Kompletno predoperativno zdravljenje lokalno napredovalega raka danke pri bolnikih z visokim tveganjem za ponovitev bolezni

Tuta, Mojca (author), Velenik, Vaneja (mentor)

Izhodišče: S standardnim zdravljenjem (predoperativna radiokemoterapija – RTKT, operacija in adjuvantna kemoterapija – KT) lokalno napredovalega raka danke (LNRD) dosegamo odlično lokalno kontrolo bolezni, vendar pa je preživetje nizko zaradi pojava oddaljenih zasevkov, ki ostajajo vodilni vzrok smrti teh bolnikov. V zadnjih letih je bil razvit koncept kompletnega predoperativnega zdravljenja (TNT, angl. total neoadjuvant therapy), kjer je sistemska KT, ki naj bi vplivala predvsem na mikrozasevke, umeščena skupaj z RTKT že pred operacijo. Metode: V retrospektivni raziskavi smo primerjali vse bolnike z LNRD z visokim tveganjem za ponovitev bolezni zdravljene standardno ali s TNT v letih 2016–2019 v Sloveniji. Dejavniki visokega tveganja za ponovitev bolezni so bili definirani kot prisotnost vsaj enega od naštetih: T4, N2, ogrožena mezorektalna fascija, prisotnost ekstramuralne žilne invazije, prisotnost lateralne bezgavke. Shemo TNT sestavlja 12-tedenska indukcijska KT po shemi CAPOX ali FOLFOX, RTKT s fluoropirimidini in šest do osemtedenska konsolidacijska KT po shemi CAPOX ali FOLFOX pred operacijo. Primarni cilj opazovanja je bil patohistološki popolni odgovor (pCR). Rezultati: V raziskavo je bilo vključenih 72 standardno zdravljenih bolnikov in 89 bolnikov, zdravljenih s TNT. Skupini se po spolu, stadiju bolezni, stanju zmogljivosti in razporeditvi tumorjev danke glede na lego nista razlikovali. Statistično značilno sta se razlikovali v starostni porazdelitvi in deležu posameznih dejavnikov visokega tveganja za ponovitev bolezni, vendar le-te lastnosti niso statistično značilno vplivale na delež pCR. Pri bolnikih, zdravljenih s TNT, smo v primerjavi s standardnim zdravljenjem beležili višji delež pCR (23 % proti 7 %; p < 0,05), nižji prognostični izračun NAR (mediana 8,43 proti 14,98; p < 0,05), višje znižanje T in N stadija (pri 70 % in 94 % proti 51 % in 86 %), primerljiv delež R0 resekcij (95 % in 93 %), krajši čas do zapore stome (povprečno 20 proti 33 tednov; p < 0,05), boljšo komplianco med sistemsko KT za vse predvidene kroge (87 % proti 76 %; p < 0,05) in nižji delež zgodnje toksičnosti stopnje ? 3 med sistemsko KT (3 % proti 14 %; p < 0,05) ob primerljivi zgodnji toksičnosti in komplianci med RTKT in v pooperativnem obdobju. Pri skupini, zdravljeni s TNT, smo ugotovili statistično značilno povezavo med doseganjem pCR in načinom obsevanja. Pri obsevanju z intenzitetno modulirano radioterapijo in z volumetrično modulirano ločno terapijo (IMRT/VMAT) je bil delež pCR v primerjavi s 3D obsevanjem višji (32 % proti 9 %; p < 0,05). Zaključki: Izid zdravljenja LNRD z visokim tveganjem za ponovitev bolezni s TNT je glede na delež pCR in prognostični izračun NAR učinkovitejši kot standardno zdravljenje. Za končno presojo je potrebna še ocena dolgoročne učinkovitosti. Višji delež pCR pri IMRT/VMAT pripisujemo krajšemu času obsevanja, natančnosti naprednejše tehnike obsevanja in hipofrakcioniranju, ki je bilo omogočeno ob naprednejši tehniki obsevanja.

• Language: Slovenian
• Keywords: rak danke, kompletno predoperativno zdravljenje, patohistološki popolni odgovor
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2020
• PID: 20.500.12556/RUL-124248
• COBISS.SI-ID: 60738819
• Publication date in RUL: 13.01.2021

Secondary language

• Language: English
• Title: Total neoadjuvant treatment of locally advanced rectal cancer in patients with high risk factors for failure

Abstract

Background: Standard therapy (neoadjuvant chemoradiotherapy - CRT, surgery, adjuvant chemotherapy- ChT) of locally advanced rectal cancer (LARC) achieves excellent local control, but survival is still poor due to distant metastases, which remain the leading cause of death for these patients. In recent years the concept of total neoadjuvant therapy (TNT) has been developed, where systemic ChT that mainly affects micrometastasis is placed with CRT prior to surgery. Patients and methods: In a retrospective study, we compared patients with LARC with high risk factors for failure who were treated with standard therapy or TNT. High risk factors for failure were defined as presence of one of the factors: T4, N2, positive mesorectal fascia, presence of extramural vascular invasion, presence of lateral lymph node. TNT consists of 12 weeks of induction ChT with CAPOX or FOLFOX, CRT with capecitabine and six to eight weeks of consolidation ChT with CAPOX or FOLFOX prior to surgery. Primary endpoint was pathological complete response (pCR). Results: 72 patients treated with standard therapy and 89 patients with TNT were included in analysis. Groups matched by gender, clinical disease stage, performance status and tumor location from anal verge. Groups differed significantly in age and in proportion of high risk factors for failure, but these characteristics alone did not have significant effect on pCR. Compared to standard therapy showed TNT higher proportion of pCR (23% vs. 7%; p 0.01), lower NAR prognostic score (median 8.43 vs. 14.98; p < 0.05), higher T- and N-downstaging (70% and 94% vs. 51% and 86%), equivalent R0 resection rate (95% vs. 93%), shorter time to stoma closure (average 20 vs. 33 weeks; p < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs. 76%; p < 0.05), lower proportion of acute toxicity grade ⡥ 3 during ChT (3% vs. 14%, p < 0.05), equivalent acute toxicitiy and compliance during CRT and in postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with IMRT/VMAT than with 3D conformal radiotherapy (32% vs. 9%; p < 0.05). Conclusion: Compared to standard therapy the outcome of patients with LARC with high risk factors for failure is better in TNT in terms of pCR and prognostic NAR score. It is necessary to continue evaluation of the long-term effects of TNT. Higher rate of pCR with IMRT/VMAT is attributed to shorter irradiation times, accuracy of more advanced irradiation technique and hypofractionation that was made possible by the more advanced irradiation technique.

• Keywords: rectal cancer, total neoadjuvant therapy, pathological complete response.