa da FDA ta amince da ita sun yi amfani da OS a matsayin farkon ƙarshen asibiti. Kamar yadda hanyoyin kwantar da hankali da aka yi niyya suka samo asali, maƙasudin ƙarshen asibiti na farko da aka yi amfani da su don kimanta magungunan ciwon daji suma sun canza. Tsakanin 2006 da 2011, adadin ya ragu zuwa kashi 14.5 cikin ɗari. Kamar yadda adadin gwaje-gwaje na asibiti tare da OS kamar yadda farkon ƙarshen ƙarshen ya ragu, amfani da maƙallan ƙarewa kamar PFS da DFS ya zama akai-akai. Kudade da ƙayyadaddun lokaci suna haifar da wannan motsi, saboda OS yana buƙatar ƙarin gwaji da ƙarin marasa lafiya fiye da PFS da DFS. Tsakanin 2010 da 2020, 42% na gwajin da bazuwar sarrafawa (RCTS) a cikin ilimin oncology suna da PFS a matsayin farkon ƙarshen su. 67% na magungunan anti-tumor da FDA ta amince da su tsakanin 2008 da 2012 sun dogara ne akan madadin ƙarshen ƙarshen, 31% wanda ya dogara ne akan PFS ko DFS. FDA yanzu ta gane fa'idodin asibiti na DFS da PFS kuma suna ba su damar amfani da su azaman ƙarshen ƙarshen gwaji a cikin gwajin neman izinin tsari. FDA ta kuma sanar da cewa za a iya amfani da PFS da sauran madadin ƙarshen ƙarshen don hanzarta amincewar magunguna don cututtuka masu haɗari ko masu haɗari.

Ƙarshen ƙarshen za su samo asali ba kawai yayin da aka haɓaka sababbin hanyoyin kwantar da hankali ba, amma har ma kamar yadda hanyoyin gwajin hoto da dakin gwaje-gwaje ke inganta. Ana tabbatar da wannan ta hanyar maye gurbin ka'idojin Hukumar Lafiya ta Duniya (WHO) tare da ma'aunin RECIST don kimanta ingancin inganci a cikin Tumors (RECIST). Yayin da likitocin likitoci ke ƙarin koyo game da ciwace-ciwacen daji, marasa lafiya da zarar sun yi la'akari da kwanciyar hankali na iya samun micrometastases a nan gaba. A nan gaba, wasu wuraren ƙarshe na iya daina amfani da su, kuma sabbin wuraren ƙarewa na iya fitowa don haɓaka amincewar ƙwayoyi cikin aminci. Yunƙurin immunotherapy, alal misali, ya haifar da haɓaka sabbin ƙa'idodin kimantawa kamar irRECIST da iRECIST.

Haɗin kai ƙarshen batu

Ana amfani da maƙasudin ƙarewa da yawa a cikin karatun asibiti, musamman a cikin ilimin oncology da ilimin zuciya. Ƙarshen ƙarewar haɗin gwiwa yana inganta ƙarfin ƙididdiga ta hanyar ƙara yawan abubuwan da suka faru, rage girman samfurin da ake buƙata, lokacin biyo baya, da kudade.
Mafi yawan abin da aka fi amfani dashi a cikin ilimin zuciya shine manyan abubuwan da ke faruwa na zuciya da jijiyoyin jini (MACE). A cikin ilimin oncology, PFS da DFS galibi ana amfani da su azaman wakili don rayuwa gabaɗaya (OS). PFS an ayyana shi azaman lokaci daga bazuwar zuwa ci gaban cuta ko mutuwa. Ana bayyana ci gaban ƙwayar ƙwayar cuta mai ƙarfi bisa ga ka'idodin RECIST 1.1, gami da kasancewar sabbin raunuka da haɓakar raunin da aka yi niyya. Rayuwa ba tare da aukuwa ba (EFS), DFS, da kuma sake dawowa-kyauta rayuwa (RFS) suma maƙasudin ƙarewa ne gama gari. Ana amfani da EFS a cikin gwaje-gwajen neoadjuvant far, kuma DFS ana amfani da shi a cikin nazarin asibiti na maganin adjuvant.

Daban-daban tasiri a daban-daban hanyoyin kwantar da hankali a kan fili endpoints

Ba da rahoto kawai sakamakon fili kuma zai iya haifar da ɗauka cewa tasirin jiyya ya shafi kowane lamari na ɓangaren, wanda ba lallai ba ne gaskiya. Mahimmin zato a cikin yin amfani da madaidaitan abubuwan ƙarshe shine cewa magani zai canza abubuwan da aka gyara ta hanya iri ɗaya. Duk da haka, tasirin maganin antitumor akan sauye-sauye kamar haɓakar ƙwayar cuta ta farko, metastasis, da mace-mace wani lokaci suna tafiya ta gaba. Misali, magani mai guba mai yawa na iya rage yaduwar ƙari amma yana ƙaruwa da mace-mace. Wannan shine lamarin a cikin gwajin BELLINI na marasa lafiya tare da sake dawowa / refractory mahara myeloma, inda PFS ya inganta amma OS ya kasance ƙasa saboda yawan kamuwa da cutar da ke da alaka da jiyya.

Bugu da ƙari, akwai bayanan da suka dace da ke nuna cewa yin amfani da chemotherapy don rage ƙwayar ƙwayar cuta ta farko yana hanzarta yadawa mai nisa a wasu lokuta saboda chemotherapy yana zaɓar ƙananan ƙwayoyin da zasu iya haifar da metastasis. Hasashen shugabanci ba zai yuwu a riƙe ba lokacin da akwai adadi mai yawa na abubuwan da suka faru a cikin ƙarshen ƙarshen, kamar yadda yake tare da wasu ma'anoni na PFS, EFS, da DFS. Alal misali, allogeneic hematopoietic stem cell gwaji gwaje-gwaje sau da yawa amfani da wani hadadden karshen wanda ya hada da mutuwa, ciwon daji sake dawowa, da graft-versus-host disease (GVHD), wanda aka sani da GVHD free RFS (GRFS). Magungunan da ke rage abubuwan da ke faruwa na GVHD na iya ƙara yawan sake dawowa da ciwon daji, kuma akasin haka. A wannan yanayin, GVHD da ƙimar komawa baya dole ne a bincika su daban don auna daidai rabon fa'idar haɗarin jiyya.

Rahoton yau da kullun na ƙimar abubuwan da suka faru daban-daban don sakamako masu rikitarwa yana tabbatar da cewa tasirin jiyya akan kowane sashi yana cikin hanya ɗaya; Duk wani “ingantattun iri-iri” (watau, bambance-bambance a cikin shugabanci) yana haifar da rashin tasiri na amfani da madaidaitan ƙarshen.

EMA ta ba da shawarar "bincike na mutum ɗaya na nau'ikan abubuwan da suka faru na mutum ta amfani da tebur taƙaitaccen bayani kuma, inda ya dace, nazarin haɗarin haɗari don gano tasirin jiyya akan kowane taron". Koyaya, saboda ƙarancin ikon ƙididdiga na karatu da yawa, ba a iya gano manyan bambance-bambance a cikin abubuwan da suka faru a cikin abubuwan da aka haɗa.

Rashin nuna gaskiya a cikin bayar da rahoton abubuwan da suka faru na ƙarshe

A cikin gwaje-gwajen cututtukan zuciya, al'ada ce ta gama gari don samar da abin da ya faru na kowane abin da ya faru (kamar bugun jini, ciwon zuciya na zuciya, asibiti, da mutuwa) tare da ƙarshen ƙarshen MACE. Koyaya, don PFS da sauran abubuwan ƙarshe masu haɗaka a cikin gwajin asibiti na oncology, wannan ma'aunin baya aiki. Nazarin binciken 10 na baya-bayan nan da aka buga a cikin manyan mujallu na oncology guda biyar waɗanda suka yi amfani da PFS a matsayin ƙarshen ƙarshen sun gano cewa kawai uku (6%) sun ba da rahoton mutuwar da abubuwan da suka faru na ci gaban cututtuka; Nazarin guda ɗaya ne kawai aka bambanta tsakanin ci gaban gida da metastasis mai nisa. Bugu da kari, binciken daya ya bambanta tsakanin ci gaba na gida da na nesa, amma bai bayar da adadin wadanda suka mutu kafin cutar ta ci gaba ba.

Dalilan bambance-bambancen ma'auni na bayar da rahoto don abubuwan da aka haɗa a cikin ilimin zuciya da ciwon daji ba su da tabbas. Wata yuwuwar ita ce abubuwan da aka haɗa kamar PFS da DFS alamun inganci ne. MACE ta samo asali ne daga sakamakon aminci kuma an fara amfani da ita a cikin nazarin rikice-rikice na tsaka-tsakin zuciya na percutaneous. Hukumomin gudanarwa suna da ma'auni masu girma don bayar da rahoton sakamakon aminci, don haka akwai buƙatar cikakkun takaddun abubuwan da suka faru a cikin gwaji na asibiti. Lokacin da aka yi amfani da MACE ko'ina azaman ƙarshen inganci, ƙila ya zama al'ada don samar da adadin kowane taron. Wani dalili na ma'auni na rahotanni daban-daban shine cewa ana ɗaukar PFS a matsayin tarin abubuwan da suka faru, yayin da MACE ana ɗaukarsa a matsayin tarin abubuwan da suka faru (misali, bugun jini vs. ciwon zuciya). Koyaya, haɓakar ƙwayar cuta ta farko da metastases mai nisa sun bambanta sosai, musamman dangane da tasirin asibiti. Duk waɗannan bayanai na hasashe ne, amma a fili babu ɗayansu da ke tabbatar da rahoton da bai cika ba. Don gwaje-gwajen oncology waɗanda ke amfani da maƙasudin ƙarewa, musamman lokacin da madaidaicin ƙarshen ƙarshen shine farkon ƙarshen ƙarshen ko kuma ana amfani da shi don dalilai na tsari, kuma lokacin da ƙarshen ƙarshen ya kasance a matsayin ƙarshen ƙarshe na biyu, rahoton abubuwan da suka faru na zahiri dole ne ya zama al'ada.