Primerjalna analiza dveh pristopov obsevanja v okviru totalnega neoadjuvantnega zdravljenja pri visokorizičnem lokalno napredovalem raku danke Comparative analysis of two radiotherapy approaches within total neoadjuvant therapy for high-risk locally advanced rectal cancer

Abstract

Izhodišča: Totalno neoadjuvantno zdravljenje (angl. total neoadjuvant therapy, TNT) je uveljavljen standard pri bolnikih z lokalno napredovalim rakom danke (LNRD; angl. locally advanced rectal cancer, LARC) z magnetnoresonančno (angl. magnetic resonance imaging, MRI) opredeljenimi dejavniki visokega tveganja. Kljub vse večji uporabi TNT pa optimalno zaporedje posameznih terapevtskih komponent ter dolgoročni izidi neoperativnega pristopa watch and wait (W&W) ostajajo nepopolno opredeljeni. Prav tako vpliv izbrane radioterapevtske tehnike na uspešnost zdravljenja, lokalno kontrolo bolezni in dolgoročne izide v vsakodnevni klinični praksi še ni jasno razmejen. Bolniki in metode: V primerjalno analizo sta bili vključeni dve zaporedni kohorti bolnikov z LNRD in vsaj enim MRI opredeljenim dejavnikom visokega tveganja, zdravljenih na Onkološkem inštitutu Ljubljana po institucionalnem »sendvič« TNT protokolu. Študijska populacija je obsegala bolnike zdravljenih s 3D konformno tehniko obsevanja (angl. three dimensional conformal radiotherapy, 3D CRT kohorta), in zdravljenih z intenzitetno moduliranim in volumetrično moduliranim ločnim obsevanjem s simultanim integriranim dodatkom doze (angl. intensity modulated radiotherapy / volumetric modulated arc therapy with simultaneous integrated boost, IMRT/VMAT SIB kohorta). Primarni opazovani izid je bil skupni popolni odgovor, opredeljen kot patohistološko popolni odgovor (angl. pathological complete response, pCR) in klinični popolni odgovor (angl. clinical complete response, cCR) ob vključitvi v skrbno spremljanje po strategiji W&W. Sekundarni izidi so bili pCR, večji patološki odgovor (MPR; angl. major pathological response, MPR), delež R0 resekcij, znižanje stadija, lokalna ponovitev, preživetje brez bolezni (PBB; angl. disease free survival, DFS) in celokupno preživetje (CP; angl. overall survival, OS). Za primarni in ključne sekundarne izide smo izvedli neprilagojene formalne primerjave deležev ter eksploratorne prilagojene analize s Firthovo logistično regresijo, za CP do 36 mesecev smo izvedli še uteženi Coxov model. Rezultati: Skupno je bilo vključenih 240 bolnikov, 35 v 3D CRT kohorti in 205 v IMRT/VMAT SIB kohorti. Skupni popolni odgovor je bil v 3D CRT kohorti dosežen pri 14,3% bolnikov, v IMRT/VMAT SIB kohorti pa pri 29,5% bolnikov, pCR pri 9,4% bolnikov v 3D CRT kohorti in pri 19,3% v IMRT/VMAT SIB kohorti, MPR pa pri 30,8% v 3D CRT kohorti oziroma 37,6% bolnikov v IMRT/VMAT SIB kohorti. R0 resekcijo smo beležili pri vseh operiranih bolnikih v 3D CRT kohorti ter pri 94,5% operiranih bolnikov v IMRT/VMAT SIB kohorti. V Firthovem modelu je bil za IMRT/VMAT-SIB nakazan trend k višjemu skupnemu popolnemu odgovoru (OR 2,39; 95 % CI 0,95 – 7,08; p = 0,064), medtem ko pri pCR statistično značilnega učinka nismo potrdili (OR 2,20; 95 % CI 0,73–8,75; p = 0,171). Zaključki: Obe radioterapevtski tehniki omogočata izvedljivo in onkološko učinkovito izvajanje institucionalnega »sendvič« TNT protokola pri bolnikih z MRI opredeljenimi dejavniki visokega tveganja. V naši enoinstitucionalni izkušnji so bili v IMRT/VMAT-SIB kohorti doseženi numerično ugodnejši lokalni odzivni izidi kot v 3D-CRT kohorti, vendar formalne primerjave teh razlik statistično niso potrdile. Zaradi retrospektivne zasnove, deloma prekrivajočih se zgodovinskih kohort in omejenega števila dogodkov dokončnih sklepov o superiornosti ene tehnike ni mogoče podati.

Abstract (Eng)

Background: Total neoadjuvant therapy (TNT) has become a standard of care for patients with locally advanced rectal cancer (LARC) who present with high risk features on magnetic resonance imaging (MRI). Despite its increasing adoption, the optimal sequencing of individual treatment components and the long term outcomes of a non operative watch and wait (W&W) strategy after TNT remain insufficiently defined. Moreover, the impact of radiotherapy technique on treatment effectiveness, local disease control, and long term outcomes in routine clinical practice has not been clearly established. Patients and Methods: This comparative analysis included two consecutive cohorts of patients with LARC and at least one MRI defined high risk feature, treated at the Institute of Oncology Ljubljana with an institutional “sandwich” TNT protocol. The study population comprised 240 patients: 35 treated with three dimensional conformal radiotherapy (3D CRT cohort) and 205 treated with intensity modulated radiotherapy/volumetric modulated arc therapy with a simultaneous integrated boost (IMRT/VMAT SIB cohort). The primary endpoint was overall complete response, defined as pathological complete response (pCR) or clinical complete response (cCR) with inclusion in a structured W&W follow up strategy. Secondary endpoints were pCR, major pathological response (MPR), R0 resection rate, downstaging, local recurrence, disease free survival (DFS) and overall survival (OS). For the primary and key secondary outcomes, we performed unadjusted formal comparisons of proportions as well as exploratory adjusted analyses using Firth logistic regression; for OS up to 36 months, we additionally performed a weighted Cox model. Results: The study population consisted of 240 patients, 35 in the 3D CRT cohort and 205 in the IMRT/VMAT SIB cohort. Overall complete response was achieved in 14,3% of patients in the 3D CRT cohort and in 29,5% of patients in the IMRT/VMAT SIB cohort. The pCR rates were 9,4% in the 3D CRT cohort and 19,3% in the IMRT/VMAT SIB cohort, while MPR rates were 30,8% and 37,6%, respectively. R0 resection was achieved in all operated patients in the 3D CRT cohort and in 94,5% of operated patients in the IMRT/VMAT SIB cohort. In the Firth model, IMRT/ VMAT-SIB showed a trend toward a higher overall complete response (OR 2,39; 95% CI 0,95–7,08; p = 0.064), whereas no statistically significant effect was confirmed for pCR (OR 2,20; 95% CI 0,73–8,75; p = 0.171). Conclusions: Both radiotherapy techniques allow feasible and oncologically effective delivery of the institutional “sandwich” TNT protocol in patients with MRI defined high risk LARC. In our single-institution experience, numerically more favourable local response outcomes were observed in the IMRT/VMAT-SIB cohort than in the 3D-CRT cohort, but formal comparisons did not confirm these differences statistically. Given the retrospective design, partially overlapping historical cohorts, and limited number of events, no definitive conclusions regarding the superiority of either technique can be drawn.